Referring to a health-related state or exposure that indicates brief (short-term) duration and strong intensity.
Adult Respiratory Distress Syndrome (ARDS)
See Acute Respiratory Distress Syndrome (ARDS)
See Acquired Immune Deficiency Syndrome
Thin-walled sac-like terminal dilations of the respiratory bronchioles where gas exchange occurs between alveolar air and pulmonary capillaries.
An insensitivity to pain.
A condition characterized by too few circulating red blood cells resulting in insufficient oxygen to tissues and organs.
Anemia, Iron Deficiency
Iron deficiency anemia is one of the most common nutritional disorders and is due to excessive loss, deficient intake or poor absorption of iron. It is also known as nutritional hypochromic anemia. Iron is required for hemoglobin synthesis, which is responsible for the transport of oxygen in red blood cells. Red cells appear abnormal and are small (microcytic) and pale (hypochromic) in iron deficiency anemia.
Angiotensin Converting Enzyme (ACE)
An enzyme (EC 184.108.40.206) that cleaves the biologically inactive decapeptide angiotensin I to the active angiotensin II. High levels of ACE (normal values = 18-67 U/ml for individuals over age 20) are seen in sarcoidosis, histoplasmosis, alcoholic cirrhosis, asbestosis, berylliosis, diabetes, Hodgkin's disease, hyperthyroidism, amyloidosis, primary biliary cirrhosis, idiopathic pulmonary fibrosis, pulmonary embolism, scleroderma, silicosis, tuberculosis, Gaucher's disease and leprosy. See also Renin-Angiotensin System
Angiotensin Converting Enzyme 2 (ACE2)
A variant of the gene encoding ACE that is unlike the ubiquitously expressed ACE gene in that ACE2 is only expressed in cardiac, renal and testicular cells. The ACE2 protein has been shown to cleave angiotensin I and other vasoactive peptides. Modulators of ACE2 may be effective in the treatment of hypertension and congestive heart failure.
A biologically inactive decapeptide hormone that is formed in the circulation from the cleavage of angiotensinogen by renin. Angiotensin I is cleaved by angiotensin converting enzyme (ACE) resulting in the biologically active angiotensin II. See also Renin-Angiotensin System
The active form of angiotensin that is an octapeptide synthesized from angiotensin I and rapidly destroyed. It induces marked vasoconstriction resulting in an increase in blood pressure. It has other effects including stimulation of aldosterone release and renal absorption of sodium. See also Renin-Angiotensin System
Angiotensin II Receptors (AT1, AT2)
Receptor subtypes identified as AT1 and AT2. The G-protein-coupled AT1 receptor is responsible for the major physiological effects of angiotensin II. Agents targeting the AT1 receptor may be effective in the treatment of hypertension, heart failure and diabetic retinopathy. AT2 receptors have been localized in the rat brain, female reproductive organs and in neuronal tumor cells.
A polypeptide hormone (60 kD) that is an alpha-2 globulin and the substrate for renin. It is released from the liver and cleaved in the circulation by renin to form the biologically inactive decapeptide angiotensin I. Angiotensin I is then cleaved to the active angiotensin II by angiotensin converting enzyme (ACE). Angiotensin is broken down by angiotensinase. See also Renin-Angiotensin System
A condition charaterized by an abnormal loss of appetite or an aversion to food. It can be caused by cancer, chemotherapeutics, AIDS, psychiatric disorder (i.e., anorexia nervosa) as well as other diseases.
A protein synthesized by B lymphocytes in response to an antigen that has the ability to specifically bind with said antigen. Antibodies are the soluble form of the B cell's specific antigen receptors and are collectively referred to as immunoglobulins (Igs). Igs are produced in many different forms, each with different amino acid sequences and antigen binding sites. Through recruiting the complement system and various white blood cells, they protect the body by inactivating viruses and bacterial toxins and by killing invading microorganisms and larger parasites.
Any molecule specifically recognized by B and/or T cells that can induce the formation of a specific antibody. For vaccines, the term antigen refers to a vaccine component that induces protection against a single disease.
Antigen Presenting Cells (APCs)
A heterogeneous population of leukocytes (i.e., Langerhans' cells, dendritic cells, B cells, etc.) with immunostimulatory properties, found predominately in skin, lymph nodes, spleen and thymus. APCs are capable of processing and presenting antigens to T cells in a class I or II restricted manner. APC function is dependent not only on surface expression of MHC I or II/antigen complexes, but also on costimulatory molecules (i.e., CD40 for B cells or CD28 for T cells) present on the surface of B cells, DCs, macrophages, endothelium and hemopoietic progenitors, which can provide a second activation signal in addition to the first signal of the antigen.
Having the properties of an antigen. Synonyms include immunogenic and allergenic.
Minor changes in viral proteins (antigens) due to gene mutations within an influenza hemagglutinin or neuraminidase subtype.
The sudden emergence of a new strain of influenza due to an abrupt change in the influenza hemagglutinin or neuraminidase protein type on the viral surface.
Refers to the complementary strand of a coding sequence of DNA (antisense DNA) or mRNA (antisense RNA). These nucleotide sequences are not templates for synthesis but interact with complementary sequences in other molecules thereby affecting their function. Antisense therapy uses a DNA or RNA sequence that has the reverse orientation (i.e., opposite "sense"; antisense oligonucleotide) of the DNA or RNA sequence present in a specific disease-causing target gene and when administered, it will bind to the target gene and inhibit its expression. See also Antisense Oligonucleotide
Complementary strands of small segments of mRNA that bind to specific mRNA sequences encoding for disease-causing proteins. Pairing of mRNA with antisense fragments blocks initiation of protein synthesis by reducing the availability of mRNA to ribosomes. Antisense oligonucleotides have been used to inhibit viral infections and to treat cancer and other diseases.
An active form of cell death in which intrinsic cellular genetic programs are activated, leading to cellular suicide. Also known as programmed cell death.
See Adult Respiratory Distress Syndrome (ARDS)
An enzyme which causes the release of the terminal (gamma) phosphate from ATP yielding ADP and inorganic phosphate. Usually the enzymic activity is not just simple hydrolysis but rather a coupled system which is responsible for an energy-requiring process such as ion pumping (e.g., H+/K+-ATPase) or the generation of motility. See also H+/K+-ATPase
A genetic trait that is expressed when it is present as a single allele. Thus, only one affected parent is needed to pass it to offspring.
A genetic trait that is only expressed when it is present on both alleles of a gene. Thus, two chromosomes bearing the gene anomaly are required, one from each parent. The risk of transmitting an autosomal recessive disease is 1/4 (25%) at each pregnancy.
A chromosome not involved in sex determination. The diploid human genome consists of 46 chromosomes: 22 pairs of autosomes in both males and females and 1 pair of sex chromosomes (XX in females and XY in males).
A single process (0.25 to more than 10 microns in diameter) of a neuron that conducts impulses away from the cell body and dendrites of that neuron. In contrast to dendrites, which are usually 1.5 mm in length, axons can reach up to 50 cm in length. Those axons that are 0.5 microns in diameter are usually encased in a myelin sheath. In the brain and spinal cord (CNS), oligodendroglia cells are responsible for the sheath, while Schwann cells make up the sheath in the peripheral nervous system. In general, axons transmit impulses to other nerve or effector cells via synaptic terminals.
One of two major classes of lymphocytes that develop in adult bone marrow and in the fetal liver of mammals. B cells express surface immunoglobulins (Igs), which act as specific antigen receptors. Naive B cells (i.e., B cells that have never been activated) express variable levels of both IgM and IgD isotypes. With a few exceptions, B cell activation is dependent on both
recognition of a specific antigen and T cell help. Activated B cells divide and differentiate into either memory cells or plasma cells. Memory B cells are long-lived and express antigen receptors other than IgM or IgD; they have undergone rearrangements in their Ig genes that result in increased affinity for that particular antigen. Plasma cells are short-lived and secrete large amounts of Igs (i.e., the soluble form of the antigen receptor).
The proportion of an administered drug absorbed into the bloodstream, indicating the physiological concentration of that drug.
Characteristic that is objectively measured and evaluated as an indicator of normal biological processess, pathogenic processess or pharmacologic responses to a therapeutic intervention.
Blind Trial, Single- or Double-
See Single-Blind and Double-Blind
Inflammation of the airways (bronchi) which connect the trachea to the lungs. Acute bronchitis occurs suddenly and is resolved within a few days, while chronic bronchitis persists over a long period of time and may recur over several years.
One of two subdivisions of the trachea that conveys air to and from the lungs. Bronchi are lined with stratified ciliated columnar epithelium, possess a lamina propria and are composed of longitudinal networks of elastic fibers. Spirally arranged bundles of smooth muscle are also present in addition to irregular plates of hyalin cartilage in the outer wall.
Calcineurin, also known as protein phosphatase 2B (PP2B; EC 220.127.116.11) is a calcium/calmodulin-dependent serine-threonine phosphatase that is composed of a catalytic subunit (A) and a regulatory subunit (B). There are three types of A subunits and two types of B subunits encoded by different genes. Calcineurin is essential for T cell activation since it dephosphorylates/activates the NF-AT transcription factor, which controls the expression of genes implicated in T cell activation. Calcineurin has been implicated in a wide variety of biological responses including lymphocyte activation, neuronal and muscle development, neurite outgrowth and morphogenesis of vertebrate heart valves. It has also been shown to have important roles in axonal guidance as well as memory and learning and plays a critical role in Ca(2+) signaling and stress responses. When a macrophage or a dendritic cell interacts with a T cell receptor (TCR), there is an increase in the calcium levels, which in turn activates calcineurin, by binding to its regulatory subunit and activating calmodulin binding. Calcineurin induces different NF-ATs that are important in the transcription of several genes encoding proinflammatory modulators. Blocking the calcineurin action would inhibit T-cell activation thus blocking transcription of these genes. Ultimately, the production of proinflammatory modulators such as interleukins, interferon gamma (IFNgamma) and tumor necrosis factor-alpha (TNF-alpha) would be decreased and the inflammatory response diminished. Inhibition of calcineurin signaling may be an effective therapeutic strategy for several autoimmune disorders such as graft-versus-host disease (GVHD).
cAMP (cyclic 3´,5´-Adenosine Monophosphate)
The 3', 5' cyclic ester of adenosine monophosphate (AMP) which acts as a second messenger in signal transduction pathways. cAMP is generated from adenosine 5'-triphosphate (ATP) by the action of adenylate cyclase which is coupled to hormone receptors by G proteins. cAMP activates a specific protein kinase and is inactivated by phosphodiesterase forming 5' AMP. cAMP is responsible for smooth muscle relaxation during bronchodilation, increased ciliary beat frequency and decreased mucus viscosity.
The abnormal, rapid, unorganized and uncontrolled proliferation of new tissue. The malignant tissue develops from a single cell that has undergone mutations in its DNA. This cell does not mature noramlly and eventually die but it divides prolifically. There are approximately 200 different types of cancers. Cancers arising from epithelial cells are called carcinomas and those arising from mesenchymal tissues are called sarcomas. Leukemias are also classified as malignant growths. Cancer cells can invade nearby tissues (i.e., metastasis) and can spread through the bloodstream and lymphatic system to other parts of the body.
A lysosomal cysteine proteinase (EC 18.104.22.168) thought to be involved in osteoclast-mediated bone resorption. Together with cathepsin B it activates caspase 3. Inhibition of this cathepsin may be effective in the treatment of neuronal injury due to ischemic stroke and COPD.
Covalently closed circular deoxyribonucleic acid.
CD3 (T Cell Receptor Complex)
The CD3 antigen is a protein complex composed of four distinct chains: CD3gamma chain, CD3delta chain and two CD3epsilon chains. These chains are highly homologous cell surface proteins that are members of the immunoglobulin superfamily and contain a single extracellular immunoglobulin domain. The transmembrane region of these CD3 chains is negatively charged allowing them to associate with the positively charged T cell antigen receptor (TCR) chains (TCRalpha and TCRbeta). The intracellular tails of the CD3 chains contain a single conserved motif known as an immunoreceptor tyrosine-based activation motif (ITAM) which is essential for the signaling capacity of the TCR. Association of the CD3 chains with TCR and the zeta-chain (accessory molecules of TCR) generates an activation signal in T lymphocytes. Thus, the TCR complex is composed of the TCR, zeta-chain and CD3 molecules. CD3+ T cells are increased in patients with Crohn's disease. Therefore modulation of the CD3 complex on T cells may be beneficial in the treatment of the disease.
CD4 (cluster of differentiation 4) is a transmembrane glycoprotein and member of the immunoglobulin (Ig) superfamily of receptors that is expressed on the surface of T helper (Th) cells, regulatory T cells, monocytes, macrophages and dendritic cells. It is a coreceptorthat together with the T cell receptor (TCR) activates the T cell following interaction with MHC class
- molecules present on the surface of antigen presenting cells. CD4 amplifies the signal generated by the TCR by recruiting the tyrosine kinase lck. It has four Ig domains (D1-D4) exposed on the extracellular surface of the cell and uses the D1 domain to interact with the beta2-domain of MHC class II molecules. T cells expressing CD4 molecules (not CD8) on their surface are MHC class II-restricted, specific for antigens presented by MHC II and not by MHC class I. CD4 is a primary receptor used by HIV-1 to gain entry into host T cells. In multiple sclerosis (MS), myelin antigen-specific CD4+ T cells become activated in the peripheral immune compartment and cross the blood-brain barrier to trigger the disease. Commitment of T cells to proinflammatory effector T helper cell lineages (e.g., IL-17-producing CD4+ T cells or Th17 cells) appears to be an important inducer of organ-specific autoimmunity and studies suggest that Th17 cells are the dominant pathogenic cellular component in MS and other autoimmune inflammatory diseases. Decreasing myelin-specific CD4+ T cell responses with an anti-CD4 antibody, for example, could reduce demyelination and decrease immune cell infiltration into the CNS and thus, reduce subsequent initiation and progression of the autoimmune response. See also CD4+ T Cells
CD4+ T Cells
T cells expressing both the T cell antigen receptor-2 (alphabeta; TCR-2) and the CD4 marker. The TCR recognizes the antigen associated with major histocompatibility complex (MHC) on the surface of the antigen presenting cell (APC), while the CD4 molecule recognizes the class II MHC molecule only. Therefore, CD4 determines that a given T cell be class II- rather than class I-
restricted. CD4 also contributes to T cell activation by providing biochemical signals to the T cell at the time of antigen presentation. CD4+ cells can be subdivided into Th0, Th1, Th2 or Th3 populations, depending upon the cytokine profile they secrete. CD4+ cells have been implicated in the development and progression of rheumatoid arthritis. See also CD4
See Complementary DNA (cDNA)
Central Nervous System (CNS)
The portion of the nervous system encompassing the brain and spinal cord.
Chemokine CXCR2 Receptor
See Interleukin 8 (IL-8) beta Receptor
G-protein-linked, 7-transmembrane (i.e., serpentine) receptors that bind chemokines and are used as coreceptors for the binding of immunodeficiency viruses (HIV, SIV, FIV) to leukocytes. Individuals deficient in particular CCRs seem to be resistant to HIV-1 infection. CXCR4 is a coreceptor for T-tropic viruses. CCR5 is the receptor for MIP-1alpha, MIP-1beta and RANTES and a primary coreceptor with CR4 for cell entry of macrophage-tropic HIV-1 strains. CCR5 is also implicated in asthma, rheumatoid arthritis and multiple sclerosis. Antagonists to the CCR1 (binds MIP-1alpha, RANTES, MIP-5/HCC-2), CCR2 (binds MCP-1, MCP-3, MCP-4) and CCR3 (binds, RANTES, MCP-2, MCP-3, MCP-4, eotaxin, MIP-5/HCC-2) receptors are under development for treatment of rheumatoid arthritis.
A large group of small polypeptide cytokines (e.g., IL-8, PF4, MCP-1, MIP-1alpha, RANTES) with proinflammatory activities synthesized by several cell types (e.g., monocytes, macrophages, T cells, mast cells, fibroblasts, endothelial cells, platelets, epithelium, microglial cells, keratinocytes). These molecules display a certain degree of selectivity for various immune cell types and are involved in activation of leukocytes during transendothelial migration and chemotaxis in tissues. The chemokine family is composed of two main subgroups: CC chemokines which contain two adjacent cysteine residues and CXC chemokines in which the two cysteine residues are separated by another amino acid. CXC chemokines are further subdivided into ELR+ or ELR- chemokines, where ELR indicates the amino acids (Glu-Leu-Arg) preceding the first cysteine residue. ELR+ chemokines are chemotactic for neutrophils and ELR-chemokines are chemotactic for lymphocytes.
An organism made up of two genetically distinct cell types. It is created by fusing two early blastula stage embryos, by reconstituting bone marrow in an irradiated recipient or by somatic segregation.
A genus of prokaryotes that replicate in cytoplasmic vacuoles within susceptible eukaryotic cells. <I>Chlamydia trachomatis</I> causes trachoma in man. Other species of <I>Chlamydia</I> can cause a variety of infections including urethritis, epididymitis and proctitis in men, cervicitis, salpingitis and acute urethral syndrome in women and conjunctivitis and pneumonia in newborn infants.
A bacteria belonging to the Chlamydiaceae family that causes pneumonia and diseases of the upper and lower respiratory tract (e.g., pharyngitis, bronchitis and pneumonia). It has recently been associated with coronary heart disease and Alzheimer's disease (AD). The bacterium was detected in AD brains and related to tau-associated neurofibrillary pathology. Persistent Chlamydia pneumoniae infections are thought to instigate or complicate the inflammatory response leading to atherosclerosis and/or angina pectoris.
A term referring to a health-related state or exposure that signifies prolonged (long-term)
duration. In some instances, it can indicate low intensity.
Complementary DNA (cDNA)
Deoxyribonucleic Acid (DNA) synthesized a mature (i.e., fully spliced) mRNA template in a reaction catalyzed by reverse transcriptase (RT). RT acts on a single strand of mRNA yielding a sequence of DNA that complements the mRNA template; this strand of DNA is cDNA and can be used to clone eukaryotic genes in prokaryotes. RT generates its cDNA based on the pairing of RNA base pairs (A, U, G and C) to their DNA complements (T, A, C and G respectively).
The solidification into a firm dense mass as in inflammatory induration of a normally aerated lung due to the presence of cellular exudate in the pulmonary alveoli.
A family of medium sized single-stranded RNA viruses some of which are responsible for upper respiratory diseases while other cause animal infections (e.g., avian bronchitis, swine encephalitis, mouse hepatitis). The outer envelope of the virus has club shaped projections that radiate outwards and give a characteristic corona appearance to negatively stained virions. Coronavirus is the only genus.
A class of steroid hormones that are produced in the adrenal cortex and are involved in many physiologic processes including among others stress responses, immune responses, inflammation, carbohydrate metabolism, protein catabolism, electrolyte homeostasis and behavior. The class includes both glucocorticoids and mineralocorticoids although corticosteroid is often used synonymously for glucocorticoid. Corticosterone, cortisone and aldosterone are common endogenous corticosteroids. Corticosteroids have been shown to be effective for a number of indications including cancer, asthma, allergic rhinitis, rheumatoid arthritis, nausea, COPD and inflammatory bowel disease.
A runny nose (also known as rhinorrhea). The word is thought to originate from the Greek "koryza" which means boiling over from the head. Coryzavirus is the former name for rhinovirus. See also Rhinorrhea
An amino acid that is found in muscle but does not occur in proteins. Phosphorylated creatine (creatine phosphate or phosphocreatine) is the energy source for muscle contraction.
A dimeric enzyme (82 kD; EC 22.214.171.124) that catalyzes the formation of ATP from ADP and creatine phosphate in muscle.
A waste product of protein metabolism found in the urine. Measurement of creatinine levels can indicate overall kidney function (i.e., high levels signify kidney dysfunction or failure).
A clinical study in which subjects receive two or more drugs separated by drug-free periods.
Soluble proteins produced by one of several cell types (i.e., T cells, B cells, fibroblasts, macrophages, epithelial cells, astrocytes, endothelium, monocytes) that are involved in signaling between cells of the immune system. Cytokines include interleukins, tumor necrosis factors (TNFs) and colony-stimulating factors (CSFs).
Acronym for "Disability Adjusted Life Years" which is the sum of years of life lost due to premature death and the years lost due to living with disability. DALYs are used to assess the magnitude of disease, health risks, and premature death. DALYs for a disease or health condition are calculated as the sum of the Years of Life Lost (YLL) due to premature mortality in the population and the Years Lost due to Disability (YLD) for people living with the health condition or its consequences. DALY = YLL + YLD.
Deoxyribonucleic Acid (DNA)
A nucleic acid which contains deoxyribose as the sugar component loosely bound to protein. It stores the hereditary information required for cell growth and reproduction. It is a linear macromolecular chain of deoxyribose molecules esterified with phosphate groups between 3' and 5' hydroxyl groups. Purines (i.e., adenosine [A] and guanine [G]) and pyrimidines (cytosine
- and thymine [T]) are linked to this structure. DNA is found in the nuclei (chromatin, chromosomes) and mitochondria of organisms. DNA is the autoreproducing component of viruses and contains all hereditary information. It may be open-ended or circular (e.g., mitochondrial DNA) and single- or double-stranded (e.g., chromosomes).
A group of metabolic diseases characterized by chronic hyperglycemia with disturbances in carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action or both. See also Diabetes Mellitus, Type 1 and Diabetes Mellitus, Type 2
A glycerol substituted on the 1 and 2 hydroxyl groups with long chain fatty acyl residues. It is a normal intermediate in the biosynthesis of phosphatidyl phospholipids and is released by phospholipase C (PLC). DAG is involved in signal transduction. Increased DAG levels in membranes activate protein kinase C (PKC). The high levels of glucose seen in diabetes increase the synthesis of DAG and PKC in vascular tissue. This can result in structural and functional abnormalities including changes in vascular permeability and gene expression in the retina (i.e., retinopathy) and kidney (i.e., nephropathy).
A symptom characterized by loose or unformed stools, frequently accompanied by other gastrointestinal symptoms. It is nearly always a symptom of another disease or condition, rather than a disease in its own right. It is considered acute when it lasts for less than 4 weeks (typically associated with a bacterial or viral infection) and chronic when it persists for more than four weeks. Diarrhea is broadly classified as secretory, osmotic or exudative. Secretory diarrhea is caused by an increase in active secretion or an inhibition of absorption. Osmotic diarrhea occurs when too much water is drawn into the bowels. This can be the result of maldigestion (e.g., pancreatic disease or celiac disease), in which the nutrients are left in the lumen to pull in water, lactose or fructose intolerance, or use of osmotic laxatives, among other causes. Exudative diarrhea is characterized by the presence of blood and/or pus in the stool. This typically occurs with inflammatory bowel disease (Crohn's disease or ulcerative colitis) and severe infections.
Dipeptidyl Peptidase IV (DPP IV)
An enzyme (EC 126.96.36.199) that removes N-terminal dipeptides from peptide hormones of the GRF superfamily, including GIP, GLP-1, GLP-2, glucagon, VIP and NPY. DPP IV plays a catalytic role in the processes of signal transduction during immune responses leading to type 2 diabetes. Inhibition of DPP IV is thought to improve glucose tolerance by rescuing intact versions of the incretins GLP-1 and GIP, or by preventing their degradation.
See Deoxyribonucleic Acid (DNA)
A research testing method characteristic of a controlled experiment/trial in which neither the participants nor the person administering the treatment know which treatment any particular subject is receiving. Usually the comparison is between an experimental drug and a placebo or a standard comparison agent.
A research testing method in which patients in all treatment groups receive medication of the same appearance, one of which is inactive (placebo) and the other active. For example, all patients would receive a topical cream and capsules. Those receiving the active cream received dummy capsules and vice versa.
Segments of nucleotide sequences of DNA or RNA that are remote from the initiation sites (i.e., codons) and are transcribed or translated later. It is also used to decribe events that occur late within sequential reactions. See also Upstream
Pathological abnormality of development such as an alteration in size, shape and organization of adult cells.
Shortness of breath and labored breathing.
The therapeutic effect of an intervention as demonstrated or observed in the real-world setting.
See also Efficacy
The therapeutic effect of an intervention as demonstrated or observed in a controlled setting, such as a clinical trial. See also Effectiveness
Emesis is the complex reflex consisting of ejecting the contents of the stomach through the mouth. Also known as vomiting, this reflex can be triggered by various endogenous or exogenous factors.
A term referring to internal, ductless, secretion (i.e., into the systemic circulation) or to the glands or the hormones which secrete or are secreted, respectively, in this manner.
Originating from within an organism, tissue or cell.
Widespread high occurrence of a disease in a population or area.
The cellular avascular tissue layer that covers all free cutaneous, mucous and serous surfaces.
The cause or origin of a disease.
An increase in the severity of a disease or in any of its symptoms.
Originating from outside an organism, tissue or cell.
A sequence of DNA that encodes information for protein synthesis that is transcribed to messenger RNA.
An inherited disorder or trait.
Formation of fibrous tissue in response to injury.
Any inanimate object contaminated with a viable pathogen (e.g., bacterium, virus, etc.) that can transfer the pathogen to a host.
One of several mediators of activated cell surface receptors and their enzymes and ion channels. They are responsible for the signal transduction pathways which alter the concentration of intracellular second messengers (e.g., cAMP, cGMP, Ca2+). These second messengers in turn regulate the behavior of other intracellular target proteins, leading to the desired cellular response.
Cell surface receptors that are coupled to G proteins (i.e., GTP binding protein). They have seven membrane spanning domains and have been divided into two subclasses: those in which the binding site is in the extracellular domain (e.g., receptors for glycoprotein hormones such as TSH and FSH) and those in which the ligand binding site is in the plane of the seven transmembrane domains (e.g., rhodopsin, receptors for small neurotransmitters and hormones such as the muscarinic acetylcholine receptor). Also called 7TM receptors.
The entire collection of genes and other functional and nonfunctional DNA sequences in the nucleus of an organism. It includes those genes that encode mRNAs, rRNAs, tRNAs and sn/scRNA and the functional sequences that occur as regulatory elements or as sites where replication begins. Much of the nonfunctional DNA consists of sequence elements repeated thousands or millions of times. Arrangement of functional and nonfunctional DNA within the genome is not fixed and existing sequences may be internally rearranged, moving from one location to another.
The genetic constitution of an organism or cell.
Glucocorticoid Receptor (GR)
A nuclear receptor of the NR3 class also known as type II glucocorticoid receptor (GR), which exists as a dimer coupled with chaperone molecules (e.g., HSP90, HSP65). Chaperone molecules are shed subsequent to ligand binding. GR binds cortisol and corticosterone and also aldosterone and deoxycortisone but with less affinity. The activated receptor then binds nuclear hormone response elements and also affects transcription via protein-protein interactions with other transcription factors such as activator protein- 1 (AP-1) and nuclear factor kappaB (NF-kappaB). Activation can result in potent anti-inflammatory activity as well as regulation of several cardiovascular, metabolic, immunologic and homeostatic responses. Synthetic glucocorticoid receptor ligands may be effective as a treatment for arthritis, dermatitis, allergic reactions, allergic rhinitis, atopic dermatitis, asthma, COPD, hepatitis, lupus erythematosus, inflammatory bowel disease, sarcoidosis, Alzheimer's-type dementia, and for glucocorticoid replacement in Addison's disease or other forms of adrenal insufficiency. On the other hand, GR antagonists
may be effective in the treatment for disorders involving pathological exposure to glucocorticoids such as Cushing's syndrome. These agents would reduce the effects of excess cortisol.
A family of steroid hormones generally synthesized and secreted by the adrenal medulla which affect intermediary metabolism such as hepatic glycogen deposition. Glucocorticoids also have potent antiinflammatory activity. Glucocorticoid receptors are found in the cells of almost all vertebrate tissues.
Cortisol (also known as hydrocortisone) is the most potent naturally occurring hormone in this class. It regulates several cardiovascular, metabolic, immunologic and homeostatic responses. Synthetic glucocorticoids have been show to be effective as a treatment for arthritis, dermatitis, allergic reactions, asthma, hepatitis, lupus erythematosus, inflammatory bowel disease, sarcoidosis and for glucocorticoid replacement in Addison's disease or other forms of adrenal insufficiency.
An enzyme (hydrogen/potassium adenosine triphosphatase; EC 188.8.131.52) isolated from gastric mucosa that catalyzes the hydrolysis of ATP coupled with the exchange of hydrogen and potassium ions across the cell wall. See also ATPase
The time required for one-half of an amount of a substance to be lost through biological processes.
Diffuse pain experienced in various regions of the head, not limited to the area of distribution of any single nerve.
An enzyme that moves along the DNA template double helix, in front of DNA polymerase, separating the two chains. Also known as the unwinding enzyme. Once unwound, the nucleotide chains are stabilized by DNA binding proteins (e.g., helix destabilizing proteins or single-strand binding proteins) that bind to the chains and prevent rewinding in the region just behind the replication fork.
A membrane glycoprotein (550 amino acids) of the influenza virus type A involved in receptor binding and fusion. The name is derived from its capacity to agglutinate red blood cells at neutral pH. There are 15 hemagglutinin (H) subtypes of which only 3 (H1, H2 and H3) are associated with human illness. No H subtypes have been identified for influenza B or C viruses.
Bleeding that classified according size (e.g., petechiae, very small; purpura, up to 1 cm; and ecchymoses, larger). Accumulation of blood within a tissue is known as a hematoma.
An inflammatory liver disease. See also Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis E and Hepatitis D.
A form of viral hepatitis that is known as infectious hepatitis because it can spread through contact with oral secretions or stool or through sexual contact. See also Hepatitis A Virus
Hepatitis A Virus (HAV)
A small (27 nm diameter) single stranded RNA virus with some resemblance to enteroviruses (e.g., poliovirus) that is a member of the Picornaviridae family. It replicates in hepatocytes and is transmitted via the oral-fecal route. It can also be sexually transmitted.
An inflammatory process in the liver caused by the hepatitis B virus (HBV) that is characterized by patchy hepatocellular necrosis affecting all acini. Liver disease caused by chronic hepatitis B can be fatal due to the development of cirrhosis leading to liver failure and an increased risk of hepatocellular liver cancer.
Hepatitis B Surface Antigen (HBsAg)
HBV surface antigen (HBsAg) is associated with the viral surface coat and several subtypes have been identified. Detection of HBsAg in serum usually provides initial evidence of acute HBV infection. In general, HBsAg appears during the incubation period, 1 to 6 weeks prior to development of clinical or biochemical illness and disappears during convalescence. Corresponding antibody (anti-HBVs) appears weeks or months later after clinical recovery and usually persists for life. Occasionally, HBsAg persists after infection and anti-HBs do not develop. These patients usually develop chronic hepatitis or become asymptomatic carriers of the virus.
Hepatitis B Virus (HBV)
A small enveloped DNA virus belonging to the Hepadnaviridae family. The infective particle of HBV consists of an inner core and an outer surface coat. The inner core contains double-stranded DNA and DNA polymerase which replicates in the nuclei of infected hepatocytes. The surface coat is added on in the cytoplasm and, for unknown reasons, is produced in large quantities. It is the surface coat which can be detected in serum as HBsAg.
An inflammatory process in the liver caused by the hepatitis C virus (HCV). Symptoms of hepatitis C may not manifest until the chronic stage and include jaundice, fatigue, abdominal pain, loss of appetite, intermittent nausea and vomiting. Cirrhosis from hepatitis C is the major condition responsible for the majority of orthotopic liver transplants in the U.S. Infection with hepatitis C has also been associated with increased risk of primary hepatocellular carcinoma.
Hepatitis C Virus (HCV)
An enveloped 9.5 kb positive strand RNA virus belonging to the Flaviviridae family. The virion consists of a nucleocapsid core and two envelope proteins within the lipid bilayer. Six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) are involved in viral replication, transcription and polyprotein processing. The virus mutates rapidly: at least six major HCV genotypes and more than 50 subtypes or quasispecies have been isolated.
A rare syndrome usually associated with hepatitis B and, in rare cases, with hepatitis A or E. It is characterized by rapid clinical deterioration and the onset of hepatic encephalopathy. The liver parenchyma undergoes massive necrosis and the organ size decreases significantly.
Hepatocellular failure and intravascular coagulation may cause bleeding. Functional renal failure sometimes occurs; in some cases, coma may develop within hours of onset.
The indirect protection of unvaccinated individuals against a given disease achieved via immunity of a sufficiently large proportion of the surrounding population against the respective pathogen, e.g., through vaccination or other methods of blocking transmission.
See Human Immunodeficiency Virus (HIV)
Human Immunodeficiency Virus (HIV)
A type of retrovirus first identified in 1983 that belongs to the Retroviridae family and genus lentivirus. HIV causes acquired immunodeficiency syndrome (AIDS) which involves a gradual
deterioration of the immune system resulting in opportunistic infections and eventual death. The virus is spread via sexual contact with an infected individual, exposure to contaminated blood (i.e., shared needles/syringes, infusions) and during pregnancy, delivery and/or through breast milk. Two HIV strains have been identified: HIV-1 the retrovirus that causes AIDS and is found worldwide and HIV-2, a virus closely related to HIV-1 that is less virulent, most common in West Africa and also causes immune system suppression. The two viruses differ in protein composition. For example, HIV-2 contains an additional accessory protein Vpx while lacking others. See also AIDS (Acquired Immune Deficiency Syndrome)
Refers to something that is clear, transparent, colorless and granule-free. Examples are hyaline cartilage and hyaline hyphae present in fungus such as Aspergillosis spp.
An integrated group of various cell types and the soluble molecules they secrete (i.e., antibodies, cytokines) responsible for immunity.
The means to produce a protective immune response in susceptible individuals by administration of a living modified agent (e.g., yellow fever vaccine), a suspension of killed organisms (e.g., pertussis vaccine) or an inactivated toxin (e.g., tetanus). Immunization can be passive or active.
The means by which antibody production or cell-mediated immunity is stimulated by giving the antigen in the form of a vaccine or through exposure to naturally occurring antigens such as bacteria, viruses or fungi.
A means to produce a temporary immune response against an infectious agent or toxin by giving preformed antibodies actively produced in another person or animal in the form of serum or gamma globulin.
Used to describe persons with an underdeveloped (as in the very young) or impaired immune system. The impairment may be a natural deterioration from age, or may be caused by disease or by the administration of immunosuppressive drugs.
An antigen that can induce antibody production.
A subgroup of globulins that are classified as alpha, beta and gamma according to lipid or carbohydrate content and physiological function. Antibodies are Igs and all Igs may function as antibodies. Serum Igs belong to the gamma group and constitute a family of glycoproteins that bind antigens. Serum Igs can be precipitated from plasma or serum and can be normal or specific. Serum Igs are classified into 5 groups: IgG, IgD, IgE, IgA and IgM.
Immunoglobulin A (IgA)
Major class of immunoglobulins found in mammalian serum, body fluids (i.e., tears and saliva) and in the respiratory, reproductive, urinary and gastrointestinal tracts. It protects the body's mucosal surfaces from infection. It is present in human colostrum but cannot be transferred across the placenta.
Immunoglobulin E (IgE)
IgE is a class of immunoglobulins or "antibodies" that attach to mast cells in the respiratory and intestinal tracts, triggering release of inflammatory modulators and resulting in manifestation of symptoms associated with allergic reactions. Of the five types of Igs (IgM, IgG, IgA, IgE and IgD) in the body, only IgE has been shown to be involved in allergic reactions. It is responsible for the symptoms seen in patients with allergic rhinitis, asthma and eczema. IgE elicits an immune response by binding to one of two Fc receptors. The high affinity receptor FcepisilonRI is expressed only on mast cells and/or basophils. Aggregation of antigens and binding of IgE to the mast cell Fcepisilon results in degranulation and the release of mediators from the cells; binding to FcepisilonRII on basophils causes release of type 2 cytokines (e.g., IL-4, IL-13) and other inflammatory mediators. The low affinity receptor Fcepisilon RII is constitutively expressed on B cells and inducibly expressed by IL-4 on macrophages, eosinophils, platelets and T cells.
Immunoglobulin G (IgG)
An immunoglobulin composed of two Fab and one Fc fragment. The Fabs include the antigen combining sites while the Fc region consists of the remaining constant sequence domains of the heavy chains and contains cell binding and complement binding sites. IgGs act on pathogens via agglutination, opsonization, activation of complement-mediated reactions against cellular pathogens and/or neutralization. Unlike other Igs, IgG can cross the placenta to the fetus as maternal antibodies. There are four known IgG subclasses. IgG2 differs from the rest in that it cannot be transferred across the placenta and IgG4 does not fix complement. IgG is present in serum at a concentration of 8-16 mg/ml.
The capacity of an organism to mediate effective responses to previously encountered antigens.
The majority of these responses are regulated by Tcells.
A Latin phrase that literally means "in the place." It is used to refer to examination of a phenomenon in exactly the place where it occurs (e.g., organ perfusions). In oncology, in situ refers to malignant cells present as a tumor. They have not metastasized beyond the original site where the tumor was discovered.
A Latin phrase that literally means "in glass." It is used to refer to a process or reaction (or experiment) occurring in an artificial environment (i.e., test tube, culture medium, etc.).
A Latin phrase that literally means "in a living being." It is used to refer to a process or reaction (or experiment) occurring in a living body.
Slowly progressing, low-grade; causing little or no pain.
The response of the immune system to an injury caused by irritation, infection, physical damage or chemically-induced cell stress. Local reactions at the site of injury cause immune cells to be recruited into the area, leading to the destruction and removal of the affected tissues and to wound repair. The five symptoms of inflammation are redness, heat, swelling, pain and dysfunction of the affected area, although not all five need be present at any one time.
An acute viral respiratory tract infection caused by influenza viruses A, B or C. It is characterized by inflammation of the nasal mucosa, the pharynx and conjunctiva and by headache, generalized myalgia, fever and chills. Necrotizing bronchitis and interstitial pneumonia are seen with severe influenza and account for the susceptibility of patients to secondary bacterial pneumonia due to Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus
aureus. The incubation period is one to three days and the disease can persist for three to ten days.
Pneumonia caused by the damage done to the cells of the lung epithelium by the replication of influenza virus.
Serologically different viruses (A, B and C) from the orthomyxovirus family that cause influenza.
Cells or viruses added to start a culture or infect a culture of cells, respectively. It also refers to injection of biological material to induce immunity (i.e., a vaccine).
Interferon alfa (IFN-alpha)
A type I interferon mainly produced by leukocytes which shows predominantly nonspecific antiviral effects via interference with the synthesis of double-stranded RNA which is essential for the replication of some viruses. IFN-alpha is used in the treatment of hepatitis. This interferon is also overexpressed together with IFN-gamma in type 1 diabetes.
Interferon beta (IFN-beta)
Type I interferon mainly produced by fibroblasts, epithelial cells and macrophages. It shows predominantly nonspecific antiviral effects via interference with the synthesis of double-stranded RNA, which is essential for the replication of some viruses.
Interferon beta-1a (IFN beta-1a)
Glycosilated, recombinant mammalian-cell product, with are aminoacid sequence identical to that of natural inferferon beta. IFNbeta-1a is used in the treatment of multiple sclerosis.
Interferon beta-1b (IFN beta-1b)
Nonglycosilated recombinant bacterial-cell product in which serine is substituted for cysteine at position 17, with respect to natural interferon beta. IFN-1b is used in the treatment of multiple sclerosis.
Interferon gamma (IFN-gamma)
A type II interferon produced by T lymphocytes which shows marked immunoregulatory activity although its antiviral activity is less potent as compared to type I interferons. Overproduction of this inflammatory cytokine may be involved in autoimmune insulitis, type 1 diabetes, IBD, rheumatoid arthritis and multiple sclerosis.
Interferon tau (IFN tau)
A recently discovered interferon that possesses activities similar to those observed for other type I interferons (IFN-alpha and IFN-beta), including antiviral, antiproliferative and immunomodulatory activities. IFN-tau has considerable potential for treatment of autoimmune and immunologically mediated disorders including multiple sclerosis and type 1 diabetes.
Cytokines, small glycoproteins released from one or several cell types (i.e., leukocytes, fibroblasts and T lymphocytes) in response to antigen. Interferons have been classified into three main subtypes (alpha, beta and gamma) based on interaction with antibodies, chemical properties and cellular origin. Interferons are used in different pathologies.
A member of a class of cytokines (IL-1 through IL-29) produced by several cell types (i.e., lymphocytes, macrophages, monocytes, fibroblasts, astrocytes, endothelium, etc) with very diverse actions. Some of these actions include effects on stem cell division (IL-11); development and differentiation of B cells (IL-5) and Th1 cells (IL-12); T cell growth and activation (IL-2); lymphocyte growth (IL-6), etc.
A soluble protein cytokine that is a member of the IL-1 superfamily which includes IL-1alpha, IL-1beta and the IL-1 receptor antagonist (IL-1RA). IL-1alpha and IL-beta are proinflammatory cytokines that are involved in inflammatory and immune responses while IL-1RA competes for receptor binding with these tow isotypes thus blocking inflammatory and/ or immune activation. Both isotypes are secreted by monocytes, macrophages and/or accessory cells early during an immune response and they activate T and B cells, stimulate T cell proliferation and enhance T and B cell responses to antigens. Overproduction of IL-1 has been implicated in several diseases including COPD, rheumatoid arthritis, type 1 diabetes, Alzheimer's disease and inflammatory bowel disease (IBD) and inhibitors of this cytokine may be effective treatment options for these disorders.
Interleukin-1 Receptor (IL-1R)
The cytokine receptor that binds members of the IL-1 superfamily IL-1alpha, IL-1beta and IL-1 receptor, type I(IL-1R1/IL-1RA). There are two identified subtypes: type I (CD121a) and type II (CD121b) which are involved in cytokine-induced immune and inflammatory responses.
Antagonism of these receptor subtypes may be effective in the treatment of inflammatory diseases such as COPD.
A cytokine released by Th2 cells that can inhibit cytokine release from Th1 cells. In addition, during late-phase inflammatory reactions, IL-10 upregulates expression of cellular adhesion molecules on endothelial and epithelial cells that are involved in recruitment of inflammatory cells from the circulation. IL-10 has been implicated in the pathogenesis of systemic lupus erythematosus. It inhibits the synthesis and release of proinflammatory cytokines produced by stimulated monocytes and macrophages and is under development for rheumatoid arthritis. Psoriatic lesions show significantly low levels of IL-10 and studies suggest that this cytokine may be an effective treatment for psoriasis.
A pleiotropic antiinflammatory cytokine that modulates antigen-specific antibody responses, potentiates megakaryocytes and regulates bone marrow adipogenesis. IL-11 has been shown to act synergistically with IL-10 to inhibit proinflammatory cytokine production and it decreases TNF-alpha, IL-1 and IL-12 production due to inhibition of NFkappaB. IL-11 may be effective as a treatment for psoriasis.
A heterodimeric cytokine that promotes cell-mediated immunity by facilitating type 1 helper T lymphocyte responses, including the production of IFN-gamma by both T cells and natural killer cells, potentiating the lytic activity of natural killer cells and boosting specific cytolytic T lymphocyte responses. IL-12 has shown potent therapeutic effects in various cancers and infectious diseases, including some viral infections. Overproduction of this inflammatory cytokine may be involved in autoimmune insulitis, type 1 diabetes, IBD, rheumatoid arthritis, psoriasis and multiple sclerosis.
Immune regulatory cytokine, predominantly produced by activated Th2 cells and mast cells, that inhibits the production of inflammatory cytokines in monocytes. IL-13 upregulates expression of cellular adhesion molecules on endothelial and epithelial cells during late-phase inflammatory reactions. Following an early-phase allergic reaction in which allergen crosslinking of IgE bound to mast cells occurs, IL-13 ( in addition to IL-4, IL-5 and GM-CSF) selectively recruits and activates eosinophils, other Th2 lymphocytes and IgE-secreting B lymphocytes into airway mucosa.
A cytokine expressed by monocytes, macrophages, dendritic cells (DC), keratinocytes, fibroblasts and nerve cells. It binds to and signals through a complex composed of the IL-2/IL-15
receptor beta chain (CD122) and the common gamma chain (gamma-C, CD132). It is expressed by T cells, monocytes and keratinocytes in psoriatic epidermis that affects T, B and NK cell division, neutrophil and monocyte activation. It also inhibits lymphocyte apoptosis. Keratinocyte-derived IL-15 has been shown to inhibit keratinocyte and lymphocyte apoptosis and it may play a role in the survival of infiltrating lymphocytes and abnormal keratinocytes features in psoriasis. This cytokine has been implicated as playing a role in rheumatoid arthritis and is overexpressed in psoriasis and pulmonary inflammatory diseases. IL-15 accumulates within synovial lesions and induces the overproduction of IL-17 within rheumatic joints. In addition, IL-15 neutralization has been shown to be beneficial in preclinical models of psoriasis, diabetes and celiac disease. IL-15 is normally not secreted. However, viral infection can cause its secretion.
IL-17 is a family of cytokines whose members include IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25) and IL-17F. These cytokines are associated with many immune regulatory effects and are associated with mediation of proinflammatory and allergic responses. IL-17 induces cytokine (e.g., IL-6, G-CSF, GM-CSF, IL-1beta, TGF-beta, TNF-alpha), chemokine (e.g., IL-8, GRO-alpha and MCP-1) and prostaglandin (e.g. PGE2) production from several cell types (e.g., fibroblasts, endothelial cells, epithelial cells, keratinocytes, monocytes and macrophages). IL-17 is secreted by the novel T helper cell subset Th17 which induces autoimmune inflammation and IL-17 receptor signaling may play a role in the development of chronic destructive arthritis from acute synovitis; IL-17 contributes both directly and indirectly to the bone and cartilage destruction occurring in rheumatoid arthritis. IL-17 may also be involved in the stimulation of osteoclastogenesis. The IL-17 family has been linked to other immune/autoimmune related diseases including asthma (i.e., plays a role in airway remodeling), lupus, allograft rejection, ankylosing spondylitis and antitumor immunity.
A proinflammatory cytokine structurally and functionally related to the IL-1 family of proteins that is a strong inducer of IFN-gamma production by T lymphocytes and NK cells. It is the only cytokine that can induce T helper 1 (Th1) and T helper 2 (Th2) cell polarization depending on immunologic context. It is implicated in several immune-mediated diseases. It is invovled in both innate and acquired immunity and its inflammation-promoting role is IFN-gamma-independent. It also plays a role in the local inflammation seen in rheumatoid arthritis. It is currently under investigation as an immunotherapeutic cancer agent and as an angiogenic factor.
Interleukin-18 Binding Protein (IL-18BP)
A constitutively secreted glycoprotein protein that exerts antiinflammatory and immunosuppressive effects. By preventing interleukin 18 (IL-18) receptor binding, it inhibits IL-18 and interferon (IFN)gamma production. Four human splice variants have been identified (IL-18BPa, IL-18BPb, IL-18BPc, IL-18BPd) of which IL-18BPa is the predominant form exhibiting the highest affinity for IL-18. While IL-18Pc also neutralizes IL-18, . IL-18BPb and IL-18BPd cannot bind to or neutralize cytokine. Inhibition of IL-18BP would be effective in suppressing high circulating levels IL-18 observed in many autoimmune diseases such as psoriasis, rheumatoid arthritis, inflammatory bowel disease psoriatic arthritis and in sepsis.
A cytokine released by mast cells following allergen-IgE binding that upregulates expression of cellular adhesion molecules on endothelial and epithelial cells during late-phase inflammatory reactions. It is also released by epithelial cells and astrocytes. An upregulation of IL-1beta production by the microvasculture has been observed in Alzheimer's disease and in response to ischemic insult. See also Interleukin-1 (IL-1)
IL-2 is a cytokine produced by CD4+ T lymphocytes upon activation by antigens and costimulators. It promotes T cell clonal expansion in the adaptative immune response and can activate B lymphocytes, monocytes and NK cells. Binding of IL2 to its receptor activates the JAK/STAT, PI3-kinase and RAS signaling pathways. Alpha chain monomers (CD25) conform a
low affinity IL2 receptor. High affinity and intermediate affinity IL2 receptors are conformed by alpha/beta heterodimers and beta chain monomers, respectively, associated to a gamma chain. It plays a role in both proliferative and activation-induced cell death (AICD) signaling of T cells. MS is in part genetically determined and the gene encoding the alpha-chain of the IL-2 receptor, IL2RA, harbors alleles associated with risk to MS and other autoimmune diseases such as GVHD. In addition, IL2RA genetic variants correlate with the levels of a soluble form of the IL-2 receptor in subjects with type 1 diabetes and multiple sclerosis (MS). IL-2 is produced by activated T cells in the synovium during the early stages of rheumatoid arthritis and in psoriatic lesions.
A new member of the IL-10 family (including IL-19, IL-22, IL-24 and IL-26) of cytokines which signals through the IL-20R1/IL-20R2 heterodimer. Together with IL-19, it is synthesized by a distinct population of keratinocytes. IL-20 induces keratin proliferation and Stat-3 signal transduction pathway and may be implicated in the pathogenesis of psoriasis.
A heterodimeric cytokine composed of a unique p19 subunit and the p40 subunit component of IL-12. It is secreted by activated dendritic cells (DCs) and macrophages and binds to memory T cells, NK cells, macrophages and DCs. In particular, this cytokine is suspected to be involved in the activation and maintenance of the Th17 subset of inflammatory T cells. It has been hypothesized that the autoimmune actions of IL-12 are attributable to IL-23 since mice lacking IL-23p19 (only IL-23 absent) and mice lacking IL-12p40 (both IL-12 and IL-23 absent) were protected from autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). On the other hand, mice lacking IL-12p35 (only IL-12 absent) developed more severe disease. Overexpression of IL-23 and/or IL-12 or defect in their receptors may be involved in conditions such as rheumatoid arthritis, psoriatic arthritis, psoriasis, multiple sclerosis, Crohn's disease and ankylosing spondylitis. Patients with Crohn's disease have been shown to have a significantly increased number of intestinal CD14+ macrophages as compared with normal control subjects and these cells produce larger amounts of IL-23 and TNF-alpha as compared to normal controls or patients with ulcerative colitis. Moreover, genomic studies conducted in patients with Crohn's disease have identified the IL-23 pathway as playing a predominant role in this disorder. Monoclonal antibodies directed against both IL-12 and IL-23 may be effective treatment options for these diseases.
A multilineage cell growth inducing cytokine (hemopoietic colony stimulating factor) secreted by lymphocytes, epithelial cells and astrocytes which stimulates clonal proliferation and differentiation of various types of blood and tissue cells.
Pleiotropic, immune regulatory cytokine released by Th2 and mast cells that upregulates expression of cellular adhesion molecules on endothelial and epithelial cells during late-phase inflammatory reactions. Following an early-phase allergic reaction in which allergen crosslinking of IgE bound to mast cells occurs, IL-4 (in addition to IL-5, IL-13 and GM-CSF) secreted by Th2 cells selectively recruits and activates eosinophils, other Th2 lymphocytes and IgE-secreting B lymphocytes into airway mucosa. Eosinophil infiltration of airway submucosa and mucosa is characteristic allergic diseases. Like IL-12, this cytokine has been found to inhibit HIV-1 replication in primary blood-derived human macrophages. Antagonizing the effects of IL-4 is a potential new approach for the treatment of for asthma, allergic rhinitis and rheumatoid arthritis. IL-4 receptors are overabundant in several tumor types therefore IL-4 fusion toxins may be an effective treatment for some forms of cancer (i.e., breast cancer).
A proinflammatory cytokine released by Th2 and mast cells that is involved in the development and differentiation of eosinophils and B cells; it also upregulates expression of cellular adhesion molecules on endothelial and epithelial cells during late-phase inflammatory reactions.
Following an early-phase allergic reaction in which allergen crosslinking of IgE bound to mast cells occurs, IL-5 (in addition to IL-4, IL-13 and GM-CSF) secreted by Th2 cells selectively recruits
and activates eosinophils, other Th2 lymphocytes and IgE-secreting B lymphocytes into airway mucosa. IL-5 is essential for eosinophilic inflammation which leads to airway hyperresponsivenes. Antagonizing the effects of IL-5 or inhibiting its production are potential new approaches for the treatment of allergic disease such as asthma and allergic rhinitis.
A member of a subfamily of related hematopoietic, proinflammatory cytokines, including leukemia inhibitory factor, ciliary neurotrophic factor, oncostatin M, cardiotrophin-1 and IL-11. The expression of IL-6 in the brain has been found to be increased in neurological disorders such as Alzheimer's disease, Parkinson's disease, trauma, stroke and meningitis. IL-6 is also present in abnormally high levels in obesity and type 2 diabetes, and has been implicated in inflammatory bowel disease. IL-6 is upregulated in epithelial cells infected with rhinoviruses and overexpression of IL-6 have been observed in the synovium in the early stages of rheumatoid arthritis, at systemic and cutaneous levels in psoriasis and in human systemic lupus erythematosus. IL-6 in the presence of sex steroids is required for osteoclastogenesis to occur.
An ELR+ (Glu-Leu-Arg) CXC chemokine suggested to be an important mediator of angiogenesis that may contribute to plaque formation in human coronary atherosclerosis. Overproduction of IL-8 may also be involved in airway inflammation characteristic of cystic fibrosis, asthma, the common cold and rheumatoid arthritis; IL-8 may also play a role in the inflammatory processes involved in psoriasis. Ischemia has been shown to increase the production of IL-8 in the brain. see Also Interleukin 8 beta Receptor (IL-8betaR)
Interleukin-8 (IL-8) beta Receptor
One of two G-protein-coupled receptor subtypes (alpha and beta) for interleukin 8 (IL-8), an ELR+ (Glu-Leu-Arg) CXC chemokine (chemokine CXCR2) produced by monocytes, fibroblasts and endothelial cells that mediates activation and chemotaxis of T cells, monocytes and neutrophils. Overexpression of IL-8 appears to be involved in airway inflammation characteristic of COPD as well as cystic fibrosis, asthma, the common cold and rheumatoid arthritis. Antagonism of this receptor could prevent recruitment of pathogenic cells into inflamed lungs thus preventing development of COPD. Antagonism of this receptor may also be effective in the treatment of psoriasis and atherosclerosis since IL-8 may also play a role in the inflammatory processes involved in psoriasis and angiogenesis that may contribute to plaque formation in human coronary atherosclerosis. Ischemia has also been shown to increase the production of IL-8 in the brain.
A cytokine secreted from CD4+ T cells that affects T cell and mast cell division/development. It may also be involved in the pathogenesis of asthma by enhancing the effects of other cytokines and inflammatory mediators. The normal nonasthmatic state is suggested to be associated with downregulation of IL-9.
See RNA Interference (RNAi)
A gentically modfied mutant organism (e.g., mouse, yeast) that carries a particular gene that is not normally present. The effect of including this gene can be provide information about a specific disease or condition.
Experimental inactivation of specific genes in laboratory organisms (e.g., mice, yeast) in order to study a specific disease or condition.
The classical requirements for disease causation that were developed by Henle and Koch in the 19th century. They are i) the infectious microorganism is present in all individuals suffering from the disease; ii) the microorganism can be isolated from the diseased host and grown in pure culture on artificial laboratory media; iii) inoculation of a healthy susceptible laboratory animal with the freshly isolated microorganism results in induction of the disease that was seen in the original host animal; and, iv) the microorganism can be reisolated in pure culture from an experimentally infected host.
A genus of rod- or coccus-shaped aerobic Gram-negative bacteria. Certain species such as L.
pneumophila, produce Legionnaires' disease, a severe form of pneumonia.
A member of a heterogeneous cell population, also known as white blood cells, found in various tissues and circulating blood that is formed in myelopoietic, lymphoid and reticular portions of the reticuloendothelial system. These cells represent three lines of development according to primitive origin, which includes myeloid (generating neutrophil, basophil and eosinophil granulocytes), lymphoid (generating B and T cells) and monocytic (generating monocytes and macrophages).
An abnormal decrease in the number of white blood cells.
A type of white blood cell formed in lymphocytic tissue (i.e., lymph nodes, spleen, thymus, tonsils, Peyer's patches, bone marrow) that is responsible for specific immune recognition of pathogens and the initiation of adaptive immune responses.
An increased number of circulating lymphocytes. Pathologic lymphocytosis occurs in chronic inflammation, recovery from acute infection, lymphocytic leukemia and hypoadrenocorticism and indicates a strong immune stimulus of chronic duration from a bacterial infection, viremia or immune-mediated disease. Absolute lymphocytosis is the presence of more than 15,000 lymphocytes/mm3 blood.
An immune cell that is capable of phagocytosis, and that may also be capable of antigen processing and presentation (APCs). These cell have different names depending upon the tissue in which they are located (e.g., Kupffer cells in the liver, alveolar macrophages in lung, histiocytes in connective tissue). Macrophages process the phagocytosed antigen and present it in association with class II molecules to CD4+ T cells. If the CD4+ T cell is Th0, antigen presentation by macrophages often results in differentiation of these Th0 cells into Th1 cells. Phagocytosis and/or cytokines induce macrophage activation, and activated macrophages secrete IL-1 and upregulate expression of costimulatory molecules (e.g., B7 and ICAM-1) on their surface.
Major Histocompatibility Complex (MHC)
The genetic loci (class I, II and III regions) found in all mammals encoding a specialized group of highly polymorphic cell surface proteins responsible for antigen recognition. Class I and II MHC gene products are involved in signaling between lymphocytes and cells expressing antigen.
Class III molecules are structurally and functionally different from the gene products of class I and II MHC and are commonly referred to as the complement system.
See Mitogen Activated Protein (MAP) Kinase (MAPK)
See Mitogen Activated Protein (MAP) Kinase (MAPK)
Matrix Metalloproteinases (MMPs)
A family of zinc-dependent enzymes also known as matrixins that catalyze the hydrolysis of peptide chains and therefore have the ability to degrade a variety of proteins (i.e., elastin, collagen, proteoglycans, laminin, fibronectin) of the extracellular matrix. They are functionally categorized into three groups according to their substrate target: collagenases, stromelysins and gelatinases which degrade fibrillar collagen, proteoglycans and glycoproteins and denatured and basement membrane collagens, respectively. MMPs are produced by neutrophils, alveolar macrophages and airway epithelial cells and have been implicated in several clinical inflammatory conditions such as COPD and asthma where inhibition would block extravasation, migration and alveolar wall degradation. Inhibitors may also be effective as a treatment for rheumatoid arthritis, inflammatory bowel disease (IBD), stroke and multiple sclerosis and for preventing tumor growth and metastasis.
See Mitogen-Activated Protein (MAP) Kinase Kinase (MEK; MAP2K)
The reversible replacement of one differentiated cell type with another mature differentiated cell type. This results in transformation of one tissue type to another.
Middle East Respiratory Syndrome Coronavirus (MERS-CoV)
The coronavirus that causes the viral respiratory illness, MERS (Middle East respiratory syndrome). MERS-CoV is a species in lineage C of the genus beta coronavirus. It is different from the coronavirus that causes severe acute respiratory virus (SARS) and appears to most closely resemble the not-yet-classified viruses from insectivorous European and African bats in the Vespertilionidae and Nycteridae families. Infection by this virus appears to be primarily zoonotic in nature, with limited human-to-human transmission. Symptoms of infection include flu-like illness with signs and symptoms of pneumonia (e.g., fever, cough, shortness of breath, nausea, vomiting, diarrhea). Symptoms are similar to those found in SARS infections with the exception that renal failure has only been reported in MERS-CoV infection.
A mutation that converts a codon coding for one amino acid to a codon coding for another amino acid.
A class of tubular-shaped organelles that reside within eukaryotic cells, converting oxygen and nutrients into adenosine triphosphate (ATP), which is required by cells for energy. Mitochondrial dysfunction has been hypothesized to contribute to the pathogenesis of Huntington's disease, Parkinson's disease, schizophrenia, and a wide range of other disorders.
Mitogen-Activated Protein (MAP) Kinase (MAPK)
A family of serine/threonine kinases that are activated when quiescent cells are exposed to mitogens and therefore potentially transmit a signal for entry into the cell cycle. One target is transcription factor p62TCF. MAPK can be phosphorylated by MAP kinase kinase (MAPKK) which is controlled by RAF1. C-Jun N-terminal kinases (JNK) are members of the MAPK family of enzymes. MAPK has been implicated in cerebral spasm and inhibitors of this kinase may be useful in the treatment of vasospasm following subarachnoid hemorrhage. See also p38 Mitogen-Activated Protein Kinases (MAPKs)
Mitogen-Activated Protein (MAP) Kinase Kinase (MEK; MAP2K)
A kinase enzyme (EC 184.108.40.206) and member of MAPK signal transduction cascade where it is lies upstream of MAPK and stimulates the enzymatic activity of MAPK. MAPKs, also known as extracellular signal-regulated kinases (ERKs), are activated by a wide variety of extracellular signals and thus serve as an integration point for multiple biochemical pathways. They are activated via rapid phosphorylation on threonine and tyrosine residues. The MAPK signaling cascade is initiated by extracellular signaling which activates (i.e., phosphorylates) MAP kinase kinase kinase (MKKK; MAP3K). Activated MAP3K phosphorylates MEK which then activates MAPK. MEK/ERK inhibitors inhibit mucin secretion which would be potentially effective as a treatment for the airway mucus hypersecretion seen in COPD and other respiratory disorders such asthma and cystic fibrosis. MEK inhibitors have also been shown to inhibit muscarinic receptor-induced human lung fibroblast proliferation which contributes to the pathology of COPD. In Crohn's disease, macroscopically noninflamed colon contributes to diarrhea via impaired epithelial sodium channel-mediated sodium absorption and studies have shown that therapeutic inhibition of MEK1/2 restores electrogenic sodium absorption. Thus, inhibition of MEK could be an effective strategy for the treatment of the chronic inflammation and diarrhea seen in Crohn's disease.
See Matrix Metalloproteinases (MMPs)
Monoclonal Antibody (MAb)
An antibody of a defined specificity that recognizes only a single epitope of an antigen. MAbs are produced by a single clone of B lymphocytes. Production of MAbs for therapeutic use is usually carried out by fusion of the relevant B cell clone with an immortalized cell line. This results in a population of hybrid cells (i.e., hybridoma) that secretes a large amount of the MAb of interest. Therapeutic MAbs can be murine, chimeric or humanized. Murine MAbs are developed in mice and can result in marked human antimouse responses (i.e., immunogenicity) in humans following administration. Thus, chimeric antibodies were developed which are composed of the murine variable region grafted onto a human MAb (two-thirds human). Humanized MAbs are less immunogenic since only the complementary determining regions of the murine antibody (only 5%) are grafted onto a human MAb.
Damage or change in a gene or chromosome so that transcription is altered.
Pain in a muscle or muscles.
Prokaryotic microorganisms lacking cell walls and therefore resistant to many antibiotics. An example is Mycoplasma pneumoniae is responsible for pneumonia in humans and some domestic animals.
The unpleasant sensation of queasiness or stomach upset that often precedes or accompanies the act of vomiting. Some common causes include motion, early pregnancy, intense pain, emotional stress, gallbladder disease, food poisoning, enteroviruses among others. It is also be an adverse effect of several chemotherapeutic agents.
Death of one or more cells of a tissue or organ. Early damage includes irreversible mitochondrial (e.g., swelling, granular calcium deposits) and nuclear (e.g., pyknosis, karyolysis, karyorrhexis) changes. Later, affected cells merge forming a focus of granular, amorphous or hyaline material.
The cell of the nervous system which is composed of a cell body, dendrites and a single axon.
See Polymorphonuclear Leukocytes.
A disease acquired or occurring in a hospital.
The coat (capsid) of a virus plus the enclosed nucleic acid genome.
The building block of DNA and RNA which is a purine or pyrimidine base linked glycosidically to ribose or deoxyribose. It lacks the phosphate residues that would make it a nucleotide. The ribonucleosides are adenosine, guanosine, cytidine and uridine and the deoxyribosides are deoxyadenosine, deoxyguanosine, deoxycytidine and deoxythymidine.
The phosphate ester of a nucleoside that is the basic constituent of DNA and RNA. Other structures (e.g., cAMP, cGMP) and molecules with two or three phosphates are also called nucleotides.
Open Reading Frame (ORF)
Part of a reading frame that has the potential to code for a protein or peptide. An ORF is a continuous stretch of codons that do not contain a stop codon (usually UAA, UAG or UGA).
A clinical study in which all participants (i.e., patient and investigator) know the identity of the administered drug.
A status granted by the FDA to unpatentable medications developed for rare diseases. Rare or orphan diseases are defined affecting fewer than 200,000 people in the US or are associated with a low prevalence of less than 5 per 10,000 in the community. This staus gives the manufacturer a seven-year right to exclusively market the compound. By increasing profitability of these agents, their production is encouraged.
A family comprised of the influenza and togotoviruses that are characterized by negative sense, single-stranded, segmented RNA genomes.
p38 MAP Kinase
See p38 Mitogen-Activated Protein Kinases (MAPK)
p38 Mitogen-Activated Protein Kinases (MAPKs)
A class of MAPKs composed of four isoforms: p38 MAPK-alpha (MAPK14), p38 MAPK-beta (MAPK11), p38 MAPK-gamma (MAPK12) and p38 MAPK-delta (MAPK13 or SAPK4) which are activated by a variety of cellular stresses including osmotic shock, inflammatory cytokines, lipopolysaccharides (LPS), ultraviolet light and growth factors. They are activated via MAP3K and MEK by phosphorylation at Thr180 and Tyr182, Activated p38 MAPKs have been shown to phosphorylate and activate mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) and the transcription factors ATF-2, Mac and MEF2. p38 MAPKs may also be involved in mucin secretion and inhibiotrs of this kinase could be potentially effective as a treatment for the airway mucus hypersecretion seen in COPD and other respiratory disorders and may also inhibit lung fibroblast proliferation which contributes to the pathology of COPD.
A treatment directed toward the control of symptoms rather than the curing of the disease.
A global epidemic of an especially strong and highly infectious virus, newly infectious for humans, with the potential to cause many cases of illness and death due to a lack of acquired immunity in the human population.
A mammal that is also known as the scaly anteater.
A family of Class V enveloped RNA viruses. Its genome consists of a single negative strand of RNA and it has a helical nucleocapsid associated with virus-specific RNA polymerase (transcriptase). Other related viruses include Newcastle disease virus, measles virus and the parainfluenza viruses. Paramyxovirus is a genus of this family of which human parainfluenza virus type 1 is a member. Virions have both hemagglutinin and neuraminidase activity and encode a
See Polymerase Chain Reaction (PCR)
A part or subunit of the peplos of a virion. See Also Peplos
The coat or envelope of lipoprotein material that surrounds certain virions.
Peripheral Blood Mononuclear Cells (PBMCs)
Lymphocytes and monocytes isolated from peripheral blood by centrifugation.
Phase 0 Trial
A phase of clinical testing that is also known as exploratory IND in the US and Microdosing in Europe. This stage of drug development is intended to facilitate the transition from animal to human studies. The trials evaluate doses determined in animal studies that are only 1/100th of those expected to be required for therapeutic effect.
Phase I Trial
The first human study of a new drug, usually conducted in a small number of healthy individuals to evaluate the biological properties of that drug, including pharmacological activity, pharmacokinetics and tolerability (i.e., toxicity). Examination of how the drug should be administered, how often and in what dosage are also assessed.
Phase II Trial
A type of study providing preliminary information on the efficacy and safety of a new drug. Phase IIa trials are conducted in a small population of patients, while phase IIb studies incorporate larger patient cohorts and can determine a range a doses to be used in phase III clinical trials.
Phase III Trial
A full-scale clinical study conducted in order to determine the efficacy and safety of a new drug prior to seeking marketing approval. These studies usually involve large patient populations randomized to receive a new or standard therapy and/or placebo.
Phase IV Trial
A large-scale clinical trial conducted following regulatory approval of a drug. Its purpose is to expand efficacy and safety information. These trials are also referred to as marketing support trials.
The observable traits of an organism (e.g., weight, height, hair color) regardless of the genotype. Phenotypic traits are not necessarily genetic and may result from an interaction between the genotype and the environment.
An inactive compound used in preclinical and clinical trials as a comparison for active compounds.
Having multiple effects.
A protozoon microorganism (e.g., frequently a ustomycetous yeast) that is now classified as Pneumocystis jiroveci. See Pneumocystis jiroveci
Pneumocystis carinii Pneumonia (PCP)
See Pneumocystis jiroveci Pneumonia (PJP)
A protozoon microorganism (e.g., frequently a ustomycetous yeast) that was previously classifed as Pneumocystis carinii. It is responsible for pneumocystis pneumonia in immunocompromised individuals.
Pneumocystis jiroveci Pneumonia (PJP)
A serious illness caused by the fungus Pneumocystis jirovecii. PJP is an interstitial pneumonia and one of the most frequent and severe opportunistic infections in people with weakened immune systems, particularly people with HIV/AIDS. It also occurs in individuals treated with steroids, the elderly or premature or debilitated babies. Formerly known as Pneumocystis carinii pneumonia (PCP).
Inflammation of the lungs with consolidation. Pneumonia is a form of acute respiratory infection that inflames the alveoli in the lungs which in healthy individuals fill with air during inhalation. When infected, these air sacs may fill with fluid or pus, leading to symptoms such cough with phlegm, fever, chills, chest pain and difficulty breathing. Pneumonia may be caused by a variety of organisms, including bacteria, viruses and fungi. Pneumonia can be classified into community-acquired pneumonia, hospital-acquired pneumonia, pneumonia in the immunocompromised and aspiration pneumonia (i.e., cause by inhaled food, drink, vomit or saliva from the mouth into the lungs and can lead to pus formation in the lung cavity). See also Consolidation
A general term for any enzyme belonging to the EC class 2, transferases which catalyze polymerization. Prokaryotic DNA polymerases are divided into types I, II and III, while eukaryotic polymerase is subdivided into polymerase alpha, -beta, -gamma, -delta and -epsilon. DNA polymerases are highly accurate, entering the correct complementary base opposite a base on the template chain; there is a low incidence of mismatching. DNA polymerases remove primers after they have served their function, refilling the gaps with nucleotides until all bases are paired. However, DNA polymerase cannot link the last nucleotide added to the 5´ end of the next-to-the-last segment; a single-chain nick remains that is later closed by DNA ligase. RNA polymerase catalyzes RNA transcription (a polymerization reaction). There are three types of eukaryotic RNA polymerase and only one bacterial RNA polymerase.
Polymerase Chain Reaction (PCR)
A technique developed in 1983 by K.B. Mullis and F. Faloona which simplifies the production of multiple DNA copies from a sample taking advantage of DNA polymerase, the enzyme which
catalyzes DNA replication. During the first cycle of PCR, a DNA double helix containing the nucleotide sequence of interest is unwound by heating to 90ºC. DNA polymerase and the nucleotide triphosphates (adenine, thymine, cytosine and guanine) required for replication are added to the unwound DNA mixture. Artificially synthesized, short (about 20 to 30 nucleosides in length) DNA, complementary to the ends of the unwound template chains, are also added and serve as the primers for the reaction. The mixture is cooled to 60ºC, allowing the artificial primers to wind to the ends of the template chains. Replication then occurs where DNA polymerase assembles complementary copies of the template chains starting from the artificial primers. The resulting reaction mixture now contains twice as many DNA molecules. The second cycle is initiated by heating the reaction mixture again which results in unwinding of the newly synthesized double helices. The mixture is then cooled allowing additional copies of the artificial primer chains to rewind with the ends of the template chains (as in the first cycle). DNA polymerase makes copies of the artificial chains and at the end of this cycle, the number of DNA molecules has doubled again. Each time the heating and cooling cycle is repeated, the number of DNA molecules in the sample doubles and, since cycling time is short, hundreds of billions of DNA copies can be generated in a few hours.
The linkage of glucose units into chains in cellulose or starch molecules. Multiple identical or nearly identical subunits called monomers are linked together in a chain to form a polymer. This process underlies the assembly of most biological macromolecules. For example, monosaccharides polymerize into polysaccharides, amino acid monomers into proteins and nucleotide monomers into nucleic acid polymers.
White blood cells with multilobed nuclei and cytoplasmic granules. They include neutrophils (granules stain with neutral dyes), eosinophils (granules stain with eosin) and basophils (granules stain with basic dyes).
Experimental in vitro and/or in vivo testing in animals performed prior to clinical studies to determine the biological activity and safety of an agent.
The number of cases of a disease or condition at a given time.
An assessment of the likely outcome of the disease judged from general experience of the disease and the age and condition of the individual patient.
Programmed Cell Death (PCD)
Growth and reproduction of similar cells.
The prevention of a disease or the process leading to a disease.
Administration of an antigenic agent to actively stimulate an immune mechanism.
Use of antiserum from another individual or animal to provide temporary (7-10 days) protection against a specific infectious or toxic agent.
Proteolytic enzymes including both endopeptidases (EC 3.4.21-24 & 3.4.99) and exopeptidases (EC 3.4.11-19), which hydrolyze peptide bonds leading to degradation of a protein (i.e., proteolysis). Proteases are classified into four general types: serine, cysteine, aspartic and matrix metalloproteinases (MMPs).
Proteolytic complexes that degrade the majority of short-lived cytosolic and nuclear proteins. They are implicated in ATP-dependent ubiquitin protein complex degradation and in antigen processing in antigen presenting cells. Proteasomes are also involved in the regulation of JAK/STAT pathways, IL-2, IL-3 and erythropoietin stimulation. Proteasome inhibitors down-regulate inflammatory mediators such as NFkappaB and may be a potential treatment for stroke and myocardial infarction. Proteasome inhibitors also induce apoptotic cell death, and thus are being studied for the treatment of cancer.
The degradation of proteins via hydrolysis of the peptide bonds resulting in the formation of smaller polypeptides. The process is catalyzed by proteolytic enzymes (e.g., protease, peptidase), acids or bases. See also Protease
Describes a cell or an individual with a new combination of genes not found together in either parent; it usually refers to linked genes. Recombinant DNA is spliced DNA formed from 2 or more different sources that have been cleaved by restriction enzymes and joined by ligases.
Use of a recombinant antigen preparation in combination with an adjuvant, which may be administered prophylactically or therapeutically to induce viral neutralizing proteins and other protective immune responses.
A disease or infection that is resistant to treatment.
An enzyme (EC 220.127.116.11) that catalyzes the cleavage of the leucine-leucine bond in angiotensinogen to generate angiotensin I. It is synthesized as an inactive protein in the kidney and released into the blood in the active form in response to various metabolic stimuli.
A system consisting of renin, angiotensin-converting enzyme (ACE) and angiotensin II that regulates blood pressure and electrolyte and fluid balance. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, resulting in formation of inactive angiotensin I. ACE in the lung acts on angiotensin I in the plasma converting it to angiotensin II.
Angiotensin II is a potent pressor substance that causes contraction of the arteriolar smooth muscle, aldosterone release and renal absorption of sodium; it also has other indirect actions mediated by the adrenal cortex. This system is a target for the treatment of arterial hypertension.
A tandem region of replication (about 30 microns in length) in a chromosome derived from an origin of replication (i.e., a regions of DNA required for initiation of replication) that must also contain an origin of replication.
Respiratory Syncytial Virus (RSV)
A RNA virus that is a major pathogen causing upper and lower respiratory tract infections in infants and younger children. Infection manifests as bronchiolitis, pneumonia and croup. It is an RNA virus that is a member of the Paramyxoviridae family.
A virus that contains RNA as its genetic material. This RNA is translated into DNA which inserts into the DNA of a viral-infected cell. Retroviruses are responsible for many diseases including some cancers and AIDS.
An inflammation of the nasal passage which is characterized by frequent and/or repetitive sneezing, runny or congested nose and itchiness of the nose, eyes and throat and may also be associated with headache, impaired smell, postnasal drip, conjunctival symptoms and sinusitis. The most common form of rhinitis is allergic rhinitis which is classified as perennial, seasonal or occupational, depending on the time of allergen exposure. Less common subtypes include hormonal rhinitis (occurring during pregnancy or in patients with hypothyroidism), nonallergic or vasomotor rhinitis, infectious rhinitis and drug-induced rhinitis.
A runny nose. See also Coryza
A member of the Picornaviridae family of viruses that commonly infects the upper respiratory tract. These viruses are responsible for the common cold virus and foot-and-mouth disease. Human rhinoviruses (HRV) are grouped according to receptor tropism, sensitivity to antiviral agents, antigenicity or genetic similarity. There are 102 different HRV serotypes. The major genetic clade for HRV species is HRV-1 (91 serotypes) that uses ICAM-1 as a receptor; HRV-1A (76 serotypes) and HRV-1B (25 serotypes) are antigenic subtypes of this group. HRV-2 (10 serotypes) that uses the LDL receptor. See also Picornaviridae
A family of nucleases (EC 2.7 and EC 3.1) that catalyze the hydrolysis of internucleotide phosphodiester bonds in RNA into smaller components thus degrading it. They can be divided into endoribonucleases and exoribonucleases which include further sub-classes (i.e., EC 2.7 phosphorolytic enzymes and EC 3.1 hydrolytic enzymes).
Ribonucleic Acid (RNA)
A macromolecule consisting of ribonucleoside residues connected by phosphate from the 3'-hydroxyl of one to the 5'-hydroxyl group of the next nucleotide. It is found in all cells in both the nuclei and cytoplasm and in viruses. RNA is divided into fractions depending on location, form or function. Messenger RNA (mRNA) reflects the exact nucleoside sequence of genetically active DNA. mRNA carries the message of the DNA coded within its sequence to the cytoplasmic areas where protein is assembled. Ribosomal RNA (rRNA) is encoded in DNA regions forming parts of the nucleolus; it is the RNA of ribosomes or polyribosomes. Transfer RNA (tRNA) refers to short-chained RNA molecules of at least 20 types (one for each of the 20 amino acids in protein synthesis). tRNA combines with amino acids during protein synthesis and interacts with mRNA codons, thus providing a link between the information coded into nucleic acids and the amino acid sequence of proteins. Small nuclear RNAs (snRNAs) are small (about 90-300 nucleotides) chains in the nucleus that are involved in processing of mRNA and rRNA. Small cytoplasmic RNA (scRNA) functions primarily in the cytoplasm and forms the signal recognition particle. scRNA participates in the process of attaching ribosomes to the endoplasmic reticulum during synthesis of membrane proteins or proteins later secreted by the cell.
A nucleotide in which a purine or pyrimidine base is linked to a ribose molecule. It is a component of RNA. See also Nucleotide
A small, sphere-shaped, cytoplasmic structures that is composed of RNA and protein and is the site of protein synthesis. Ribosomes are free in the cytoplasm and often attached to the membrane of the endoplasmic reticulum. Ribosomes exist in both eukaryotic and prokaryotic cells. Bacterial ribosomes are composed of two subunits: the smaller 30S subunit containing 21 proteins and a single 16S RNA molecule, and the larger 50S subunit containing 32 proteins and two RNA molecules (23S and 5S). 16S serves as a scaffold defining the positions of the ribosomal protein with the 3' end containing the anti-Shine-Dalgarno sequence. This sequence binds upstream to the
AUG start codon on the mRNA. 16S interacts with 23S and facilitates binding of 50S and 30S. Many antibiotic agents bind to the 30S and 16S subunits of the bacterial ribosome. This action inhibits translocation of peptidyl-tRNA from the A-site to the P-site and also causes misreading of mRNA, interrupting bacterial protein synthesis necessary for survival and reproduction.
A nonprotein biological catalyst consisting of specific domains of ribonucleic acid (RNA) that can recognize, bind and digest nucleic acids thus playing a key role in intron splicing events. Several cleave precursors of tRNA resulting in functional tRNA while others act on rRNA.
Ribozymes induce conformational changes which involve bringing the hydroxyl groups of RNA molecules into positions where their reactivity leads to hydrolysis and breakage of RNA chains. Ribozymes have been investigated as a potential therapeutic approach for diseases such as HBV infection, since their enzymatic activity can be used to block pathogenic protein synthesis. The utility of ribozymes as biologic and therapeutic agents has been limited due to their susceptibility to chemical and enzymatic degradation and to restricted target site specificity.
A diverse family of small, Gram-negative obligately intracellular bacteria found in ticks, lice, fleas, mites, chiggers and mammals. Examples include: genera Rickettsiae, Ehrlichia, Orientia and Coxiella. They are zoonotic pathogens that cause infections transmitted by invertebrate vectors.
See Ribonucleic Acid (RNA)
RNA Interference (RNAi)
RNA interference (RNAi) is an endogenous process of gene silencing that is due to interruption in the cell's translation. This interruption is triggered by the cell's own mRNA in response to the presence of and consequent destruction of matching double-stranded RNA sequences. Gene expression is inhibited in a sequence-dependent manner. The process endogenously protects the cell against viruses and other insults. The process has also emerged as a powerful gene silencing technique that is useful in research and development of therapeutics. See also Small interfering RNA (siRNA)
A virus in which the genetic information is stored in RNA as opposed to DNA. The RNA is usually single-stranded although there are some that are double-stranded. human diseases caused by RNA viruses include Ebola, hemorrhoragic fever, SARS, rabies, common cold, influenza, hepatitis C, West Nile fever, polio and measles.
See Ribonucleases (RNAases)
A rare multisystem inflammatory disorder characterized by chronic inflammatory granulomatous lesions (i.e., granuloma) in the lymph nodes and other organs. These granulomas are made up of epithelioid cells, macrophages, giant cells, fibroblasts and CD4+ T lymphocytes and their
formation occurs in response to immune response to poorly soluble antigen (e.g., mycobacteria or other pathogen) in genetic predisposed individuals. The most commonly affected sites are the lungs, lymphatic system, skin and eyes; the upper respiratory system, liver, bone marrow, spleen among other organs can also be affected.
See Severe Acute Respiratory Syndrome (SARS)
Systemic inflammatory response syndrome (SIRS) accompanied by a confirmed infectious process. See also Sepsis, Severe and Septic Shock and Systemic inflammatory response syndrome (SIRS)
A stage in the continuum of clinical response to infection defined as sepsis associated with organ dysfunction; sepsis associated with hypotension; or sepsis associated with hypoperfusion abnormalities. See also Sepsis and Sepsis, Severe and Systemic Inflammatory Response Syndrome (SIRS)
A condition of clinical shock caused by endotoxin in the blood and characterized by hypoperfusion, multiple organ failure and persistent hypotension in a septic patient. See also Sepsis and Sepsis, Severe
The development of detectable specific antibodies to a virus or other microorganism in the serum as a result of infection or immunization.
A blood test that detects the presence of antibodies to a particular antigen (e.g., rheumatoid factor, HIV test).
The genotype of a unicellular organism that is defined by antisera against antigenic determinants expressed on the surface.
Severe Acute Respiratory Syndrome (SARS)
A respiratory disease of unknown etiology that apparently originated in Guandong, possibly in November 2002, and was first reported at the beginning of 2003 in mainland China in 2003. It is characterized by fever and coughing or difficulty breathing or hypoxia and can be fatal. A novel, previously unknown coronavirus is associated with SARS and has been named "Urbani SARS-associated coronavirus" by WHO.
A research testing parameter in which patients do not know which of several treatments they are receiving, thus preventing personal bias from influencing their reactions and study results.
Single-Nucleotide Polymorphism (SNP)
Single-nucleotide polymorphisms are the most common type of genetic variation. Each SNP represents a difference in a single nucleotide (e.g., a SNP may replace the nucleotide cytosine
- with the nucleotide thymine [T]). SNPs occur approximately once in every 300 nucleotides. They are frequently found in the DNA between genes. SNPs can be used as biomarkers for diseases and may predict response to drugs and environmental factors (i.e., toxins).
See Small interfering RNA (siRNA)
A large family of compounds derived from cholesterol which are structurally similar in that they contain the tetracyclic cyclopenta[a]phenanthrene skeleton. Examples include plant and animal hormones, body constituents and drugs.
Large multinucleated cellular aggregates resulting from fusion of cells.
One of two major classes of lymphocytes that develop in the thymus. T cell lineage markers are the expression of two T cell antigen receptors (TCR-1gammadelta and TCR-2alphabeta). TCR-2+ cells are further classified into two nonoverlapping populations that express the CD4 marker and help or induce immune responses (Th cells) or carry the CD8 marker and are predominately cytotoxic (CTLs). In general, CD4+ and CD8+ T cells recognize specific antigens in association with MHC class II and I molecules, respectively. CD4+ T cells can be further divided into Th0, Th1, Th2 and Th3 cells based on their cytokine production profile.
T Cell Antigen Receptor (TCR)
Cell surface receptor on T cells made up of a disulfide-bridged heterodimer, which recognizes processed antigen associated with an MHC molecule. Several polypeptides that form the CD3 complex associate to the TCR and are involved in TCR expression and signal transduction. Four different gene loci (alpha, beta, gamma and delta) encode the antigen-binding part of the TCR heterodimer and define the two types of TCR: TCR-2alphabeta and TCR-1gammadelta. Only one single type of TCR is expressed on a given T cell. TCR vaccines are under development for the treatment of rheumatoid arthritis.
T Helper Cell (Th)
MHC class II-restricted T cells expressing the CD4 marker. Depending on their cytokine profile, they are divided into Th0, Th1, Th2 and Th3 subsets. Th1 secrete IL-2 and IFN-gamma. Th2 secrete IL-4, IL-5, IL-6, IL-10 and IL-13. Th3 cells produce the immunosuppressor molecule, TGF-beta, and contribute to down-regulating the immune response. Th0 may secrete all of the above cytokines. See also Th0 Cell, Th1 Cell, Th2 Cell and Th3 Cell
T Suppressor Cell (Ts)
A T cell with no unique marker that downregulates function of other T and B cells and antigen presenting cells (APCs). TGF-beta-secreting Th3 cells and/or CTL cells may actually be responsible for this suppressor activity.
A T helper cell population from which Th1, Th2 and Th3 subsets are thought to develop. Th0 cells represent a less differentiated T cell population whose commitment towards Th1, Th2 or Th3 is determined by several factors, including the cytokine environment or the type of APC that activates the cell.
A T helper cell expressing the CD4 marker that produces IFN-gamma and IL-2 and promotes cell-mediated immunity. Th1 cells recognize antigen associated with class II MHC molecules and mediate inflammatory reactions. These cells are effective against intracellular pathogens such as viruses, bacteria and parasites.
A T helper cell expressing the CD4 marker that produces IL-2, IL-4, IL-5, IL-10 and IL-13. These cytokines enhance humoral responses by helping B cells in the production of different classes of immunoglobulins (Igs). Th2 cells are important in eliciting both antibody-mediated cytotoxicity against extracellular parasites and antibody responses against viral proteins.
A T helper cell expressing the CD4 marker and producing TGF-beta that strongly inhibits immune responses by suppressing B and T cell proliferation. These cells may be partly responsible for the activity attributed to T suppressor (Ts) cells.
A condition characterized by a decrease in the number of platelets in the blood. This can result in increased bleeding and decreased clotting.
An actin binding protein. It is an interferon-induced peptide expressed in hematopoietic cells and it regulates actin cytoskeleton by preventing G-actin polymerization. It is involved in cell proliferation, differentiation and motility. It is cleaved into seraspenide which inhibits the entry of hematopoietic pluripotent stem cells into the S-phase.
The ability to endure unusually large doses of a drug or toxin. An acquired drug tolerance is a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response.
Toll-Like Receptor 3 (TLR3)
A member of the toll-like (TLR) receptor family which includes key recognition structures of the innate immune system. When activated TLRs initiate production of inflammatory cytokines, chemokines, tissue destructive enzymes and type I interferons (IFNs). TLR signaling is also involved in activation of the adaptive immune system via upregulation of costimulatory molecules of antigen presenting cells (APCs). TLRs therefore can link innate and acquired immune responses. TLR3 has been shown to be expressed in the brain with significantly increased levels observed in the brains of patient's with Alzheimer's disease (AD). Studies have also shown that TLR3 may mediate the amyloid beta-induced activities of innate immunity in the neurodegenerative processes of AD.
Toll-Like Receptors (TLRs)
A class of single membrane-spanning, non-catalytic receptors that are a type of pattern recognition receptor (PRR). They are the key recognition structures of the innate immune system that recognize molecules shared by pathogens but distinct from host molecules. When activated, they initiate the production of inflammatory cytokines, chemokines, tissue degrading enzymes and type I interferons (IFNs). TLR signaling is also involved in activation of the adaptive immune system via upregulation of costimulatory molecules of antigen presenting cells (APCs). TLRs therefore can link innate and acquired immune responses. TLR signaling is thought to be involved in the pathogenesis of rheumatoid arthritis. Signaling via TLR7 has been shown to markedly induced IFN-alpha which enhances Th1-mediated cellular antiviral and antitumor immunity. TLR7 agonism has been shown to be effective in the treatment of actinic keratosis. TLR3 has been shown to be expressed in the brain with significantly increased levels observed in the brains of patients with Alzheimer's disease (AD). TLR4 is the main receptor for bacterial endotoxin and is a potential target for the treatment of sepsis. It has also been identified as a potential risk factor for asthma.TLR9 agonists have been developed that enhance anthrax vaccines.
The air passage responsible for conveying air to and from the lungs that extends from the larynx into the thorax, where it branches into the right and left main bronchi.
The process by which genes are copied into RNA, resulting in three major RNA types that interact in protein synthesis: messenger RNA (mRNA), ribosomal RNA (rRNA) and transfer RNA (tRNA). See also Ribonucleic Acid (RNA)
Endogenous substances (usually proteins) that bind to the promoter regions of genes and regulate the start, stimulation or termination of the genetic transcription process. Examples include NFkappaB, nuclear factor of activated T cells (NF-AT), activator protein-1 (AP-1), CREB and signal transduction-activated transcription fators (STAT).
Refers to an organism in which gene(s) or DNA from another organism were incorporated via injection into the nucleus of the ovum. The resulting transgenic animal expresses the protein(s) that the new gene(s) encodes.
Protein synthesis resulting from the interaction of mRNA, rRNA and tRNA transcribed in the nucleus. The genetic code or sequence of nucleotides in mRNA is translated into a sequence of amino acids during polypeptide assembly. During translation, ribosomes read along the mRNA molecule, gradually assembling a corresponding amino acid sequence. Nucleotides are read three at a time as codons.
Movement of an organism in response to an external source of stimulus (e.g., toward or away from the stimulus).
Tumor Necrosis Factor (TNF)
A group of cytokines that includes TNF-alpha, released by activated macrophages and lymphocytes, and TNF-beta, released from cytotoxic T lymphocytes (CTLs). The TNF family of receptors are important mediators of cellular immune responses including proliferation, differentiation, apoptosis and cytokine production.
Tumor Necrosis Factor-alpha (TNF-alpha)
TNF-alpha is a proinflammatory cytokine (also known as cachectin) and member of the TNF family of cytokines that is released by activated macrophages and lymphocytes. It acts via receptors belonging to the TNF family of receptors, among which TNF receptor 1 and 2 (TNFR-1, TNFR-2) trigger several signal transduction pathways, resulting in the activation of transcription factors such as NF-kappaB and cFos/cJun. TNFR-1 (also known as CD120a; p55/60) is expressed in most tissues and is fully activated by both the membrane-bound and soluble trimeric forms of TNF. TNFR-2 (also known as CD120b; p75/80), however, is found only in cells of the immune system and is activated by the membrane-bound form of the TNF homotrimer. Activated factors induce the transcription of antiapoptotic, proliferative, immunomodulatory and inflammatory genes. NF-kappaB is the major survival factor in preventing TNF-alpha-induced apoptosis and inhibition of this transcription factor may improve the efficacy of apoptosis-inducing cancer therapies; TNF-alpha-targeted therapies are also being tested in the regional treatment of locally advanced soft tissue sarcomas and metastatic melanomas. In addition, TNF-alpha-induced insulin resistance is believed to be a major contributor to the development of type 2 diabetes in obesity and elevated brain levels of TNF-alpha have been observed in Alzheimer's Disease (AD) and ischemic stroke patients. TNF-alpha is also a crucial cytokine in the establishment and maintenance of inflammation in multiple autoimmune diseases. Studies have reported elevated TNF levels at the site of active MS lesions in postmortem brain samples from patients with MS and CSF and serum TNF levels in individuals with MS are elevated compared to unaffected individuals with TNF levels correlating to the severity of the lesions. In addition, peripheral blood mononuclear cells from MS patients just prior to symptom exacerbation display increased TNF secretion after stimulation as compared to cells from the same patients during remission and inhibition of the TNF-alpha signaling pathway (e.g., TNF-alpha blockers, blockers of p38, JNK and/or ERK kinases, antagonists of transcription factor NF-kappaB activation) is a viable therapeutic strategy for the treatment of Crohn's disease, psoriasis, psoriatic arthritis, uveitis, sarcoidosis, Behcet's syndrome, graft versus host disease and ankylosing spondylitis.
The nucleotide sequences in DNA or RNA that precede the codons specifying the mRNA for transcription or the protein coding sequences for translation. It is also used to describe events that occur early on within sequential reactions. See also Downstream
Any preparation intended for active immunological prophylaxis or therapy. Routes of administration include inoculation, ingestion and nasal spray.
Viral Envelope Proteins
Layers of protein which surround the capsid in animal viruses with tubular nucleocapsids. The envelope consists of an inner layer of lipids and virus-specific proteins also called membrane or matrix proteins. The outer layer consists of one or more types of morphological subunits called peplomers which are glycoproteins and project from the viral envelope.
The expelling of virus particles from the body, one route for which is through the respiratory tract. Virus shedding is an important means of transmission, although evidence of virus shedding does not necessarily equate trasmmissibility.
The presence of viruses or viral particles in the circulation.
A single virus particle that includes the viral coat or envelope.
The disease-producing ability of an infectious organism.
A small infectious particle between 10 and 300 nm in diameter, not visible with a light microscope. Viruses have no cell structure and thus differ from other infectious agents or cells. They have no wall and the genetic material is contained in either DNA or RNA encased within a protein shell or capsid. Some viruses may also have an outer membrane composed of lipoprotein. They are obligate parasites and need to enter a plant or animal cell in order to reproduce. Their RNA or DNA encodes for various proteins which are made by the host cell.
West Nile Virus (WNV)
The flavivirus first discovered in the West Nile area of Uganda and now spreading from tropical and subtropical areas to more temperate regions. WNV is a small, single-stranded RNA virus of approximately 40-50 nm in size and has a host-cell derived lipid envelope enclosing an icosahedral nucleocapsid core of 30-35 nm.
The normal, nonmutated version of a gene. Also the parent strain of a virus, bacteria, mouse, or other laboratory organism that are found in the wild.
Acronym for "Years Lost due to Disability" which is calculated by the number of years lived in a condition multiplied by a disability weight for that condition assigned on a scale from 0 (perfect
health) to 1 (death). YLD = number of incident cases in reference period x disability weight x average duration of condition.
Acronym for "Years of Life Lost" which is calculated by the number of deaths multiplied by the standard life expectancy at the age at which death occurs. YLL = number of deaths + standard life expectancy minus age of death.
An acronym for "Years of potential life lost" which is also known as potential years of life lost (PYLL). YPLL is a statistic that is a measure of premature mortality. It is an estimate of the average years a person would have lived if he or she had not died prematurely and therefore can it indicate the impact of various diseases and other lethal factors on a population.
A disease of animals that may be transmitted to humans.