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| Ligand that is expressed on injured endothelial cells. |
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| The TCR contains the alpha and beta chains that bind antigen (some TCR use the gamma and delta TCR chains). The two antigen binding domains are stabilized at the cell surface by the several members of CD3. The antigen-binding chains do not signal directly but bind CD3, which have cytoplasmic domains with ITAM. The CD3 zeta chain contains several ITAM. |
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| Immunoglobulin exists as a transmembrane protein or a soluble molecule. In the former, it binds to Igα an Igß, which functlon like CD3 for the TCR. Ig “monomers” consist of two identical heavy chains and two identical light chains (kappa or lambda), forming the classic “Y” structure with two antigen-binding sites. Secreted Ig is monomeric with two exceptions: IgM is nearly always a pentamer of monomers joined at the tip of their Fc regions by the J chain; IgA is a dimer or trimer of monomers joined by J chain. |
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| The co-receptor on class II MHC-restricted T cells. The external domain binds class II MHC and the cytoplasmic domain binds Lck. When engaging a complex of TCR +MHC, Lck phosphorylates the ITAM of CD3 molecules. |
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| The co-receptor on class I MHC-restricted T cells. The external domain binds class I MHC and the cytoplasmic domain binds Lck. When engaging a complex of TCR +MHC, Lck phosphorylates the ITAM of CD3 molecules. |
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| The two “B7”molecules are encoded by different genes. They are expressed by professional APC (B cells, macrophages and DC) and some other cells. They co-stimulate T cells through CD28 on T cells and inhibit T cells through CTLA-4 on T cells. Immature DC receiving I nnate stranger or danger stimuli up-regulate expression of B7. |
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| CD28 is the receptor on T cells for B7. |
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| CD40 is the costimulatory receptor on B cells and dendritic cells for CD40L on T cells. CD40 is also agonized by complement C4binding protein. CD40 activation co-stimulates and upregulates AID. |
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| LFA-1 consists of the heterodimer CD11a and CD18. Found on T cells and NK cells. Binds to ICAM-1 found on many cells but particularly on HEV of lymph nodes. |
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| This integrin, a heterodimer of CD11 and CD18, is found on macrophages and NK cells and is also known as CR3 (complement receptor 3), with high affinity for iC3b. Macrophages in the spleen use CR3 to steal immune complexes and other proteins containing iC3b from RBC (car wash model), allowing the RBC to return to circulation. iC3b/MAC-1 also opsonizes, removing apoptotic cells. Defects in production of iC3b mean immune complexes are not cleared from circulation, leading to SLE. Defects in clearance of apoptotic cells leads to secondary necrosis and release of intracellular autoantigens such as DNA, chromatin and ribonucleoproteins, and danger signals, helping to drive SLE. |
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| CD11c binds to CD18 to form an integrin characteristic of many dendritic cells and also constituting CR4, a receptor for iC3b and also fibrinogen. |
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| A co-receptor on B cells. Binds CD21 aka Complement receptor 1 (CR2); complement on antigen helps cross-link the BCR to CD19/CD21 enhancing response to antigen. Patients deficient in CD19 have deficient B cell responses. CD19 and CD21 are excellent flow markers on B cells (serving like CD3 for purposes of cell identification). Not expressed on plasma cells. |
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| Another excellent marker for B cells. It is thought to be a calcium channel required for optimal B cell responses. Not expressed on plasma cells. Therapeutic monoclonal antibodies specific for CD20, such as RITUXIMAB are used to treat B lymphomas. |
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| FAS is the receptor for FAS-Ligand. Cross-linking FAS activates apoptosis. FAS is upregulated on activated lymphocytes, including T cells, thus being part of a negative feedback system to prevent run-away activation. FAS is also expressed on liver cells. |
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| IFN gamma is secreted by TH1 cells and NK cells and sometimes by macrophages. IFNgamma maintains the Th1 differentiated state and suppresses Th2 cells; it also upregulates killing activity by CD8 T cells and NK cells, and phagocytosis and killing activity by macrophages. It also upregulates class I MHC expression on most cell types and a variety of innate anti-viral activities in most cell types. The “interferons” are so-named because they interfere with viral replication. IFNy also activates Immunoglobulin class switching to the “cytolytic “human odd IgGs (IgG1 & 3). Hence, IFNgamma can be seen as driving a cytolytic lymphocyte response by T, B and NK cells. |
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| IL2 is secreted by Th1 cells and NK cells and is a growth factor for T cells and B cells. In high concentrations it can induce “promiscuous” killing by CD8 T cells, activate killing by natural killer cells, and overcome T cell anergy. Along with several other important cytokines, it uses the common gamma chain signaling receptor. The high affinity subunit is CD25, upregulated on activated T cells and constitutively expressed on Treg cells. |
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| IL4 is produced by basophils and TH2 cells. In some ways, IL4 produced by basophils may function for Th2 cells as IL12 produced by DC does for Th1 cells: both produced by cells of the myeloid cells. IL4 suppresses TH1 and T17 cells, and activates Ig class switching to the non-cytolytic EVEN human IgG2 & 4 and IgE. Like IL-4, it signals through the common gamma chain. Homozygous loss of the common gamma chain causes SCID (severe combined immunodeficiency) characterized by profound loss of T, B and NK functions. |
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| IL-5 is produced by Th2 cells and mast cells and eosinophils and is important for recruiting and activating eosinophils; thus critical for responses to worms (helminths, etc). It also stimulates Ig production. |
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| IL-6 is produced by many different cell types in response to viral infection and other innate stimuli (danger/stranger signals). IL-6 in the presence of TGFbeta induces T17 cells which are inflammatory T cells important for anti-bacterial responses and some autoimmune diseases including multiple sclerosis. |
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| IL7 is a common gamma chain cytokine found on B cells. It is required for production of CD8 cells in the thymus and maintenance of lymphocytes. IL7 deficiency closely resembles common gamma chain deficiency. |
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| IL-10 is produced by Treg and Th2 cells, macrophages and mast cells. It suppresses IL12 production by DC and Th1 cells. |
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| IL12 is produced by DC in response to innate stimuli and is critical for initiating Th1 lineage commitment and production of IFN gamma. IL12 is also a growth factor for NK cells. |
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| IL17 is produced by “T17” cells, a type of inflammatory T cell. It potentiates Delayed Type Hypersensitivity (DTH) aka type 4 hypersensitivity by activating macrophage in much the same way that IFNgamma does. |
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Term
TGFβ tumor growth
Factor ß |
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Definition
| TGFß is produced by many cell types and is important in a variety of cell differentiation mechanisms in many tissues. TGFbeta is suppressive of T and B cells but with IL6 helps generate T17 cells, and in the absence of IL6 induces Treg cells. TGFß helps drive Ig class switching to IgA. Many “Treg” cells are found in the mucosal immune system where they probably suppress inflammatory T cells but stimulate IgA production. |
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Term
TNFα Tumor necrosis
Factor α |
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Definition
| TNFα is an inflammatory cytokine produced chiefly but not exclusively by activated macrophages and mast cells. It stimulates the acute phase reaction of the liver, endothelial activation and leakiness, and apoptosis in many cell types. |
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| TLR4 is the first described “stranger” receptor. It is expressed on many cell types but especially macrophages and DC. It responds to LPS (bacterial lipopolysaccharide aka endotoxin) and CD14 is a coreceptor for LPS on macrophages. TLR4 binds to many other ligands including saturated lipids (“bad fats”) (and the danger signal HMGB1 released by dying cells and secreted by activated macrophages). TLR4 is expressed at the cell surface and binds extracellular ligands. |
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| TLR9 is located in endosomes with its ligand binding site facing the endosomal lumen where it responds to unmethylated CpG DNA derived from bacteria but also viruses. CpG base pairs are usually methylated in mammalian DNA but are usually NOT methylated in bacteria, so that “naked” CpG is a “microbe-associated molecular pattern”. [FYI only: The basis for the selectivity of TLR9 for non-methylated CpG is actually not known, and might not be an intrinsic property of TLR9]. |
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| C1q is the first discovered member of the complement system and binds to cross-linking IgM, IgG1 and IgG3: triggering C1q thus activates the classical complement pathway. |
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| C5 is activated by C3b (as part of the C5 convertase enzyme) by cleavage to produce C5b and C5a. C5a is an anaphylaxatoxin binding to G-coupled protein receptors on mast cells and macrophages (thus working like a chemokine and opsonin). C5b recruits C6 and the rest of the membrane attack complex (MAC; C6, C7, C8, C9). |
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| C9 is the terminal factor in the complement cascade; a ring of C9 are assembled by C5678 to form a membrane spanning channel, punching a hole in cellular membranes. |
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| Several different receptors for the Fc region of IgG (with highest affinity for IgG1 & 3). IgG has low affinity for FcγR but the affinity increases by cross-linking with antigen. Thus, cells are not usually decorated with “empty” IgG but bind antigen-bound IgG. FcγR on macrophages induces phagocytosis and ADCC. FcγR on NK cells induces ADCC. FcγR on B cells is inhibitory, leading to suppression of antibody secretion. |
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| It binds equivalently to both even and odd human IgGs. It is expressed in the placenta, mammary gland epithelia, mucosal epithelia, and endothelial cells. Is a bidirectional IgG transporter, transcytosing IgG from mother to fetus through the placenta, into the milk, and from the gut to the neonatal blood stream, and from the adult blood stream into the gut. It stores IgG in endothelial cells which acts as buffers or depots for storing and stabilizing IgG, explaining its very long half-life (~23 days; three weeks) compared to other IgG (~1 week in the blood). |
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| FcεR is the very high affinity receptor for IgE on mast cells and eosinophils. It binds with high affinity in the absence of antigen, so that mast cells and eosinophils are always coated with these receptors, despite the fact that IgE is present at very low levels in the blood stream. Cross-linking FcεR induces mast cell and eosinophil degranulation. |
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| RAG (recombination activating gene)mediates VDJ recombination of TCR and BCR in the thymus and bone marrow, respectively. RAG CAN also be re-expressed during the germinal center reaction, permitting receptor editing in peripheral tissues. Patients lacking RAG cannot make either T cells or B cells. |
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Definition
Activation-induced (cytosine) deaminase. An important enzyme for B cell function but with no direct role on T cells. AID is expressed only in germinal centers, not the bone marrow. AID is turned on by activation of CD40, which can be induced by CD40L (very important) and by complement C4 binding protein (a minor role in most of us). AID deaminates cytosines in DNA, creating lesions recognized by DNA repair enzymes. AID has three main functions in immunoglobulin gene modification
1. Random point mutation of the V region of expressed immunoglobulin genes, leading to somatic hypermutation which allows affinity maturation.
2. Concentrated mutation of the switch elements upstream of heavy chain segments initiates switching: deletion of the DNA between activated switch elements and thereby causing class switching.
3. [FYI: Mutation of the V region can also initiate a kind of recombination called gene conversion , through which germline V genes can “donate” their sequences to the expressed immunoglobulin locus, thus working much like RAG-dependent editing radically to change antigen specificity. AID-mediated gene conversion of the type is the preferred mechanism (relative to RAG) for immunoglobulin gene rearrangement in rabbits and camels and the ONLY mechanism in chickens, facts which are admittedly of little use to the healer of humans. Bottom line: DNA deaminaton=>mutation [=>DNA repair =>DNA recombination.] |
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