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A small molecule that reacts with a specific antibody but cannot induce the formation of antibodies unless bound to a carrier protein or other large antigenic molecule. |
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An adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect in itself. |
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What cells are involved in eradicating the virally infected cells? |
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KIT (SCF) Development IL-4 (memory) 7 (development) 10 (plasma) Receptors VLA-4 (VCAM-1 Development) ICAM-1 (LFA-1 for Tcell signaling) CCR7 (CCL21 from HEV to LN) BAFF Receptor (Bcell activating factor) CD40R (T-cells) CD40L (Dendritic) |
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B-cell Receptor and co-receptor |
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Ig, Ig alpha, Ig beta, CD19, CR2, CD81 |
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CD4 (Th) CD8 (Tc) CD2, 5 and 44 (Attachment and signaling) IL-7R and Notch-1 Receptor (Signaling Thymocyte --> T-cell) |
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TCR ( Alpha/beta or gamma/delta) 2 zeta chains 2 CD3 Receptors (delta, gamma and 2 epsilon) CD4 and 8 |
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Tcells: CD28 --> B7 (CD80)increases proliferation and CTLA --> B7 decreases B-cells:CD40L (Dendritic) CD40R (Tcell) *this second signal is not required for Tc Cells! |
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Antibody Dependent Cell Mediated Cytotocxicity (ADCC) |
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Definition
ADCC is mediated by the NK cells
When NK cell (loaded with pre-formed cytotoxic granules) encounters the target cell coated with Abs its FcRs interact with Fc portions of the Abs Cross-linking of the FcgammeRs leads to release of the toxins that kill the target cell |
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Cellular Funtion - macrophage activation |
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Humoral Fuction - antibody production, need for ADCC |
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An MHC Class I molecule is composed of one membrane-bound heavy alpha chain and noncovalently bonded beta2 microglobulin
The heavy chain has three extracellular (alpha1, alpha2 & alpha3) domains
1 & 2 domains form the peptide (Ag-derived) binding site |
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An MHC Class II molecule is composed of two membrane-bound chains: a chain and b chain. Each of them have two extracellular domains
a1 & b1 domains form the binding site fro the Ag-derived peptide |
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Alternative C3 Convertase |
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Ab predominate in the blood |
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IgM, IgG, and monomeric IgA |
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IgG transported by FcR of mother |
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The ability of an antigen to elicit immune responses is called immunogenicity, which can be humoral and/or cell-mediated immune responses. |
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Some self-reactive T cells leak the negative selection mechanisms in the thymus & enter peripheral circulation
However, they are not going to be activated because when APCs present self-Ags, they do not express co-stimulatory molecules
Without 2nd signal T cell instead of activation becomes anergic (not responding to Ag) |
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IL-2 is secreted by T cells during their activation & is a major cytokine of the adaptive immunity
Secreted IL-2 is a ligand of IL-2R of the T cells, promoting their proliferation & differentiation
Both signals (through MHC/Ag & TCR and CD28 & B7) are required for expression of IL-2 gene |
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Is costimulation necessary for effector functions? |
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Definition
Effector cells recognize Ag on the target cells & mediate their function without requirement for 2nd signal |
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Outcomes of opsinization through antibody |
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Definition
The opsonization thus promotes phagocytosis of pathogens
Alternative role of opsonization is in the classical pathway of complement activation because Abs bound to the surface of the pathogen cause complement fixation |
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Induce local & systemic inflammatory reactions |
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Lymphocytes’ activation, Production of IL-6 |
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Innate Immunity - viral infections |
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Definition
Extracellular phase Complement system Virolysis Neutralization (Abs-mediated)
Intracellular phase Type I interferon Activation of the NK cells Increases expression of ligands on the infected cells specific to the receptors on the NK cells
Natural killer cells Destroy the virally infected cells |
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Innate Immunity - Bacterial Infectin |
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Definition
Macrophages are the first responders: Phagocytosis Synthesis of cytokines
Stimulating the liver
Chemokines promoting chemotaxis of neutrophils to the center of infection
Growth Factors for bone marrow
Liver Acute-phase proteins Complement system Tagging the pathogen for phagocytosis Lysing the pathogen
Bone marrow More macrophages and neutrophils |
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All reactions are Ag non-specific (just against any molecular structures foreign to the human body)
Remaining major features of the innate immunity are: No increase in response with repeated exposure to a given pathogen (no memory cells) It is nonclonal defense mechanism |
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MHC Class I molecules are assembled in the ER, where they make complexes with antigenic peptides derived from the cytosol
The CD8 receptors bind to MHC I molecules to insure that Tc cells recognize a cytosol-derived Ag |
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MHC Class II molecules are also assembled in the ER (as MHC Class I) but they make complexes with antigenic polypeptides derived from the endocytic vesicles
The CD4 receptors bind to MHC II molecules to insure that TH cells recognize a endocytic vesicles-derived Ag |
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regulate migration (trafficking) of cells (chemotaxis)
Combined with cell-adhesion molecules, the chemokines facilitate the extravasation of leukocytes and homing in the tissues in areas of the immune reaction |
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Interferons were originally so named because they interfere with viral replication
There are two types of the Interferons: Type I (IFN-α & IFN-β), Type II (IFN-gamma)
Mechanisms of action:
Activation of natural killer (NK) cells
Upregulation of the expression of MHC class I molecules (thus increasing the recognition and killing of virus-infected cells) |
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can be produced by ANY infected cell |
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secreted by TH, TC & NK cells |
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The transforming growth factor beta
The overall function of TGF-β is to down-regulate the inflammatory response, it is a negative feedback mechanism ‘switching off’ the inflammation-related reactions of the immune system when they are no longer needed
Mechanism of action:
It suppresses proliferation & differentiation of the immunocompetent & somatic cells
It is involved in regulation of cells apoptosis
Inhibit activation of macrophages |
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Definition
Interleukins (IL-3; IL-5; IL-7) erythropoietin (EPO) Granulocyte CSF (G-CSF) macrophage CSF (M-CSF) Granulocyte-macrophage CSF (GM-CSF) |
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CSFs are produced in the bone marrow in response to inflammatory cytokine IL-1
They promote maturation of the corresponding lineages of hemopoietic cells |
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Interleukin 12 Innate immunity |
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Definition
Innate Immunity: Stimulates production of tumor necrosis factor-alpha (TNF-α)
Mediates enhancement of the cytotoxic activity of NK cells |
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Interleukin 12 Adaptive immunity |
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Definition
Adaptive immunity: It stimulates the production of interferon-gamma (IFN-γ)
Mediates enhancement of the cytotoxic activity of CD8+ TC cells A T cell stimulating factor and growth factor
It promotes differentiation of naive T cells into Th1 cells |
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IL-1 is secreted by monocytes & macrophages, fibroblasts, Dendritic cells and upon activation by many other types of blood cells
Its functions:
An endogenous pyrogen (induces fever)
Induces accumulation of leukocytes to the center of inflammation by regulating chemotaxis:
Promotes the expression of cell-adhesion molecules & chemokines
Activates vascular endothelium
Plays a role in regulation of the hematopoiesis Induces secretion of IL-6 |
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IL-6 is produced by both lymphoid and nonlymphoid cells (T & B cells, monocytes and macrophages, fibroblasts, hepatocytes, keratinocytes, astrocytes, endothelial cells, and various tumor cells)
Secretion of IL-6 is primarily triggered by IL-1
IL-6 is a pleiotropic cytokine, affecting:
Production of the acute phase proteins by liver
Activation of B cells
Promotes B cells differentiation into plasma cells & immunoglobulins (Ab) synthesis
Activation of T cells
Promotes production of cytokines by CD4+ cells |
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Tumor Necrosis Factor (TNF-α) |
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TNF-α is secreted by monocytes, macrophages, neutrophils, NK cells and CD4+ T cells and some tumor cells TNF-α is the major member of the TNF superfamily The main trigger for its production are lipopolysaccharides in gram-negative bacteria TNF-α exists in both membrane-bound and soluble forms TNF-α functions: Causes vasodilation and increased vasopermeability Induces secretion of the cell-adhesion molecules & chemokines Promotes expression of MHC class II molecules Anti-tumor immunity |
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The major cytokines involved in triggering innate immunity reactions are: |
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Interleukin-1 (IL-1)
Tumor necrosis factor-α (TNF-α)
Interleukin-6 (IL-6) |
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Major cytokines mediating Treg cells function are |
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There are several genes encoding MHC proteins with different Ag-binding specificities |
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There are multiple alleles of each gene |
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The diversity of MHC molecules is due to |
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Existence of the gene families, consisting of multiple genes encoding different chains of MHC molecules
Genetic polymorphism, which is presence of multiple alternative forms (alleles) of a gene |
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Neutrophils’ Extravasation 4 steps |
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Step I: rolling of neutrophils along the blood vessel wall is slowing down Step II: neutrophils hold to endothelial cells and stop rolling
Step III: diapedesis (neutrophil squeezes between neighboring endothelial cells & leave the blood vessel)
Step IV: movement into the center of the infection |
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type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family
Its binding with its corresponding receptor induces apoptosis |
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FasR forms the Death-Inducing Signaling Complex (DISC) upon binding with FasL |
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Pathogen-Associated Molecular Patterns
highly conserved among microorganisms, BUT NOT expressed by human tissues
Molecular structure recognized by the innate immune system
A typical PAMP is bacterial DNA |
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PAMPs are recognized by specific Pattern Recognition Receptors (PRRs) |
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opsonins that bind to microbial walls to tag them for degradation by the complement system or by phagocytosis
Mannose-binding lectin (MBL) is secreted by liver as one of acute-phase proteins. It recognizes carbohydrates on bacteria, yeast & some parasites |
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are expressed on the surface of phagocytes and mediate the uptake & transport of the pathogen to lysosomes
Mannose receptors Scavenger receptors NOD1 & NOD2 (proteins with nucleotide-binding domain) |
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expressed on monocytes, macrophages & dendritic cells
alpha and gamma chains, gamma chain mediates function
FcRI can bind to IgG in the absence of Ag *
Once IgG traps an Ag on the surface of monocytes, macrophages & dendritic cells it leads to its uptake and destruction |
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high affinity membrane receptors for Fc portion of IgE |
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In the follicular centers |
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T cell area T cells already differentiated in the thymus |
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antigen presentation iDC recognize specific chemical signatures on the pathogens through pattern recognition receptors (PRRs) such as the toll-like receptors (TLR)
In the process of phagocytizing and degrading the proteins of the pathogens and migrating to the lymph nodes they become mature Ag-presenting DCs (mDC) Upon maturation DCs acquire CD80, CD86 and CD40 receptors (co-stimulatory molecules) important for their function in T Cell activation.
Link between adaptive and innate immunity |
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WBC, granulocyte, which granules are susceptible to staining by base dyes Express receptors for IgE, IgG, complement & histamine (role in allergic reactions) Granules of the basophils contain: Heparin & Peroxidase Prostaglandins & Leukotrienes (factors of anaphylaxis) Platelet activating factor IL-4, cytokine that stimulates the proliferation of activated B-cells IL-5, the growth factor for eosinophils |
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are residents of the connective tissue of bone marrow origin They secrete: Histamine Leukotrienes Different enzymes |
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First class of ab made in immune response |
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Which IgG does not cross placenta easily? |
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IgG not a complment activator |
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digests into 3 segments 2 Fab and one Fc |
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digests into 2 segments F(ab)2 and Fc |
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2 H chains and 2 L chains |
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process of constructing an exon which includes a single version of all variable constituents of each segment (VL & JL for light chain & VH, JH & D for heavy chain) to be transcribed into mRNA
This is the first factor contributing to the ultimate diversity of Abs. |
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recombination signal sequences (RSSs) |
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Definition
The recombination of V, J & D regions of gene segments is directed by recombination signal sequences (RSSs) |
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The set of enzymes that combine V, D & J segments is called V(D)J recombinase & is encoded by recombination-activation genes (RAG-1 & RAG-2) |
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Steps in Somatic Recombination |
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Definition
Step 1: RAG-1 binds to one type of RSS & RAG-2 to another Step 2: Interaction between two RAGs Step 3: Detachment of the formed loop Step 4: Removal of nonfunctional ‘signal joint’ Step 5: Formation of coding joint |
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Definition
The second factor contributing to diversity of the Abs hypervariable regions
addition of nucleotides (that were not encoded in the germline DNA) by the enzymes involved in formation of the coding joint
The added nucleotides are:
P nucleotides
N nucleotides |
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Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene (pre-mRNA) are reconnected in multiple ways during RNA splicing. The resulting different mRNAs are translated into different protein isoforms. |
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After maturation in the bone marrow B cells are released into peripheral blood circulation & before encounter with an Ag
Only IgM & IgD Both these isotypes can be expressed simultaneously on the same cell (an unique feature, characteristic only for naïve B cells) |
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Combinatorial Association |
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Definition
(third*) contribution to the overall diversity of Ig molecules
the association of heavy & light chains, the combinatorial (in different combinations, either , or light chains & either one of 9 heavy chains isotypes with the same Ag specificity) association |
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naive B cells encounter ag |
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Definition
triggers their proliferation (clonal expansion in the secondary lymphoid tissues, mainly in the lymph nodes) & differentiation
Ultimately these processes lead to evolvement of Plasma cells and production of Abs
As the immune response progresses, Abs with different properties are made as a result of:
Somatic hypermutation
Isotype switching |
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Definition
The point mutations (single-nucleotide substitutions) are randomly introduced at a high rate throughout the rearranged V regions (only!) of heavy chain & light chain genes |
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Somatic hypermutation is dependent on the enzyme |
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Definition
activation-induced cytidine deaminase (AID) |
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After somatic hyper mutation
As the adaptive immune response proceeds, Abs of progressively higher affinity are produced |
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Isotype switching occurs only in B cells primed with Ag (proliferating in the response to antigenic stimulus) and, as somatic hypermutation, is dependent on AID enzyme (activation-induced cytidine deaminase)
Occurs by somatic hypermutation |
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B cell development stages |
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Definition
Precursors in BM > - selection> + selection > blood/lymph circulation > priming > activation > Proliferation and differentiation |
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HSC > Lymphoid cell > Pro B > Pre B > Immature > Mature > Activated > IgM secreting > class switching >Memory and Plasma cells |
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Difference is in the lack of Ig light chain, which is replaced by the surrogate light chain made up from the VpreB & 5 polypeptides
Pre-B cell receptor is not expressed on the cell membrane, it remains in the cell’s cytoplasm |
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In a developing B cell, the process of Ig gene rearrangement is tightly controlled that only one heavy chain & one light chain of the same specificity are expressed |
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Pre B cell receptor role in allelic exclusion |
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Definition
Once rearrangement of the first immunoglobulin locus is successful, the synthesis of chain & assembly of the pre-B cell receptor signals:
To stop transcription of RAG genes To degrade the existing RAG proteins To stop further somatic rearrangement in the M heavy chain locus |
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the strength of the reaction between a single antigenic determinant and a single combining site on the antibody |
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a measure of the overall strength of binding of an antigen (by its multiple epitopes) with multivalent antibodies
It is influenced by both the valence of the antibody and the valence of the antigen and is more than the sum of the individual affinities |
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Stromal Cells of the Bone Marrow |
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Definition
provide special microenvironment for B cells maturation. They make direct contact with developing B cells & produce specific growth factors, such as Stem Cell Factor (SCF), IL-7 and some others |
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IL-6, IL-15, 8D6 & BAFF, which induce transformation of B cells into large centroblasts |
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Thymus-Independent (TI-2) Ags |
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Definition
TI-2 Ags are composed of repetitive epitopes expressed on the surface of microorganism at so high density that they cross-link B cell receptors & co-receptors so extensively that there is no need for additional signals |
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