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Ab Structure & B cells
Mathew - 1 hr
11
Medical
Graduate
04/05/2011

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Term
Heavy and light chains
Definition
Ab are built from 2 H chains, 2 L chains

2 types of L: lambda, kappa

5 types of H: mu, gamma, delta, alpha, epsilon
-give rise to: IgM, IgG, IgD, IgA, IgE

The H & L chains are held together by disulfide bonds & noncovalent interactions
Term
the immunoglobulin domains
Definition
Ig domain consists of 110 AA, 2 cysteine residues which form intrachain disulfide bond

N domain of H & L chains are the "variable" domains, others are "constant"

each L chain has 1 VL and 1 CL

each H chain has 1 VH, CH1, CH2, CH3
Term
Fab and Fc fragments

Proteolytic cleavage:
-papain
-pepsin
Definition
Fab: Two fragments of IgG, contain Ag-binding activity
Fc: readily crystallizable

papain: cleaves IgG -> 2 Fab, Fc
pepsin: IgG -> F(ab')2, several other fragments, largest called pFc'
Term
Hinge region
Definition
Segment of 10-15 AA residues b/t CH1 & CH2

rich in cys & pro residues, allows segmental flexibility so that Ab can bind repetitive antigens simultaneously

found in alpha, gamma, delta chains but absent in mu and epsilon chains
Term
CDRs (Complementarity Determining Regions)
Definition
Hypervariable regions
Wu and Kabat plot: 3 distinct hypervariable regions (HV1, HV2, HV3) are found in the variable domains

CDRs: hypervariable residues form the antigen binding site, interact with Ag on the basis of structural complementarity
-CDR1, CDR2, CDR3
-most variable part is in the HV3 (CDR3) region

flanked by less variable regions: framework regions
-FR1, FR2, FR3, FR4
Term
Compare and contrast the effector functions of major isotypes of immunoglobulins
Definition
IgG
-75% of Ig
-IgG1 (70%): neutralization. opsonization, sensitization for killing by NK cells, complement activation
-IgG2 (20%): neutralization
-IgG3 (8%): neutralization, complement activation, opsonization, NK sensitization
-IgG4 (4%): neutralization
-can cross placenta (passive immunity to newborn)
-*Erythroblastosis fetalis*: hemolytic disease of the newborn, caused by IgG ab (anti-Rh), cross placenta & destroy fetal RBC (mom is Rh-, fetus is Rh+)

IgM
-the first Ab produced in a humoral immune response
-complement activation
-a pentamer, has 10 active antigen binding sites
-each contains a joining piece (J), disulfide-linked to molecule
-activates complement

IgA
-mucosal secretions, colostrum
-IgA1, IgA2
-neutralization
-monomeric & dimeric forms (dimeric has the J chain)
-secretory IgA is bound with "secretory piece" (derived from poly-Ig receptor on epithelial cells), protects dimeric IgA from proteolytic cleavage

IgD
-low serum conc (<1%)
-found on surface of B cells
-fn not well characterized

IgE
-lowest conc in serum
-allergic reactions
-mast cell sensitization
-binds to R on mast cells & basophils, release mediators (eg histamines) upon binding of antigens
Term
Production of monoclonal antibody
Definition
used as treatment (rituximab, herceptin, elotzumab)

B cells are immunized with antigen + myeloma cells -> fusion -> grow, only hybrid cells live -> select for Ag-specific hybridoma -> clone selected hybridoma cells
Term
Describe the generation of diversity in immunoglobulins
Definition
combinatorial diversity: random combo of VJ (L chain) & VDJ (H chain) segments

junctional diversity: intro of additional nucleotides (P & N) at junctions b/t gene segments during recombination
-recombination of V,J,D is imprecise
-i/c by endonuclease cleavage of DNA loops at break point, creates P-nucleotides
-N-nucleotides are added at break point by Tdt

Combinatorial association of H & L chains

somatic hypermutation
-introduces point mutations into the V regions of L & H chains
-occurs after VJ or VDJ joining, cont throughout life of B cell (thus more observed in IgG than IgM)
-B cells that express somatic variants with i/c affinity for antigen are preferentially stimulated to mature into AFC: affinity maturation
Term
Define Immunoglobulin Class switching
Definition
mature B cells express both IgM & IgD at cell surface
-mu and delta mRNAs are made by differential splicing of hnRNA

upon stimulation by antigen, B cells proliferate, cont to differentiate

VDJ joined by another C gene, B cell may switch from expressing IgG to any other isotype (isotype switching)

involves recombination b/t switch regions and the DNA b/t the switch regions are deleted
Term
Immunoglobulins
Definition
Serum glycoproteins - i/c when exposed to antigen or immunogen

expressed on B cells as BCR

secreted by AFC or plasma cells

All are bifunctional
-Fab binds antigen
-Fc involved in effector function
Term
Ag-Ab interactions
Definition
reversible, non-covalent

electrostatic forces, hydrogen bonds, Van der Waals forces, hydrophobic forces

do not involve covalent bonds
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