BIEB 152: Week 3 + 4

antibody class

encoded by unique amino acid sequence in the heavy chain constant region (IG)

IGG

most abundant class in serum (opsonization, complement activation, crossing placenta)

IGM

monomer on B cell membrane but forms large pentamer when secreted

IGA

predominant class in external secretions, where pathogens are likely to enter

IGE

involved in hypersensitivity reactions and immune responses to worms, binds to basophils/mast cells and causes them to release granules (allergic reaction)

IGD

role is unknown

Ig-b and Ig-a

initiate intracellular signaling cascade when antigen binds to IGM, cause changes in gene expression and activation of B cell

How is such a huge amount of antibody diversity produced?

germline DNA contains limited number of gene segments, can be combined in unique ways to make unique antibodies

Where is antibody specificity generated?

in bone marrow during B cell production

1.before antigenic stimulation: rearrangement of gene segments

2.after antigenic stimulation: further modifications that refine specificity

junctional flexibility

joining of V and J sequences can be imprecise, influences specificity and increases antibody diversity

combinational association between heavy and light chains

random pairing of an independently rearranged heavy chain with an independently rearranged light chain, increases antibody diversity

allelic exclusion

a given B cell can only express one antibody specificity, does NOT contribute to antibody diversity

allelic exclusion “problem”

B cells are diploid so could in theory express 2 antibody specificities, solution is to randomly silence one of the copies

somatic hypermutation

mutations occur in the VJ and VDJ units, can improve or worsen fit of antibody to its antigen (long interaction and survival or short interaction and death)

affinity maturation

“selection” of the best fitting antibody variants

class switching

a B cell can switch expression to different antibody classes through splicing the transcript RNA

naive B cell

B cell that has not encountered its antigen, dies if not activated and replaced by others with random specificities

clonal expansion divisions

repeated mitosis of an activated B cell that binds its antigen, somatic hypermutation and affinity maturation occur

thymus-dependent (TD) B cell response

requires direct contact with a helper T cell, strong response

-signal 1: antigen binding to B cell receptor

-signal 2: T cell help

thymus-independent (TD) B cell response

does not require contact with helper T cells, weak response and no memory

-signal 1: antigen binding to B cell receptor

-signal 2: cross-linking/interaction between different B cell receptors on membrane

How helper T cells recognize antigens on surface of B cell

B cell produces and exports proteins to the membrane, forms MHC complex for T cell to bind

B cell memory - secondary response

elevated persistence and faster activation of memory B cells

T cell receptor

structurally and functionally similar to B cell antibody

1st type of interaction between T cell and antigen

a CD8+ T cell kills an infected cell

2nd type of interaction between T cell and infected cell

a CD4+ helper T cell activates immune response for antigen presenting cell

genetic organization of MHC complex (HLA complex)

encoded by several genetic loci that are very polymorphic (many allelic variants in a population)

MHC class I

each locus encodes only one gene product

MHC class II

surface protein on APC cells that display exogenous antigens to helper T cells

peptide binding cleft

where antigen binds to MHC

MHC molecules are not …

specific in their binding, binds to a varied group of antigens

MHC I antigen processing

endogenous pathway - infected cell cleaves virus into peptides (proteolysis), TAP actively transports peptides into ER where MHC I is located, exported to cell surface in vesicle

MHC II antigen processing

exogenous pathway - antigen engulfed by phagosome, forms phagolysosome that cleaves peptides, MHC in ER moves to golgi to digest invariant chain, they fuse and travel to surface

functions of invariant chain of MHC II

guides folding of MHC II, prevents binding of MHC II to proteins in ER destined for class I, provides trafficking signal for MHC II

CTL activation process

activated APC ends up with MHC I (cross-presentation), naive CTL binds and turns into dividing activated CTL

costimulatory signals of APC to Helper T cell

B7 to CD28, CD40 to CD40L

effector CTL

fight the virus, lytic = kill infected cell, nonlytic = don’t

perforin-mediated killing (lytic)

perforin molecules on T cell reorganize, they release and puncture infected cell

non-lytic CTL effector activity

CTL releases mediators that bind to infected cell, silence viral genome inside

effector memory cells

do not show effector function but not completely resting, remain at site of infection and can be reactivated

central memory cells

completely resting, not at site of infection, located at secondary organs