PHRD5015 Lecture 16 (Ju) - Regulation of the Immune System

Ab specificity and diversity

constant region (Fc)

variable region (Fab)

disulfide bonds

• complementary-determining region
• location of Ag binding 
• determines specificity

• 2 heavy chains, 2 light chains
• variable (V) domain located at N-terminus

affinity between antigenic determinant/epitope & Ab

• Ag tells the immune system to make Ab of appropriate conformation 
• ("tailor made dress")

• each cell of immune system is programmed to make only 1 Ab - entire population preexists before Ag contact
• choice of which Ab to make is RANDOM
• ("store bought dress")

• 1) multiple germ line V genes
• 2) V-J & V-D-J recombination
• 3) combinatorial diversity (recombinational inaccuracies)
• 4) somatic point mutation
• 5) pairing of heavy & light chains

V-J-C

ONE

V-D-J-C

RAG recombination enzyme

VDJ joins are sloppy, with some nucleotides lost/added (by TdT) at random without a template -> increased diversity

• terminal deoxynucleotide transferase
• replaces lost nucleotides during VDJ recombination

all nucleated cells

• B cells
• APCs (DCs)
• macrophages

CD8⁺ cells (CTLs)

CD4⁺ cells (Th1 & Th2)

•  and  chains are folded to form a groove
• groove base is a beta sheet, and sides are 2 alpha helices
• Ag peptide is in groove & presented to T cells

• 1) not recognize or bind too tightly to self 
• 2) recognize Ag-selfMHC complex
• 3) not recognize free Ag

cells are eliminated through apoptosis if they recognize self peptides with too high affinity or don't recognize self MHC at all

thymus

• selection of T cells with low (but real) affinity for self MHC
• low affinity for self may = high affinity for self+Ag

• 1) negative selection
• 2) rescue from programmed cell death
• 3) lineage determination (based on low affinity to specific MHC class)

• 1) anergy
• 2) activation-induced cell death
• 3) suppression by regulatory T cells

B7 on APC binds to CD28 on T cell

• incomplete activation
• absence of sensitivity to substances that would normally elicit an antigenic response

• 1) lack of costimulatory molecule
• 2) inhibition of/competition with costimulatory molecule for B7 binding

• cytotoxic T lymphocyte associated molecule
• competes with CD38 for binding to B7 -> T cell anergy/suppression of activation

TLR binding activates NF-B pathway -> costimulatory molecules expressed

activation-induced T cell death

Fas & FasL

• 1) IL-10
• 2) TGF-

• 1) acts as an IL-2 "sink"
• 2) secrete IL-10 & TGF