Immunology B And T Cell

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MHC Restriction

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Need to present a peptide with HLA to TCR. TCR is specific for the peptide and MHC marker. Only detect antigen with self MHC marker

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TCR education

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T cell in thymus are taught to recognize self MHC

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Chromosome location of MHC

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Chromosome 6

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1 Class II region

2 Codes for

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1 DPA,DPB,DQA,DQB,DRA,DRB

2 DPA/DPB=alpha/beta peptide DP marker

DQA/DQB=alpha/beta peptide DQ marker

DRA/DRB=alpha/beta peptide DR marker

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1 Class I region

2 Codes for

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B,C,A

alpha peptide of MHC B,C,A respectively

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MHC Polymorphism

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existence within the population of many alternative forms of MHCI/MHCII. Passed as haplotypes with little cross over. Binding site differences.

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Clinical Significance of MHC Polymorphism

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Organ transplant and allogeneic differences in

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Immunological Significance of MHC Polymorphism

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Binding groove of varies by allotype. Homozygote is more limited and less variable.

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Three components of B cell coreceptor which are invariant

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1 CR2 (CD21) which recognizes C3b on pathogen

2 CD19 which binds to B cell surface signaling

3 CD81 which brings CD19 to surface

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Components of BCR antigen binding site

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Variant Light and Variant Heavy 3CDR

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Ig Diversity

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IGM/IGD function as antigen recognition.

New genes are created for variable domain

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Events in Pro-B cell

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First: DJ recombination of heavy chain gene (Chromosome 14)

Then: V-DJ recombination variable domain gene/heavy chain.

Non productive rearrangement proceed to second chromosome. Then apoptosis or survival. 50% survival rate.

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Events of Pre-B cell

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Transcribe VDJ and mu heavy chain.

2 surrogate light chains. Must have H/L dimerization.

V-J recombination on kappa locus (chromosome 2) with kappa constant regions

Translation of mRNA if productive and combines with mu heavy chain

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Two b cell checkpoints

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First: Select for functional heavy chains

Second: selects for functional light chain

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Allelic exclusion of b cell

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Halt gene rearrangement a second heavy chain at second locus. Only 1 heavy chain per BCR

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Stromal cells

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Located in bone marrow, provide stimulation for B cell maturation via cell adhesion molecules and growth factors (stem cell factor and IL7)

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Recombination Signal Sequence

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Specific base sequences associated with VDJ segments. RSS

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RSS structure

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1. Conserved 7 bp heptamer

2. Unconserved 12/23 bp spacer

3. Conserved 9 bp nonamer

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RSS location

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Downstream (3') of V segment and upstream (5') of J segment

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RSS function

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ensure gene segments are joined in proper order

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12/23 rule

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gene segment with a 12 bp spacer can only combine with a gene segment with 23 bp spacer. This ensures correct gene recombination (V to J in light V to D to J in heavy)

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RAG 1

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Recombination Activating Gene recognizes RSS nonamer. Makes first cut endonuclease

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RAG 2

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Combines with RAG 1 to form RAG complex

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DNA repair proteins

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DNA-PK: phosphates Artemis

Artemis:

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Ku Protein

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A DNA repair protein (heterodimer 70/80) forms ring around both ends of DNA and recruits DNA-PK

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DNA-PK

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A DNA repair protein. DNA dependent protein kinase phosphorylates and activates Artemis

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Artemis

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A DNA repair protein. Nuclease opens hairpin with ss nic

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DNA ligase IV

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A DNA repair protein

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XRCC4

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A DNA repair protein. Scaffolding protein

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IgM and IgD production

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Transcribe VDJ through C-mu and C-deltaalternative RNA splicing 1 gene codes for more than 1 polypeptide. For mu heavy chain: cut off C-delta and receive mature mu chain

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Membrane bound vs secreted

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MC encodes hydrophobic C terminus heavy chain= mu in cell membrane

SC encodes hydrophilic C terminus heavy chain= mu not in cell membrane

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B cell tolerance

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Located in bone marrow. Exposed to self antigen on stromal cell. If there is a reaction, receptor editing must occur until no reaction. This allows continued maturation.

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Receptor editing

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Rescues self reactive B cell and continues RAG proteins sythesis, light chain rearrangement

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Anergy

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Located in bone marrow. Inactivation of self reactive IgM BCR

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Central tolerance

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bone marrow via anergy/clonal deletion

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Peripheral tolerance

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tissues outside bone marrow

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CCL21,CCL19

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Chemokine attractant in stromal and dendritic cells

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BAFF

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B cell Activating Factor. Immature B cell is attracted to dendritic primary follicle by CXCL13 and receives survival signal. Competition to access FDC. Not all make it.