immunology wk 2

• BCR - immunoglobulin variable heavy and light chains
• TCR - variable alpha and beta chains
• V(D)J genes (variability, diversity, joining)
• variable region is the part that binds to antigens

intact (unprocessed) antigen INDEPENDENTLY of MHC

• processed peptides expressed on MHC molecules on antigen presenting cells
• TCR is molecule expressed on cell surface

• unprocessed (intact) antigens
• BCR is cell surface immunoglobulin plus signal transduction molecules

• 
• variable region (aV, bV) binds to antigen, constant region (aC, bC) anchors to membrane and signals

• during development in thymus
• a chain variable region has many V and J genes (like light chains in B cells)
• B chain variable region has many V, D, J genes (like gamma T cells and heavy chains in B cells).  
• any alpha can pair with any beta (more diversity)
• recombinase (RAG) binds to DNA around chosen DNA, creates a loop.  DNA-PK (DNA-dependent protein kinase) cuts, discards. enzyme TdT (deoynucleotidyl transferase) adds random nucleotides to sticky ends of hairpin to reconnect (JUNCTIONAL DIVERSITY), extra variability

• fewer genes (less diversity), but
• delta: D, J genes
• gamma: V, D, J genes (like heavy chain B cells and beta T cells)

• 
• 2 heavy chains, two light chains (light chains are shorter than heavy chains, only 1 constant region).  Heavy have 3.  
• Heavy chains have V, D, J genes (like beta T cells and gamma T cells)
• light chains have V, J (like alpha T cells), but in both KAPPA AND LAMBDA families
• Constant is IgM initially (in most species)
• 
• includes signal transduction molecules (Igα and Igβ, two each)

• progenitor cells have 2 chromosomes so 2 alleles (mom and pop)
• tries one, if successful, other allele is not tried or used.  If fails, tries the other.  
• ONLY ONE WILL BE EXPRESSED (only ONE ANTIGENIC SPECIFICITY)

• Negative selection.  If BCR recognizes self (tested in bone marrow)
• 1. apoptosis
• 2. anergic (alive but a vegetable)
• 3. edit variable light chain region (RECEPTOR EDITING) to fix.  Eventually run out of DNA, then apoptosis

• if B cell recognizes self when tested in bone marrow, can try to rearrange variable light chain region to fix.  
• T CELLS DO NOT REARRANGE

species-specific

• all immature B cells have the same heavy and light chain genes
• insert variable pseudogenes through gene conversion to be diverse

before meeting antigen (bone marrow, +/- Peyer's patches, bursa of fabricius, appendix

• ONLY TIME two isotypes are expressed on same (immature B) cell.  Alternative splicing allows binding to delta vs mu chain to make both IgM and IgD.  VARIABLE REGION/ANTIGEN BINDING THE SAME
• used to age cells (more IgM when leaving marrow, more IgD after circulating)

• T cells undergo (in order) positive and negative selection
• B cells undergo negative selection

• produced in bone marrow CD4 and CD8 negative
• move to thymus
• try to develop β chain.  
•         If successful, creates an α and becomes CD4+ and CD8+, then loses one.  
•         If unsuccessful, becomes γδ

• CD3 molecule, bookend TCR as part of signal transduction molecule.
• 

• positive selection (thymic cortex): αβTCR interacts with MHC expressed on thymic epithelial cells.
• Recognize MHC I = CD8
• Recognize MHC II = CD4
• negative selection (thymic medulla): elimination/apoptosis if bind too strongly with self-peptide complex presented by macrophages and dendritic cells
• more selection after encountering antigen in secondary tissues

• gene AIRE is expressed in thymus, allows production and expression of all the proteins in the body
• allows APCs to perform negative selection of T cells on more self-proteins

• VASCULAR, cellular, chemical response to injury meant to destroy, dilute or wall off
• initiation, amplification, repair
• Classification: distribution (organ involvement), extent (severity), duration, exudate, etiology

• focal: single discrete
• multifocal: several lesions separated by normal
• coalescing: lesions grow into each other
• locally extensive: a LOT but not all of an organ
• generalized: multiple lesions distributed throughout whole organ/lobe, often add another word.  Lots of tiny dots are miliary pattern
• diffuse: entire organ affected
• interstitial: in interstitial/CT of organ
• Can also be unilateral/bilateral in paired organs
• symmetrical or asymmetrical
• cortex vs medulla
• specific lobe
• unique anatomic structure based on organ

mild, moderate, severe

• peracute: Exceptionally rapid and severe
• acute: edema, neutrophils, around 48h (could be up to 5 days)
• subacute: 3-4d to 1w, acute inflammation with some signs of early repair, lymphocytes, macrophages
• chronic: FIBROSIS, signs of persistence/repair, fibroblasts and new vessels

• exudative
• edema, neutrophils (suppurative)
• rubor, tumor, calor, dolor, loss of function

• non-exudative, proliferative
• recurrent (don't seem to re-start at acute)
• proliferation of vessels and CT
• emigration of leukocytes: lymphocytic, plasmacytic, granulomatous

• transudates (lear, low protein from starling, sodium or blocked lymph) vs exudates (proteins, leukocytes due to vascular permeability.  
• serous (inflammatory transudate like anaphylaxis)
• fibrinous (fibrinogen leaking, coag contacting collagen and making fibrin, becomes fibrosis in 7 days)
• purulent (suppurative - can be abscess vs cellulitis)
• hemorrhagic
• mucoid (catarrhal).  
• Cause can be infectious vs non-infectious

sometimes not known, describe location (enteritis, pleuropneumonia, blepharitis)

• accept tumors as self ("transmissible allograft").  Non-genetic infectious tumors like canine transmissible venereal tumor and tasmanian devil facial tumor
• This is the danger of the bottleneck--no variety in MHC so all susceptible to same diseases

molecule that can be recognized by a T or B lymphocyte receptor

part of antigen bound by lymphocyte receptor

• antigen that induces immune response
• must be organic, large (more epitopes), complex (whole microbes are more immunogenic than peptides)

• T cells only recognize PROCESSED antigens from APCs
• dendritic cells (SUPREME - can activate naieve T cells
• macrophages
• B lymphocytes (only recognize one antigen)
• Pathogen gets into cell, "processed" or broken down to size, put onto MHC (dimer) for presentation, recognized by appropriate T cell (antigen and MHC both recognized)

• for INTRACELLULAR/endogenous to trigger CD8 T cells
• can be on ANY nucleated cell
• proteosome chops up intracellular antigen, sent to ER by TAP.  Chaperones are helping MHC I fold, bind.  MHC has single transmembrane protein and a beta2 microglobulin.  Once assembled, golgi exocytic vesicle to cell surface.  CD8 recognizes BOTH MHCI and antigen ON APC to activate.  
• Activated T cell = proliferation (clonal expansion) and cytotoxic molecule increase (perforin and granzyme)

• EXTRACELLULAR antigens trigger CD4 helper T cells
• ONLY EXPRESSED ON APC
• Endocytosis (phag, pino, clathrin-mediated).  Processed, peptides loaded into special phagolysosome.  
• MHCII created in ER, alpha and beta segments with transmembrane proteins, "clip" in groove until released, fuses with phagolysosome and exchanges for antigenic peptide.  Traffics to surface.  
• CD4 T cell binds, recognizes both MHC II and antigen (and APC), activates, proliferates, produces cytokines (not cytotoxic) to communicate with other cells

• Viruses often don't infect APC, but only MHCI (INTRACELLULAR) can activate CD8.  
• So Exogenous antigens are taken up by APC, shuttled to cytoplasm and given to MHCI

• encoded in clusters.  Multiple genes that encode for same protein (POLYGENIC), three major loci (so three alleles from each parent, 6 total).  POLYMORPHIC too, multiple alleles that can be inherited at each locus (LOTS of variations in population).
• ALL SIX are expressed (CO-DOMINANCE)

• a series of HLA "genes" (loci-alleles) on the chomosomes, one passed from mother and the other from father.  
• each animal has two complete sets of MHC genes, inherited together as a haplotype

• can bind many peptides but only one at a time
• no discrimination between self and pathogen - gives a snapshot of every peptide
• ANCHOR RESIDUES are specific spots on a peptide that the MHC binds (a specific amino acid in a particular place) - determines which peptides bind to which MHCs.  
• Also T-cell rules.  LOTS of checks and balances.

TCR only engages with appropriate MHC (T4 to MHCII, T8 to MHCI) and presenting correct antigen.