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Variable region on B and T cells
- 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
γδ T cell receptor binds to
intact (unprocessed) antigen INDEPENDENTLY of MHC
αβ T cell receptor binds to
- processed peptides expressed on MHC molecules on antigen presenting cells
- TCR is molecule expressed on cell surface
B cell receptor binds to
- unprocessed (intact) antigens
- BCR is cell surface immunoglobulin plus signal transduction molecules
ab T cell structure
- variable region (aV, bV) binds to antigen, constant region (aC, bC) anchors to membrane and signals
alpha beta T cell gene rearrangement
- 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
gamma delta T cell rearrangement
- fewer genes (less diversity), but
- delta: D, J genes
- gamma: V, D, J genes (like heavy chain B cells and beta T cells)
B cell structure
- 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)
B cell fate with self-molecules
- 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
numbers of variable gene segments
Chicken receptor rearrangement
- all immature B cells have the same heavy and light chain genes
- insert variable pseudogenes through gene conversion to be diverse
pre-immune repertoire of B cell
before meeting antigen (bone marrow, +/- Peyer's patches, bursa of fabricius, appendix
coexpression of IgM and IgD
- 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)
selection in B and T cells
- T cells undergo (in order) positive and negative selection
- B cells undergo negative selection
αβ vs γδ (T cell development)
- 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
Marker of T cells
- CD3 molecule, bookend TCR as part of signal transduction molecule.
T cell selection
- 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
distribution of inflammation
- 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
extent of involvement or severity of inflammation
mild, moderate, severe
duration of inflammation
- 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
acute inflammation signs (path)
- edema, neutrophils (suppurative)
- rubor, tumor, calor, dolor, loss of function
chronic inflammation signs (path)
- non-exudative, proliferative
- recurrent (don't seem to re-start at acute)
- proliferation of vessels and CT
- emigration of leukocytes: lymphocytic, plasmacytic, granulomatous
exudate character (path) of inflammation
- 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)
- mucoid (catarrhal).
- Cause can be infectious vs non-infectious
etiology of inflammation
sometimes not known, describe location (enteritis, pleuropneumonia, blepharitis)
problems with low MHC diversity
- 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
immunogen (and what makes it up)
- antigen that induces immune response
- must be organic, large (more epitopes), complex (whole microbes are more immunogenic than peptides)
antigen presenting cells and why they're important
- T cells only recognize PROCESSED antigens from APCs
- dendritic cells (SUPREME - can activate naieve T cells
- 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)
Major histocompatibility complex I
- 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)
Major histocompatibility complex II
- 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.
T-cell MHC response rules
TCR only engages with appropriate MHC (T4 to MHCII, T8 to MHCI) and presenting correct antigen.