Immunology Concepts Flashcards
three phases of autoimmune disease pathogenesis
induction, inflammatory, destructive phases
elimination of auto reactive t cells
when immature t cells encounter a high affinity Ag-MHC complex for their TCR, they are deleted in the thymus or periphery
signal 1
specific recognition of Ag/MCH complex by TCR
Signal 2
co-stimulation via CD28 on T cell with APC CD80/86
T cell inactivation/anergy
occurs when T cells encounter signal 1 without signal 2
inhibitory co-receptor on T cells that binds to CD80/86
CTLA4
how can tolerance be broken?
defective thymic deletion, aberrant help and lack of normal regulation
mechanisms for loss of tolerance
defective apoptosis in thymus, immunization with auto antigen, exposure to cross reactive antigens, lack of normal regulation/supression
Fas mutation
no apoptosis in the thymus=no selection or tolerance induction. clinically: lymphoproliferation, autoantibodies, nephritis, arthritis
how many hyper variable regions do antibodies have?
6
function of hyper variable regions on antibodies?
antigen binding (specificity)
heavy chain antibody rearrangement
VDJ
light chain antibody rearrangement
VJ
how many antibody hyper variable loops does it take to bind an antigen?
just 1
cross reactivity
other antigens may fit the same antibody, either with similar shapes or by binding in a different way (6 hyper variable loops but only 1 needed)
molecular mimicry
when a external antigen looks like an auto antigen. can bypass tolerance.
how do autoantibodies cause cellular damage?
they bind to cell receptors and can either initiate abnormal cell activation or prevent normal ligand binding. or they can form immune complexes when bound to soluble antigens (deposit in vessels, complement activation).
serum sickness
immune complex mediated disease caused by immunization with a foreign protein can elicit
HLA alleles
associated with certain rheumatic diseases
how do MHC molecules bind to peptides?
either by binding the peptide backbone (class 2, plasticity) or through the use of specificity pockets (class 1, semi-specificity). both classes do both.
MHC1 pathway
endogenous. antigen is synthesized within a cell, degraded by ER, and associated with MHC1 on cells surface to be recognized by CD8 T cell
MHC2 pathway
exogenous. endocytosed antigen is degraded by endosome and peptides are associated with HC2 on surface of APC to be recognized by CD4 t cell.
TH2 cell
induced via IL4. secretes IL4. defense against parasitic worms, allergy, asthma
TH1 cell
induced via IL12. secretes IFNgamma. defense against intracellular pathogens
TH17 cell
induced by TGFb & IL6, secretes IL17, defense against extracellular bacteria, AUTOIMMUNITY, cancer
Treg
induced by TGFb, secretes TGFb, immunosuppression
epitope spreading
stems from the ability of a single activated APC to present multiple antigens. normal. additional t cells may become activated when antigens are complexed together.
Autoantigens in RA
T cell immunity to cartilage auto antigens (Type 2 collagen, aggrecan, HC gp39), ubiquitous BiP from the ER, Rheumatoid factor, citrullinated peptide and protein antibodies
rheumatoid factor
IgM anti-IgG. enhances the antigen presentation of immune complexes, may have regulatory role
citrullinated protein/peptide antibodies
bind to synovial lining cells, fibrinogen, collagen type 1. more likely than rheumatoid factor to be pathogenic.
non HLA genes linked to rheumatoid disease
all regulate NO production. their mutations are thought to be a consequence of natural selection against TB. so when we treat patients with anti-TNF therapy, need to be mindful of TB reemergence
environmental triggers of RA (combined with HLA DR allele)
smoking, coffee drinking, oral contraception (oxidative stresses)
how does oxidative stress possibly lead to RA?
results in protein mutation –> increased protein citrullination –> anti-citrullinated protein antibody generation
which antibodies are indicative of lupus?
anti-nuclear antibodies (ANA)
