Physiology Flashcards
Complement activation pathways (4) and outcomes of activation
Classical - Ag:Ab complex
Alternative: microbial cell wall proteins bind directly to C3
Lactin: soluble PRR in blood bound to microbial proteins
Amplification: activated by active C3
Results in opsonisation, cell lysis through MAC; Mast cell activation promoting inflammation; angiogenesis; phagocyte chemotaxis; procoagulant activity
Antigen, Epitope and Hapten definition
Antigen = any substance that induces an immune response (toxin, chemical, protein, carb)
Multiple per pathogen/substance
Epitope = Regions on large complex molecule surface that lymphocyte antigen receptors bind to (multiple per antigen)
Hapten = small molecules, normally non-immunogenic, that bind to protein forming new epitope
Primary and secondary lymphoid organs
Primary (sites of lymphocyte development) = thymus, bone marrow, Peyer’s patches
Secondary (where antigen response generated) = tonsils, LNs, Spleen, Peyer’s patches, bone marrow
B cell - surface CD protein, costimulatory cytokines and activation
CD20 +
Activation - free antigen binds to BCR which is internalised and presented on MHC2
If costimulation by Th2 cell with IL 4 and 5 then proceed to proliferate and differentiate to memory B cells and plasma cells
Memory B cells do not need Th cell costimulation at future exposure
Where do T cells mature and how are they activated to different pathways
Initial maturation in thymus where self reactive cells are selected against and undergo apoptosis, also undergo apoptosis if not binding MHC2
In LNs, spleen and BM they are activated by Ag bound to MHC
MHC II (APCs) -> CD4+ T helper cells. APC costimulation results in different type
Any cell presenting Ag with MHC I -> CD8+ T cell
Requires Th1 costimulation with IFN Y and IL 2 to mature into cytotoxic Tcell for viral and intracellular infections
Types of CD4 T cell and how they form
Th1 form in response to IFN y and IL 12 (intracellular pathogen defence). Produce IFN Y and IL 2
Th2 form in response to IL1 and IL6.. Extracellular pathogen defence and B cell activation via IL 4 and 5
Th17 form in response to IL 6 and TGF B. Promote inflammation and innate clearance of extracellular bacterial/fungal infection. Produce IL 17
Treg - form in response to IL 10 and TGF B. Promote immunotolerance and downregulation of inflammation via IL 10 and TGF B.
Suppress APCs
Different Ig classes and their functions
A - produced by B cells near epithelial surfaces, involved in microbial exclusion by binding and preventing adherance mostly. Cannot opsonise.
M - produced first, a large 5xIG complex. Cannot diffuse into tissues as too bid. Strong opsonisation and complement stimulation. Also agglutinates
G - most common. Opsonises and agglutinates pathogens. Can enter tissue when vascular permeability is increased
E - bound to mast cells triggers degranulation when bound. Mostly reactive against helminths.
Central and Peripheral immune tolerance mechanisms
CENTRAL - in BM for B cells
Thymus for Ts
B cells reacting to low doses of self antigen in BM undergo apoptosis
T cells reacting to the large array of self antigens expressed in thymus, or not reacting to MHC2 undergo apoptosis.
PERIPHERAL - LNs, Spleen, BM, Peyers
T cell clonal anergy when exposed to very high antigen dose downregulating NFkB.
Treg cells induce apoptosis if react with TCR or BCR
Antigen sequestration - immune privileged sites, folding of proteins, binding of antigens to proteins, intracellular proteins
B cells require T cell costimulation to activate
Excessive antibodies will negatively feedback by binding to B cell Fc region receptors. (Causes immunosuppression in
MM and maternal Ab)
Very high antigen doses may result in full differentiation of B to plasma cells and no memory cell generation.
Mechanisms of auto immunity - 2 main ways then subcauses
Normal response to unusual antigen:
- Bystander effect: exposure of antigen sequestered in privileged tissue or intracellular due to traumatic damage
- molecular change to self antigen: may be due to change in formation from mutation, binding to another protein/substance (such as with RF generation)
- Inappropriate expression of foetal antigens
Abnormal response to normal antigen
- Impaired Treg response (seen in thymoma induced MG)
- Excessive Th17, 1 or 2 response or reactivity
- Infection induced molecular mimicry (cross reactivity with self proteins) or epitope spread (polyclonal B/T expansion inadvertently results in self reactivity
- Bacterial superantigens: causing polyclonal T cell expansion and increased risk of epitope spread
- Infection stimulation of inflammatory reactions reducing the threshold for Th activation
Genetic causes of increased risk of autoimmunity
Mutations in MHC2 resulting in increased risk of self antigen presentation (seen in Portugese waterdogs)
Gain of function in JAK or STAT pathways
Restricted expression of MHC polymorphism associated with inbreeding.
Reasons Inflammation causes hypercoagulability
- Platelet hyperaggregability (due to endothelial damage)
- Reduced removal of coagulation factors
- anti-coagulant deficiency (antithrombin is an acute phase protein)
- reduced fibrinolysis
Important cytokines
IL1 – acute phase, neutrophil production
IL2 – CD8+ lymphocyte stimulation produced by Th1
IL3 – Myeloid stem cell and mast cell stimulation
IL4 – Th2 stim of B cells
IL5 – Eosinophil and mast cell production in BM, Th2 activation of B cells
IL6 – acute phase; Th17 and B cell differentiation
IL7 – involved in early T cell development
IL8 – neutrophil chemotaxis
IL9 – as IL7
IL10 – induction of Tregs, suppresses Th1 and favours Th2
IL11 - ˄PLTs
IL12- Th1 and NK cell differentiation
Mechanism and example of Type I hypersensitivity reaction
Immediate, IgE mediated reaction
Prior sensitisation has resulted in excessive Th2 stimulus of B cell IgE production (though to be complex genetic predisposition). IgE is bound to mast cell surface and re-exposure to antigen result sin IgE cross-linking and mast cell (eos and baso) degranulation within 10-20mins of exposure.
Release of vasoactive mediators, smooth muscle contraction, increased vascular permeability, proinflammatory
(Histamine, COX, LT, 5HT)
Acute localised reaction - flea allergy dermatitis, asthma GI upset
Systemic reaction - anaphylaxis (hypotension, tachycardia, reduced CO)
Dogs develop pooling of blood in liver due to local vasodilation (GB wall oedema)
Cats more likely to have respiratory signs and URT swelling
Mechanism and example of Type II hypersensitivity reaction
Antibody mediated destruction of target cells, most often IgG.
Ab bind to target cell and cause opsonisation for phagocytosis or NK cell destruction as well as complement mediated destruction by MAC
The cause of most autoimmune diseases: IMHA, ITP, Myaesthenia gravis
Mechanism and example of Type III hypersensitivity reaction
Ag-Ab complex mediated
Generation of excessive Ig following initial sensitisation then sudden exposure to large amount of antigen results in large amounts of complexes depositing in capillary walls. These result in complement activation and innate mediated inflammation.
Causes membranoproliferative glomerulonephritis; IMPA; uveitis
May be linked to viral infections.
Also promote hypercoagulable state through platelet hyperactivity and hyperaggregability.
