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Case immunology
Autoimmunity, hypersensitivity, transplantation
| Term | Definition |
|---|---|
| Common organs for autoimmune diseases | Thyroid (Hashimoto's, Grave's), adrenals, stomach (pernicious anaemia), pancreas (T1 D) |
| Non-organ specific targets for autoimmune diseases | Skin (scleroderma), kidney (SLE), joints (RA) |
| 3 mechanisms of autoimmunity | // hypersensitivity, type II -> Ab, III -> immune complex, IV -> cell-mediated |
| Ab mediated autoimmune diseases | Grave's disease, Hashimoto's thyroiditis, myasthenia gravis, autoAb in serum -> direct role in disease/result of tissue damage |
| Grave's disease | Ab to TSH R -> stimulation -> no feedback inhibition -> unregulated overproduction of thyroid hormones/hyperthyroidism -> Th2 response (little inflammation/lymphocyte infiltration) -> women > men -> goitre |
| Hashimoto's thyroiditis | Ab against thyroid peroxidases/thyroidglobulin/TSH R -> block stimulation -> underproduction of thyroid hormones/hypothyroidism -> Th2 response -> CD4/8 T cells infiltrate thyroid -> women > men -> goitre |
| Myasthenia gravis | Ab against AChR -> diminish NMJ transmission from cholinergic neurons -> block ACh binding/downregulate AChR -> ptosis, diplopia |
| Immune complex mediated autoimmune diseases | SLE/vasculitis, inefficient immune complex removal from RBC CR1 receptor by liver/spleen -> autoimmunity |
| SLE/vasculitis | Immune complex disease -> anti-cytoplasmic/nuclear Ab in kidney/vascular endothelium -> complement depletion -> butterfly/wolf rash on face -> women > men |
| T cell mediated autoimmune diseases | MS, T1D, RA, tissue destruction via CD8 T cells, TNF directs destruction, macrophage recruitment and subsequent bystander killing, Fas ligand apoptosis induction |
| MS | T cell mediated -> brain focused inflammation -> BBB now permeable to leukocytes/blood proteins -> T cells cross (specific for CNS Ag from microglia/DCs) -> inflammatory reaction -> mast cell/component/Ab/cytokine activation -> damage myelin sheath |
| T1 D | T cell mediated -> recognise beta cell specific protein -> attack insulin producing pancreatic beta cells -> low insulin release -> hyperglycaemia -> alter ionic gradients, microvascular damage, neurological damage |
| RA | T cell mediated -> synovial membrane inflammation -> leukocytes migrate into tissues -> autoreactive CD4 T cells activate macrophages -> proinflammatory IL-6/TNF-alpha induce fibroblast MMP/RANK ligand production -> attack cartilage/activate osteoclasts |
| Autoimmune haemolytic anaemia | Ab against Rh blood group -> RBC destruction |
| Goodpasture's syndrome | Ab against collagen type IV -> gomerulonephritis -> attack basement membrane in lungs/kidneys -> lung haemorrhage/kidney failure |
| Mixed essential cryoglobulinemia | Immune complex disease -> Ab against IgG rheumatoid factor -> failure to clear -> systemic vasculitis (IgG insoluble at low temp) |
| Predisposing genetic/environmental factors | >1 MHC HLA allotype -> polymorphic variants in normal population, twin concordance rate -> 20-40% for diabetes/RA, environment contributes 50% T1D susceptibility, MHC/tolerance genes contribute 25% T1D susceptibility |
| Ankylosing spondylitis | Long-term spinal joint inflammation -> autoimmune -> HLA B27 Ag -> aberrant CD8/CD4 T cells -> intervertebral disc ossifies -> marginal syndesmophytes btwn adjoining vertebrae |
| Molecular mimicry | Ab/T cells generated in response to infectious agents cross-react w/ self Ag -> Ab against streptococcal cell wall cross reacts w/ heart tissue -> rheumatic fever |
| Initiation of autoimmune responses | Sequestered Ag release, bypassed T cell tolerance, molecular mimicry |
| Sequestered Ag release | Immunoprivileged sites compromised -> autoimmune sympathetic ophthalmia -> damage to one eye leads to autoimmune attack of contralateral eye |
| Bypassed T cell tolerance | Modifications of proteins -> RA -> protein citrullination by peptidylarginine deiminase -> neoAg generation now recognisable by T cells -> new Ab raised -> autoimmune |
| CTLA4 | Expressed in naive T cell intracellular vesicles -> binds to CD80/86 (B7.1/2) w/ high affinity -> prevents CD28 costimulation -> induce tolerance -> approved for RA treatment |
| Periodontitis | Immune complex formation -> teeth/gum infection w/ gingivitis -> epitope citrullation -> Ab to modified proteins (ACPA - anticitrullinated protein Ab) -> joint inflammation -> bone erosion |
| Organ specific autoimmune treatments | Thyroxine for hypothyroidism, insulin for T1D |
| Immunosuppresive drugs | Steroids -> general immune response dampening -> effective but unwanted side effects w/ long term use Cyclosporin/rapamycin -> inhibit T cell activation |
| Ab autoimmune treatments | Ab against TNFalpha/receptor -> adalimumab -> blocking effect -> anti-inflammatory |
| Type I hypersensitivity mediation | IgE-mediated -> host contacts Ag w/ pre-existing IgE Ab -> mast cell activation via FCepsilonRI receptor cross-linking -> degranulation -> inflammatory mediators/cytokines released -> bronchoconstriction, vasodilation, blood vessel permeability |
| Type I allergens | Pollen, food, drugs, insect products, animal hair -> low MW proteases -> highly soluble (mucus diffusion), stable -> survive dessication, contain peptides -> bind MHC II to prime T cells, low allergen dose -> favours T cell IL-4 release -> Th2 response |
| Systemic anaphylaxis | Extreme type I hypersensitivity -> increased blood vessel permeability -> drop in blood Pa -> anaphylactic shock (fatal) |
| Type I hypersensitivity examples | Asthma, hay fever, local/systemic anaphylaxis |
| Local anaphylaxis | Type I hypersensitivity -> generalised hives/itchiness/swelling of skin, bronchospasm |
| Asthma | Type I hypersensitivity -> chronic airway inflammation (increased Th2 lymphocytes, eosinophils) -> promote further IgE production -> airways occluded by mucus plugs |
| Type II hypersensitivity mediation | IgM/G mediated -> Ab binds to cells/tissue self Ag -> triggers cell clearance by splenic macrophages w/ FcgammaR complement lysis |
| Type II hypersensitivity examples | Hemolytic anaemia, thrombocytopenia, blood transfusion |
| Who can type A individuals donate to? | Plasma contains anti-B Ab, RBCs have A Ag -> can donate to A and AB |
| Who can type B individuals donate to? | Plasma contains anti-A Ab, RBCs have B Ag -> can donate to B and AB |
| Who can type AB individuals donate to? | Plasma doesn't contain Ab, RBCs have A and B Ag -> can donate to AB |
| Who can type O individuals donate to? | Plasma contains anti-A and B Ab, RBCs have no Ag -> can donate to everyone |
| Rhesus reaction | Type II hypersensitivity -> mother rhesus -ve, child is rhesus +ve -> mother produces Ab to rhesus +ve Ag -> 2nd birth some Rh+ cells leak from fetus into maternal circulation at birth -> anti rhesus +ve IgG Ab crosses placenta -> compromise Rh+ baby |
| Rhesus reaction circumvention | Type II hypersensitivity -> mother takes anti-Rh Ab (RhoGam) before giving birth -> mask/eliminate fetal Rh Ag before mother has chance to react, suppress B cell reactivity -> inhibits Fcgamma RIIB cross-linker |
| Type III hypersensitivity mediation | IgM/G mediated -> soluble high [Ag] -> immune complex formation -> reduce solubility -> tissue deposition (vascular endothelium, kidney) -> trigger mast cells -> low affinity FCgammaRIII -> complement activated -> local tissue damage/inflammation |
| Type III hypersensitivity examples | Arthus reaction, farmer's lung, SLE, serum sickness |
| Arthus reaction | Type III hypersensitivity -> skin w/ previous IgG against sensitising Ag -> local vasculitis (IgG immune complex deposition in dermal blood vessels) -> complement activation -> C3/5a production -> activate PMN recruitment/local mast cell degranulation |
| Serum sickness | Type III hypersensitivity -> reaction to non-human animal antiserum -> horse serum treating pneumonia |
| Farmer's lung | Type III hypersensitivity -> inhalation of biological dusts from hay/mold spores -> IgG complexes form in alveoli walls -> fluid/protein/cell accumulation -> slow blood-gas exchange -> compromised lung function |
| Type IV hypersensitivity mediation | T cell mediated -> Th1 cells release cytokines -> IFNgamma -> vascular adhesion molecule expression (ICAM-1/LFA), TNF alpha/beta -> local tissue destruction, IL3/GM-CSF -> stimulate bone marrow stem cell monocyte production |
| Abacavir sensitivity syndrome | Type IV hypersensitivity for individuals w/ HLA-B*5701 allele, normally treats HIV-1 -> binds to Ag binding cleft allowing alternative peptides to bind -> presents as non-self to T cells |
| Contact dermatitis | Type IV hypersensitivity -> cutaneous response to haptens -> form stable complexes w/ host proteins (poison ivy, metal salts, zinc TB injection) -> Th1 CD4 response to Ag -> localised rash |
| Type IV hypersensitivity examples | Abacavir sensitivity syndrome, contact dermatitis, TB lesions |
| Delayed type hypersensitivity | Type IV hypersensitivity -> Th1 cells release cytokines -> recruit macrophages -> tubercular lesions |
| Types of transplantation | Autologous (same person), syngeneic (identical people), allogeneic (other people), xenogeneic (other species) |
| How does body recognise transplanted tissue? | Ab mediated -> recognition of foreign Ag by host Ab T cell mediated -> recognition of foreign MHC (direct recognition), recognition of foreign Ag on self MHC (indirect recognition) |
| Acute graft rejection | Main barrier to allotransplantation -> T cell recognition of transplanted tissue MHC molecules -> not an issue in blood transfusion (RBCs don't carry MHC) -> type IV hypersensitivity -> B cells (Ab -> ADCC complement mediated lysis), CTL, macrophages |
| Direct recognition in acute graft rejection | Direct recognition of donor MHC molecules -> autoreactive cells against donor DC w/ MHC molecule transplanted over -> migrates to lymph node -> activates host T cells |
| Indirect recognition in acute graft rejection | Indirect recognition of minor H Ab/allo-MHC -> host APC processes donor peptides and presents on MHC -> migrate to lymph node and activates host T cells |
| Chronic rejection | Immune response -> inflammatory cell recruitment -> endothelial injury -> compromised organ blood supply -> ischaemia -> loss of function Type III hypersensitivity -> IgG Ab against allogeneic HLA I molecules -> immune complex depositions |
| Sources of stem cells | Peripheral blood enriched by cytokine administration (CD34+ pluripotent stem cells mobilised by GM-CSF), bone marrow, umbilical cord blood |
| Haploidentical transplant | Close relative sharing HLA haplotype selected as donor (parent/sibling) -> host immune system depleted to prevent strong reaction |
| HLA matching importance | Haemopoietic stem cells -> important, kidney/heart -> significant, liver -> no effect |
| HLA haplotypes | 6 polymorphic genes on each haplotype -> series of genes that are inherited -> one from maternal/paternal -> each exhibits different allele -> class I A, B, C -> class II, DR, DP, DQ |
| EAE experiment | Experimental autoimmune encephalitis -> model MS (T cell mediated) -> mice injected w/ myelin basic protein/complete Freund's adjuvant -> MBP specific Th1 CD4+ T cells isolated -> developed EAE -> mice paralysed |
Created by:
vykleung
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