Immuno - Autoinflammation/Autoimmunity, Hypersensitivity Disorders and Transplantation Flashcards
Familial Mediterranean Fever
- MEFV mutation (monogenic auto inflammatory condition)
- Periodic fevers and serositis
- Abnormal TNFa/IL1 signalling
- Affects pyrin-mamrenostrin complex which controls activation of neutrophils
Rx:
oColchicine - disrupts tubules in neurophils
oAnakinra- IL1-R antagonist
oEntanercept- TNFa inhibitor
Crohn’s
- NOD2/CARD15 mutations (polygenic auto inflammatory disease)
- Affects ability of innate immune system to recognise bacteria = abnormal inflammatory response to microbes
- Risk also affected by: other genes, environment
HLA-B27 Mutations
Ank spon, psoriatic arthritis, behcets. HLA-B27 affects CD8 T cells, Th17 cells, NK cells etc.
RA, Myasthenia Gravis, pernicious anaemia, SLE
Polygenic autoimmune diseases
Risk affected by: HLA associations Mutations in: - PTPN22 -ve T cell regulator - CTLA4 -ve T cell regulator - Dysregulation of T cells → autoimmunity
Goodpastures HLA
DR15
Graves HLA
DR3
SLE HLA
DR3
T1DM HLA
DR3/DR4
Rheumatoid arthritis HLA
DR4
APECED
Central tolerance breakdown - mutation of TF AIRE – usually causes expression of self-antigens in thymus to enable -ve selection of autoreactive T cells
- Autoimmune
- PolyEndocrinopathy - hypoparathyroidism
- Candidiasis
- Ectodermal - skin/nails
- Dystrophy
IPEX
Mutation in FoxP3 – required for T reg cell development
CD25+ FoxP3+ = T reg cell
- Immune dysregulation
- Polyendocrinopathy
- Enteropathy
- X-linked
ALPS
Mutation of Fas pathway (apoptosis)
T cells not killed in thymus → enter periphery untolerised
- Autoimmune
- Lymphoproliferative
- Syndrome
Splenomegaly, lymphadenopathy, autoimmune cytopenia, lymphoma
T1 Hypersensitivity Reactions
IgE and mast cell mediated –> vasodilation, increased permeability and smooth muscle spasm
Sx: angioedema, urticaria, rhino conjunctivitis, wheeze, D&V
Conditions: atopic dermatitis, food allergy, oral allergy syndrome, latex food syndrome (certain foods associated with latex allergy), allergic rhinitis, acute urticaria (50% idiopathic, 50% food/drugs/febile illnesses etc - wheals completely resolve within 6 weeks), anaphylaxis
Anaphylaxis
IgE-mediated mast cell degranulation - peanut, penicillin, stings, latex
Non-IgE-mediated mast cell degranulation: NSAIDs, IV contrast, opioids, exercise.
Rx: elevate legs, adrenaline, chlorphenamine, hydrocortisone
Ix:
Skin prick testing
RAST –> measure levels of IgE in serum against specific antigen. Less sensitive than skin prick.
Component-resolved diagnostics - tests for specific allergen proteins
Challenge test - do in hosp
During an acute ep -mast cell tryptase
Type 2 Hypersensitivity Disorders
Ab mediated
- Haemolytic disease of the newborn
- Autoimmune haemolytic anaemia (+ITP = Evan’s syndrome)
- ITP - abs to glycoprotein IIb/IIIa on platelets
- Goodpastures
- Pemphigus vulgaris
- Graves
- Myasthenia gravis (ACh receptor)
- Acute thematic fever
- Pernicious anaemia
- Wegner’s
- Churg Strauss
- Microscopic polyangitis
- Chronic urticaria (wheals lasting >6 weeks, associated with angioedema in most cases. IgG against FceR1 or IgE)
Type 3 Hypersensitivity Disorders
Immune complex mediated
SLE
Serum sickness
Polyarteritis nodosa - assoc with Hep B
Mixed essential cryoglobulinaemia
SLE - Presentation and Rx
Main intercellular components (e.g. dsDNA).
4 of these 11: serositis, seizures, apthous ulcers, arthritis, photosensitivity, discoid rash, malar rash, haematology, kidney findings, Antinuclear antibody (ANA +ve), immunological findings (anti- dsDNA, anti-sm).
SOAP BRAIN MD: serositis, oral ulcers, arthritis, photosensitivity, blood disorders, renal involvement, ANA+, immunologic (anti-SM, anti-dsDNA), neurologic, molar rash, discoid rash
↓C4 (↓C3 only in SEVERE
disease) Ab’s to dsDNA, Histones (Drug Induced), Ro, La, Sm, U1RNP
↑ESR, normal CRP
(N.B.
Hydralyzine, Procainamide and Isoniazid can cause
Drug induced SLE).
Rx:
Analgesia Steroids and cyclophosphamide
Serum Sickness - Presentation and Rx
Reaction to protein in penicillin. Rashes, Itching, arthralgia, lymphadenopathy, fever and malaise. Symptoms take 7-12 days to develop.
↓C3
Blood shows immune complexes or signs of blood vessel
inflammation.
Rx: Discontinue pen and give steroids, antihistamines and analgesia.
Polyarteritis nodosa
Hep B, Hep C virus Antigens
Fever, fatigue, weakness, arthralgia, skin, nerve and kidney involvement, pericarditis and MI. Associated with Hep
B
Diagnosed by clinical criteria and Biopsy (↑ESR, ↑WCC,
↑CRP)
‘Rosary sign’
Rx: Prednisolone and Cyclophosphamide
Mixed Essential Cryoglobulinaemia
IgM against IgG +/- hepatitis C antigens
Joint pain, splenomegaly, skin, nerve and kidney involvement.
Associated with Hep C.
A mixture of clinical and biopsies
Rx: NSAIDs,
Corticosteroids and plasmaphoresis
Type 4 Hypersensitivity Reactions
Delayed hypersensitivity - T cell mediated
T1DM
MS - demyelinating. CSF shows oligoclonal bands of IgG on electrophoresis
RA (can also be type 3), Rheumatoid factor (85% sensitive), Anti-CCP (95% specific)
Contact dermatitis
Mantoux test
Crohn’s- TH1 mediated NOD2 gene mutation in 30%
Stages of transplant rejection
Recognition
Activation
Effector function
Transplant - HLA Matching
Matching DR, A and B is most important (as they are highly polymorphic) –> 2 of each so there is the potential for up to 6 mismatches
Parent to child - >=3 matches Sibling to sibling: 25% 6 mismatches e.g. 2:2:2MM 50% 3 mismatches 25% 0 mismatches --> 0:0:0MM
Immune reaction to transplant - Recognition stage
HLA
ABO blood antigens
Can be DIRECT: DONOR APC (expresses high levels of MHC and costimulatory molecules) presenting antigen and/or MHC to recipient T cells (Tc and Th response). --> acute rejection mainly by this mechanism.
or INDIRECT:
RECIPIENT APC presenting DONOR antigen to recipient T cells –> i.e. immune system working as it would normally. Mainly chronic rejection (CD8 cells can’t kill the graft cells as they recognise it as self, CD4 mediated - principal mechanism = cytokine production and inflammation).
Immune reaction to transplant - Activation Stage
Activation of antigen-specific lymphocytes; proliferation and maturation of B cells with Ab production
Immune reaction to transplant - Effector Stage
1) Graft infiltration by alloreactive CD4+ cells
2) Cytotoxic T cells – release of toxins to kill target (granzyme), punch holes in target cells (perforin), apoptotic cell death (fas-ligand)
3) Macrophages – phagocytosis, release of proteolytic enzymes, production of cytokines, production of oxygen radicals and nitrogen radicals
4) Abs bind to graft endothelium (HLA peptides)
–> complement activation –> MAC –> cell lysis
OR
Endothelial cell activation –> increase in procoagulant factors –> increased risk of thrombus formation.
Hyperacute Graft Rejection
Mins-hours
Preformed ab –> activates complement
Thrombosis and necrosis
Rx: main prevention - HLA and ABO matching
Acute - Cellular Graft Rejection
Weeks-months
CD4 activating a T4 hypersensitivity reaction
Cellular infiltrate
Rx: T-cell immunosuppression
Acute - Antibody Mediated Graft Rejection
Weeks-months
B-cell activation –> ab attacks vessels/graft endothelium (happens within the capillary space not the interstitium)
Vasculitis and CD4 deficiency
Rx: ab removal (plasmapheresis) and B cell immunosuppression (rituximab)
Chronic Graft Rejection
Months-years
Immune and non-immune mechanism
RFs: multiple acute rejections, HTN, hyperlipidaemia
“Chronic allograft vasculopathy” - Fibrosis, glomerulopathy, vasculopathy (ischaemia), bronchiolitis obliterates (lung)
Rx: minimise organ damage
Graft vs Host Disease
Days-weeks
Donor T cells attacking recipient MHC.
RFs: BM/liver transplant, T cell immunodeficiency, newborns.
FTT, skin rash, GI problems (D&V, bloody stool), liver involvement (jaundice) –> need to biopsy
Prophylaxis: methotrexate/cyclosporine/tacrolimus
Rx: steroids
Check matching of ABO and HLA by
CDC = Complement Dependent Cytotoxicity
FACS = Flow Cytometry
Luminex = like solid phase FACS – can pick up Abs to individual HLAs
Recheck these post transplant to check for the formation of new antibodies.
