Immuno 5 - Autoinflammatory and Autoimmune disease Flashcards
Immunopathology in the absence of infection
Innate Immune response
Adaptive immune response
Innate Immune response -> auto-inflammatory
Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage
Adaptive immune response -> auto-immune
Aberrant T and B cell responses in primary (where they are produced) and secondary lymphoid organs (where they encounter an antigen) breaking of tolerance development of immune reactivity towards self-antigens
Classical presentation of monogenic auto-inflammatory diseases
Periodic fevers
Skin/ joint/ serosal/ CNS inflammation
High CRP
FMF gene, protein, inheritance
Monogenic autoinflammatory disease
MEFV gene
Pyrin-Marenostrin protein
AR
Pathogenesis of FMF
MEFV mutation
Inactivation of pyrin-marenostrin
Failure to regulate cryopyrin
Cryopyrin activates apoptosis associated speck like protein (ASC) –> increases expression of procaspase 1
Increased production of IL1, NFkappa B –> TNFa
Apoptosis
What is NFkappaB
TF that regulates expression of genes involved in immunity e.g. TNFa
FMF clinical presentation
3 Ps
o Periodic fevers lasting 48-96 hours, associated with o Abdominal pain (peritonitis) o Chest pain (pleurisy and pericarditis) o Arthritis o Rash
FMF mx
o Clochicine 500ug BD
Binds to tubulin in neutrophils disrupts neutrophil functions incl. migration + chemokine secretion
Baseline treatment
o IL-1 blocker anakinra, canukinumab
o TNFα blocker Etanercept
FMF complication
AA amyloidosis
deposition in kidney most clinically important - nephrotic syndrome (proteinuria) + renal failure
Give 3 examples of monogenic auto-immune diseases
IPEX - immune dysregulation, polyendocrinopathy, enteropath, X-linked syndrome - abnormality of regulatory T cells
ALPS - autoimmune lymphoproliferative syndrome - abnormality of lymphocyte apoptosis
APS1 - APECED - Autoimmune polyendocrine syndrome Type 1 - Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome - abnormality in tolerance
IPEX
Inheritance
Mutation
Effect
Sx
Xliked
foxp3 (forkhead box 3)
TF, required for the development of regulatory T cells
failure to negatively regulate T cell responses –> failure of peripheral T cell tolerance –> Alloreactive B cells –> autoantibody formation
“DM, Diarrhoea (enteropathy), dermatitis (eczema), hypothyroidism”
ALPS
Inheritance
Mutation
Effect
Sx
AD
Mutation in FAS pathway
failure of apoptosis of T cells in thymus –> no central tolerance –> failure of lymphocyte homeostasis
lymphocytosis + lymphadenopathy + lymphoma (double negative cells CD4-, CD8-) + large spleen
Autoimmune diseases
APS1 - APECED
Inheritance
Mutation
Effect
Sx
AR
AIRE (autoimmune regulator) defect - TF involved in the development of T cell tolerance in the thymus - upregulates expression of self-antigens by thymic cells and promotes spoptosis
Defect in AIRE - failure of central tolerance - autoreactive T and B cells
Hypoparathyroidism, Hypothyroidism
Addison’s, Vitiligo
Diabetes, Enteropathy
Antibodies vs IL17, IL22 - candidiasis
Give examples of poly-genic autoinflammatory conditions
o IBD – CD, UC
o Osteoarthritis
o GCA
o Takayasu’s arteritis
Which gene is implicated in CD?
IBD1 gene on Chr 16 identified as NOD2
NOD 2
Gene
Expressed in cytoplasm of myeloid cells – macrophages, neutrophils, dendritic cells
Cytoplasmic microbial sensor recognizes muramyl dipeptide on bacterial products stimulates NFK-beta ( TNFa) promotes clearance of bacterial products
Give examples of mixed pattern diseases
o Axial spondylarthritis - Ankylosing spondylitis
o Psoriatic arthritis
o Behcet’s syndrome
- HLA associations may be present
- Auto-antibodies not usually a feature (having auto-antibodies is usually classified as an autoimmune disease)
o Axial spondyloarthritis - Ankylosing spondylitis HLA associations + Interleukins
HLAB27 - presents antigen to CD8 - ligand for killer immunoglobulin receptor
IL23R - IL23 promotes th17 cell differentiation
ILR2 - inhibits activity of IL1 - reduced TNFa production
o Axial spondyloarthritis - Ankylosing spondylitis treatment
NSAIDs
Anti-TNFa
Anti-IL17
Which of the following is an example of a monogenic auto-inflammatory disease?
Familial Mediterranean fever Graves’ disease Crohn’s disease Axial spondyloarthritis IPEX syndrome due to FoxP3 mutation
Familial Mediterranean fever
Which of the following is an example of a monogenic auto-immune disease?
Familial Mediterranean fever Graves’ disease Crohn’s disease Axial spondyloarthritis IPEX syndrome due to FoxP3 mutation
IPEX syndrome due to FoxP3 mutation
Which of the following is an example of a polygenic auto-inflammatory disease?
Familial Mediterranean fever Graves’ disease Crohn’s disease Axial spondyloarthritis IPEX syndrome due to FoxP3 mutation
Crohn’s disease
