Imm - Autoinflammatory and Autoimmune Disease 1

Question 1

Define immunopathology

Answer 1

damage to the host caused by the immune response

Question 2

What are the similarities and differences between auto-inflammatory and auto-immunity

Answer 2

Both are immunopathology in the absence of infection

Auto-inflammatory = abnormality in the innate immune system (macrophages, neutrophils)

Auto-immune = abnormality in the adaptive immune system (aberrant T and B cell response) where they may be a breaking of tolerance → immune reactivity toward self-antigens

Question 3

How does genetics contribute to auto-inflammatory or auto-immune diseases

Answer 3

Most are polygenic, but may also be monogenic

Genetics: mutation in DNA (germline or somatic)
Epigenetics: heritable changes in gene expression e.g. via methylation
MicroRNA: small, non-coding, ssRNA that targets mRNA and regulates protein production

Question 4

Give examples of monogenic immunological disease and state whether they are auto-inflammatory or auto-immune

Answer 4

Familial mediterranean fever (auto-inflammatory)
APECED/APS-1 (auto-immune)
IPEX (auto-immune)
ALPS (auto-immune)

Question 5

Describe the pathogenesis of familial Mediterranean fever

Answer 5

Autosomal recessive
Mutation in the MEFV gene → pyrin-marenostrin inactivated (normally expressed in neutrophils) → increased pro-caspase 1 → increased inflammation → lots of neutrophils

Characterised by IL-1, (NF-kappa-B) TNFa, apoptosis

Question 6

What are the clinical features of familial Mediterranean fever

Answer 6

Periodic fevers lasting 48-96 hours
Abdominal pain (peritonitis)
Chest pain (pleurisy and pericarditis)
Arthritis
Rash

Question 7

What investigations should be done for familial Mediterranean fever and what would they show

Answer 7

CRP: high
Serum amyloid A (SAA): high
Blood sample testing for MEVF mutations

Question 8

What condition does familial Mediterranean fever increase the risk of

Answer 8

AA amyloidosis
Liver produces serum amyloid A as an acute phase protein → deposits in kidneys, liver, spleen
Kidney deposition → proteinuria (nephrotic syndrome), renal failure

Question 9

What conditions are associated with AA amyloidosis

Answer 9

Autoimmune diseases – rheumatoid arthritis, ankylosing spondylitis, IBD (CD & UC)
Autoinflammatory diseases – familial Mediterranean fever(FMF), Muckle–Wells syndrome(MWS)
Chronic infections – TB, bronchiectasis, chronic osteomyelitis
Cancer – Hodgkin’s lymphoma, Renal cell carcinoma
Chronic foreign body reaction
HIV/AIDS

Question 10

What is the management for familial Mediterranean fever

Answer 10

Colchicine (binds to tubulin in neutrophils → disrupts function + secretion)
IL-1 and TNFa inhibitors (Anakinra, Etanercept respectively)

Question 11

What is IPEX

Answer 11

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)

Mutation in FOXP3 (required for T-reg cell development) → abnormality in T-reg cells
Failure to negatively regulate T cell reponse → auto-reactive B cells → autoantibody formation

Question 12

How does IPEX present

Answer 12

With other autoimmune diseases
Enteropathy
Diabetes mellitus
Dermatitis
Hypothyroidism

Question 13

What is ALPS

Answer 13

Autoimmune lymphoproliferative syndrome (ALPS)

Mutation in FAS pathway (e.g. TNFRSF6 mutation) → Abnormality of lymphocyte apoptosis (failure of tolerance + lymphocyte homeostasis)

Question 14

What are the clinical features of ALPS

Answer 14

Lymphocytosis + large spleen + lymph nodes
Autoimmune diseases (i.e. autoimmune cytopenias)
Lymphoma

Question 15

What is APECED/APS-1

Answer 15

Autoimmune-polyendocrine syndrome type 1 (APS1) or Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED)

Autosomal recessive
Defect in autoimmune regulator AIRE (transcription factor involved in thymus T-cell tolerance) → failure of central tolerance → autoreactive T and B cells

Question 16

Which conditions does APECED predispose toward

Answer 16

Hypoparathyroidism
Addison’s
Candidiasis
Hypothyroidism
Diabetes
Vitiligo
Enteropathy

Question 17

Give examples of polygenic autoinflammatory disease

Answer 17

Crohn’s disease
ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takyasu’s arthritis

Question 18

Which group of immune diseases are not characterised with autoantibodies

Answer 18

Polygenic auto-inflammatory (innate immune system) and mixed pattern disease

Question 19

What have familial association studies shown about Crohn’s disease

Answer 19

> 200 polymorphisms
Monozygotic twins: 50%
Dizygotic twins: 10%

Question 20

What is the most significant gene mutation associated with Crohn’s disease

Answer 20

IBD1 gene on Chr16 (NOD16/CARD-15)
3 different mutations of this gene are associated
NOD2 mutations are present in 30% of patients (but is not necessary)
Increased risk if 2 copies instead of 1
Also found in Blau syndrome and sarcoidosis

Question 21

What is NOD2

Answer 21

Cytoplasmic microbial sensor (expressed in the cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells)
Recognises muramyl dipeptide → stimulates NFK-beta
Activation induces autophagy in dendritic cells

Question 22

What are the clinical features of Crohn’s disease

Answer 22

Abdominal pain, tenderness
Diarrhoea – blood, pus, mucus
Fevers and malaise

Question 23

What are the treatments for Crohn’s disease

Answer 23

1) Diet-induced remission (80-100% works; whole protein modular diet)
- Corticosteroid
- Anti-TNF-a antibody
2) Maintain remission with aminosalicylates (i.e. mesalazine)

Question 24

Give examples of mixed pattern immunological diseases

Answer 24

Ankylosing spondylitis
Psoriatic arthritis
Behcets syndrome

Question 25

In what proportion of people with ankylosing spondylitis are genetic polymorphisms found

Answer 25

>90% → very heritable

Question 26

Which alleles/receptors are associated with ankylosing spondylitis

Answer 26

HLA B27 (presents antigen to CD8 T cells) - RR 87 IL23R (receptor for IL23 which promotes Th17 differentiation) ILR2 (inhibits IL1 activity)

Question 27

What are the clinical features of ankylosing spondylitis

Answer 27

Low back pain and stiffness Enthesitis Large joint arthritis

Question 28

What is the treatment for ankylosing spondylitis

Answer 28

NSAIDs Immunosuppression (anti-TNFa or antiIL17)

Question 29

Give examples of polygenic autoimmune diseases

Answer 29

Rheumatoid arthritis Myasthenia Gravis Pernicious anaemia Addison's disease

Question 30

What are the HLA associations for the following: Goodpasture's disease, Grave's disease, SLE, T1DM, Rheumatoid arthritis

Answer 30

Goodpasture's: HLA-DR15 (RR 10) Grave's: HLA-DR3 (4) SLE: HLA-DR3 (6) T1DM: HLA-DR3/4 (25) RA: HLA-DR4 (4)

Question 31

What is PTPN22 and what is it associated with

Answer 31

Protein tyrosine phosphatase non-receptor 22 Suppresses T cell activation SLE, rheumatoid arthritis, T1DM

Question 32

What is CTLA4 and what is it associated with

Answer 32

Cytotoxic T lymphocyte associated protein 4 Transmits inhibitory signals to control T cell activation Auto-immune thyroid disease SLE T1DM

Question 33

What is Gel and Coombs classification

Answer 33

Classifies Hypersensitivity reactions according to type of immune response Antibody or T cell mediated

Question 34

What are Type 1 hypersensitivity reactions

Answer 34

Rapid allergic reaction e.g. anaphylaxis, atopic asthma Involves pre-existing IgE → binds to Fc R on mast cells and basophils → cell degranulation Increased vascular permeability, leukocyte chemotaxis and SM contraction Usually pollens, drugs, food, insect, animal hair (or self-antigens with eczema)

Question 35

Which inflammatory mediators are released in type I hypersensitivity reactions

Answer 35

Pre-formed → histamine, serotonin, proteases Synthesised → leukotrienes, prostaglandins, bradykinin, cytokines

Question 36

What are type 2 hypersensitivity reactions

Answer 36

Antibody reacts with cells with displayed complement (cellular antigen) → destruction OR activation/blockage e.g. Goodpasture's disease, Grave's disease

Question 37

What are the two mechanisms of type 2 hypersensitivity reaction

Answer 37

1. Antibody-dependent destruction (NK cells, phagocytes, complement) 2. Receptor activation or blockade (may be considered type V response)

Question 38

Which auto-antibody is associated with the following: Goodpasture's disease, Pemphigus vulgaris, Graves disease, Myasthenia Gravis, membranous glomerulonephritis

Answer 38

Goodpasture's: non-collagenous domain of the basement membrane collagen type IV Pemphigus vulgaris: epidermal cadherin Grave's: TSH Myasthenia Gravis: acetylcholine receptor Membranous glomerulonephritis: Phospholipase A2-receptor Type M

Question 39

What are type 3 hypersensitivity reactions

Answer 39

Immune complex hypersensitivity, involving deposition of antigen/antibody complexes in tissue e.g. SLE, serum sickness Antibody binds to soluble antigen → immune complex → immune complex deposits in blood vessels:

Question 40

What does damage to vessels in type 3 hypersensitivity reactions cause

Answer 40

Cutaneous vasculitis Glomerulonephritis Arthritis

Question 41

Which auto-antigens are associated with SLE and rheumatoid arthrits

Answer 41

SLE: ds-DNA, histones, RNP RA: Fc region of IgG

Question 42

What are type 4 hypersensitivity reactions

Answer 42

Delayed type hypersensitivity involving T-cell responses HLA-class 1: Self-antigens to CD8 T cells → cell lysis HLA-class 2: self-antigens to CD4 T cells → cytokine production → inflammation and tissue damage (activated macrophages to produce TNF-alpha)

Question 43

Which autoantigens are associated with the following: T1DM, rheumatoid arthritis, multiple sclerosis

Answer 43

T1DM: pancreatic B-cell antigen Rheumatoid: unknown synovial joint antigen Multiple sclerosis: myelin basic protein