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Y5 Pathology > Imm - Autoinflammatory and Autoimmune Disease 1 > Flashcards

Imm - Autoinflammatory and Autoimmune Disease 1 Flashcards

1
Q

Define immunopathology

A

damage to the host caused by the immune response

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2
Q

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

A

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

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3
Q

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

A

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

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4
Q

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

A

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

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5
Q

Describe the pathogenesis of familial Mediterranean fever

A

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

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6
Q

What are the clinical features of familial Mediterranean fever

A

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

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7
Q

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

A

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

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8
Q

What condition does familial Mediterranean fever increase the risk of

A

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

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9
Q

What conditions are associated with AA amyloidosis

A

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

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10
Q

What is the management for familial Mediterranean fever

A

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

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11
Q

What is IPEX

A

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

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12
Q

How does IPEX present

A

With other autoimmune diseases
Enteropathy
Diabetes mellitus
Dermatitis
Hypothyroidism

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13
Q

What is ALPS

A

Autoimmune lymphoproliferative syndrome (ALPS)

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

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14
Q

What are the clinical features of ALPS

A

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

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15
Q

What is APECED/APS-1

A

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

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16
Q

Which conditions does APECED predispose toward

A

Hypoparathyroidism
Addison’s
Candidiasis
Hypothyroidism
Diabetes
Vitiligo
Enteropathy

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17
Q

Give examples of polygenic autoinflammatory disease

A

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

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18
Q

Which group of immune diseases are not characterised with autoantibodies

A

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

19
Q

What have familial association studies shown about Crohn’s disease

A

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

20
Q

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

A

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

21
Q

What is NOD2

A

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

22
Q

What are the clinical features of Crohn’s disease

A

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

23
Q

What are the treatments for Crohn’s disease

A

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

24
Q

Give examples of mixed pattern immunological diseases

A

Ankylosing spondylitis
Psoriatic arthritis
Behcets syndrome

25
Q

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

A

> 90% → very heritable

26
Q

Which alleles/receptors are associated with ankylosing spondylitis

A

HLA B27 (presents antigen to CD8 T cells) - RR 87

IL23R (receptor for IL23 which promotes Th17 differentiation)

ILR2 (inhibits IL1 activity)

27
Q

What are the clinical features of ankylosing spondylitis

A

Low back pain and stiffness
Enthesitis
Large joint arthritis

28
Q

What is the treatment for ankylosing spondylitis

A

NSAIDs
Immunosuppression (anti-TNFa or antiIL17)

29
Q

Give examples of polygenic autoimmune diseases

A

Rheumatoid arthritis
Myasthenia Gravis
Pernicious anaemia
Addison’s disease

30
Q

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

A

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

31
Q

What is PTPN22 and what is it associated with

A

Protein tyrosine phosphatase non-receptor 22
Suppresses T cell activation

SLE, rheumatoid arthritis, T1DM

32
Q

What is CTLA4 and what is it associated with

A

Cytotoxic T lymphocyte associated protein 4
Transmits inhibitory signals to control T cell activation

Auto-immune thyroid disease
SLE
T1DM

33
Q

What is Gel and Coombs classification

A

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

34
Q

What are Type 1 hypersensitivity reactions

A

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)

35
Q

Which inflammatory mediators are released in type I hypersensitivity reactions

A

Pre-formed → histamine, serotonin, proteases

Synthesised → leukotrienes, prostaglandins, bradykinin, cytokines

36
Q

What are type 2 hypersensitivity reactions

A

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

37
Q

What are the two mechanisms of type 2 hypersensitivity reaction

A
  1. Antibody-dependent destruction (NK cells, phagocytes, complement)
  2. Receptor activation or blockade (may be considered type V response)
38
Q

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

A

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

39
Q

What are type 3 hypersensitivity reactions

A

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:

40
Q

What does damage to vessels in type 3 hypersensitivity reactions cause

A

Cutaneous vasculitis
Glomerulonephritis
Arthritis

41
Q

Which auto-antigens are associated with SLE and rheumatoid arthrits

A

SLE: ds-DNA, histones, RNP

RA: Fc region of IgG

42
Q

What are type 4 hypersensitivity reactions

A

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)

43
Q

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

A

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

Y5 Pathology (71 decks)

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