Autoimmune and Autoinflammatory diseases

Question 1

Define immunopathology

Define autoimmune and autoinflammatory diseases

Answer 1

Damage to the host cause by the immune response

Immunopathology in the absence of infection

Question 2

What is the difference?

Answer 2

Autoinflammatory = abnormal response of innate system (macrophages, neutrophils). Often localised site

Autoimmune = breaking of tolerance in adaptive immune system (B and T cells. May get organ-specific Abs in preclinical period

Question 3

Monogenic autoinflammatory diseases:
MOA
Examples

Answer 3

Single gene mutation -> abnormal cytokine TNF/IL-1 signalling

Familial mediterranean fever, TRAPS

Question 4

Pyrin-Marenostrin -ve regulator and cryopyrin +ve on ASC protein.
ASC -> procaspase 1-> IL-1, NFkappaB, Apoptosis

Answer 4

inflammasome complex

(which is activated by toxins, microbial antigens and urate)

Monogenic autoinflammatory diseases there is loss function pyrin and gain function cryoparin

Question 5

MEFV gene mutation

loss function pyrin-marenostrin on neutrophils

Answer 5

Familial mediterranean fever

Monogenic auto-inflammatory disease

Question 6

Presentation of Familial mediterranean fever

Answer 6

Periodic fevers lasting 48-96 hours
+ ‘-itis’
Abdominal pain due to peritonitis

Chest pain due to pleurisy and pericarditis

Arthritis
Rash (often red)

Question 7

Tx Familial mediterranean fever

Answer 7

Colchicine 500ug bd (binds to tubulin in neutrophils and disrupts neutrophil functions)

2nd line: Anakinra or Etanercept

Question 8

Complications Familial mediterranean fever

Answer 8

AA Amyloidosis
(Inflammation stimulates liver to produce lots of acute phase proteins amyloid A which deposits in kidneys, liver, spleen)

Question 9

Monogenic Autoimmune diseases 3 kinds:
Abnormality in tolerance
Abnormality of regulatory T cells
Abnormality of lymphocyte apoptosis

Answer 9

Abnormality in tolerance = APS1/APECED, due to defect in AIRE

Abnormality of regulatory T cells = IPEX due to Foxp3 mutation

Abnormality of lymphocyte apoptosis
= ALPS due to defect in death pathway of lymphocytes

Question 10

APS1/APECED

Defect in AIRE transcription factor leads to failure of central tolerance and -> Autoreactive T and B cells

Answer 10

Monogenic autoimmune disease

Leads to abnormality in tolerance

Question 11

Clinical presentation of APS1/APECED

Answer 11

auto-immune diseases

• Hypoparathyroidism
• Addisons
• Hypothyroidism,
• Diabetes, Vitiligo,
• Enteropathy
• Candidiasis infections due to anti-cytokine antibodies (IL-17 and IL-22)

Question 12

Monogenic AI disease

Abnormalities of regulatory T cells

Answer 12

IPEX

Mutations in Foxp3 ->
Failure to negatively regulate T cell responses + Autoantibody formation

Question 13

Clinical presentation of IPEX

Answer 13

Autoimmune diseases - 3 D's (diarrhoea, diabetes, dermatitis) 
	Enteropathy
	Diabetes Mellitus
	Hypothyroidism 
	Dermatitis (eczema)

Question 14

Monogenic AI disease

Mutations within FAS pathway - >Abnormality of lymphocyte apoptosis

Answer 14

ALPS

Question 15

Clinical presentation of ALPS

Answer 15

High WCC 
large spleen and lymph nodes
double negative (CD4-CD8-) T cells
Auto-immune disease 
commonly auto-immune cytopenias
Lymphoma

Question 16

Single gene mutation involving FOXp3 resulting in abnormality of T reg cells

Answer 16

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X linked)

Question 17

Single gene mutation involving MEFV and affecting the inflammasome complex, resulting in recurrent episodes of serositis

Answer 17

Familial Mediterranean Fever

Question 18

Mutation within the Fas pathway associated with lymphocytosis, lymphomas and auto-immune cytopenias

Answer 18

Auto-immune lymphoproliferative syndrome (ALPS)

Question 19

Polygenic Autoinflammatory diseases

Examples

Answer 19

Crohns, UC, osteoarthritis, giant cell arteritis, Takayasu’s arteritis

Local factors at sites predisposed to disease
Weak HLA associations
No auto-antibodies

Question 20

Polygenic Autoinflammatory diseases

RF: NOD2 gene mutations are present in 30% patients/CARD15 mutation
Also Other genetic influences/Environmental factors
-> crypt inflammation, granulomatas, tissue damage, mucosal ulceration

Answer 20

Crohns disease

Question 21

Abdominal pain and tenderness
Diarrhoea (blood, pus, mucous)
Fevers, malaise

Answer 21

Crohns disease

Question 22

Tx of Crohns disease

Answer 22

• Corticosteroid
• Azathioprine
• Anti-TNF alpha antibody
• Anti-IL12/23 antibody

Question 23

Mutations in genes encoding proteins involved innate and adaptive immune cell
HLA associations may be present
Auto-antibodies are not usually a featur

Answer 23

Mixed pattern diseases

E.g. ankylosing spondylitis, psoriatic arthritis, Behcet’s syndrome

Question 24

Enhanced inflammation occurs where there are high tensile forces
(entheses - sites of insertions of ligaments or tendons) e.g. affects sacroiliac joints

Heritability >90%
HLA B27
(Accounts for <50%overall genetic risk)

Answer 24

Anklyosing Spondylitis

Question 25

Clinical presentation of Anklyosing Spondylitis

Answer 25

Low back pain and stiffness Large joint arthritis Enthesitis Uveitis

Question 26

Tx of Anklyosing Spondylitis

Answer 26

``` Non-steroidal anti-inflammatory drugs Immunosuppression Anti-TNF alpha Anti-IL17 Anti-IL12/23 ```

Question 27

Rheumatoid arthritis, Myaesthenia Gravis, Pernicious anaemia, Addison disease, Systemic lupus erythematosus, Primary biliary cirrhosis

Answer 27

Examples of Polygenic AI diseases

Question 28

Genetic polymorphisms of | Polygenic AI diseases

Answer 28

HLA (HLA presentation of antigen is required for development of T cell and T cell-dependent B cell responses) HLA -DR3/DR4 - Type I diabetes HLA-DR4 - Rheumatoid arthritis

Question 29

Mechanism of AI disease

Answer 29

Autoimmune disease involves a loss of self-tolerance of Bc and Tc -> autoreactivity Auto-antibodies are found

Question 30

Principles of Gel and Coombs

Answer 30

What is actually causing the polygenic autoimmune disease? (want to separate cause from genetic mechanism driving it e.g. HLA mutation)

Question 31

Immediate hypersensitivity which is IgE mediated

Answer 31

Type 1

Question 32

Antibody reacts with cellular antigen

Answer 32

Type II

Question 33

Antibody reacts with soluble antigen to form an immune complex

Answer 33

Type III

Question 34

Delayed type hypersensitivity…T-cell mediated response

Answer 34

Type IV

Question 35

ALLERGIC REACTION Allergen binds to Pre-existing Ig E Ab -> Ig E bound to Fc epsilon receptors on mast cells and basophils -> mast Cell degranulation Release of inflammatory mediators: Histamine, serotonin, proteases Leukotrienes, prostaglandins, bradykinin, cytokines are Synthesised -> Increased vascular permeability,Leukocyte chemotaxis, Smooth muscle contraction

Answer 35

Ig E mediated reactions (Type I)

Question 36

Antibody binds to cell-associated antigen -> antibody dependent destruction (through complement, NK cells and phagocytes) all leading to cell damage OR autoantibodies blocking/activating receptors

Answer 36

Antibody driven immune reactions (Type II)

Question 37

Auto-antigen = Noncollagenous domain of basement membrane collagen type IV expressed in lung and kidneys -> Glomerulonephritis, pulmonary hemorrhage

Answer 37

Goodpasture disease (Type II hypersensitivity AI disease)

Question 38

Auto-antigen = Epidermal cadherin -> Blistering of skin

Answer 38

Pemphigus vulgaris | Type II hypersensitivity AI disease

Question 39

Auto-antigen = Thyroid stimulating hormone (TSH) receptor -> Hyperthyroidism

Answer 39

Graves disease | Type II hypersensitivity AI disease

Question 40

Auto-antigen =Acetylcholine receptor -> Muscle weakness

Answer 40

Myaesthenia gravis | Type II hypersensitivity AI disease

Question 41

hypersensitivity reactions where antibodies bind to soluble antigen and deposit in blood vessels in the kidneys, joints and skin Fc region of antibodies can activate complement cascade, macrophages, neutrophils -> cell damage

Answer 41

Type III

Question 42

Example of type III Autoantigen = DNA, Histones, RNP --> Rash, glomerulonephritis, arthritis

Answer 42

Systemic lupus erythematosus

Question 43

Example of type III Autoantigen = Fc region of IgG --> arthritis

Answer 43

Rheumatoid arthritis

Question 44

Hypersensitivity reaction - autoimmunity with CD8 Tcells (HLA I present self-peptides to CD8Tc and activate them

Answer 44

Type IV

Question 45

Examples Type IV hypersensitivity reactions

Answer 45

Insulin dependent diabetes mellitus (autoaAg = Pancreatic b-cell antigen -> b-cell destruction: CD8+ T-cells) RA (Auto-Ag = unknown, but -> joint inflammation + destruction) MS (Auto Ag = Myelin basic protein -> Brain infiltration by CD4 Yc)

Question 46

Which Hypersensitivity type is SLE?

Answer 46

Type III

Question 47

Which Hypersensitivity type is Eczema?

Answer 47

Type I

Question 48

Which Hypersensitivity type is Goodpasture disease?

Answer 48

Type II

Question 49

Which Hypersensitivity type is MS?

Answer 49

Type IV

Question 50

Polygenic Autoimmune diseases divided into...

Answer 50

organ-specific (e.g. Graves, Hashimotos, PA, MG, Goodpastures, T1DM) or Organ non-specific (SLE, Sjogrens, systemic sclerosis, Dermato/polymyositis, ANCA vasculitis)