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Year 5 Pathology > Autoimmune and Autoinflammatory diseases > Flashcards

Autoimmune and Autoinflammatory diseases Flashcards

1
Q

Define immunopathology

Define autoimmune and autoinflammatory diseases

A

Damage to the host cause by the immune response

Immunopathology in the absence of infection

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2
Q

What is the difference?

A

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

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3
Q

Monogenic autoinflammatory diseases:
MOA
Examples

A

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

Familial mediterranean fever, TRAPS

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4
Q

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

A

inflammasome complex

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

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

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5
Q

MEFV gene mutation

loss function pyrin-marenostrin on neutrophils

A

Familial mediterranean fever

Monogenic auto-inflammatory disease

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6
Q

Presentation of Familial mediterranean fever

A

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

Chest pain due to pleurisy and pericarditis

Arthritis
Rash (often red)

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7
Q

Tx Familial mediterranean fever

A

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

2nd line: Anakinra or Etanercept

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8
Q

Complications Familial mediterranean fever

A 
AA Amyloidosis
(Inflammation stimulates liver to produce lots of acute phase proteins amyloid A which deposits in kidneys, liver, spleen)
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9
Q

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

A

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

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10
Q

APS1/APECED

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

A

Monogenic autoimmune disease

Leads to abnormality in tolerance

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11
Q

Clinical presentation of APS1/APECED

A

auto-immune diseases

  • Hypoparathyroidism
  • Addisons
  • Hypothyroidism,
  • Diabetes, Vitiligo,
  • Enteropathy
  • Candidiasis infections due to anti-cytokine antibodies (IL-17 and IL-22)
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12
Q

Monogenic AI disease

Abnormalities of regulatory T cells

A

IPEX

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

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13
Q

Clinical presentation of IPEX

A 
Autoimmune diseases - 3 D's (diarrhoea, diabetes, dermatitis) 
	Enteropathy
	Diabetes Mellitus
	Hypothyroidism 
	Dermatitis (eczema)
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14
Q

Monogenic AI disease

Mutations within FAS pathway - >Abnormality of lymphocyte apoptosis

A

ALPS

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15
Q

Clinical presentation of ALPS

A 
High WCC 
large spleen and lymph nodes
double negative (CD4-CD8-) T cells
Auto-immune disease 
commonly auto-immune cytopenias
Lymphoma
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16
Q

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

A

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

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17
Q

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

A

Familial Mediterranean Fever

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18
Q

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

A

Auto-immune lymphoproliferative syndrome (ALPS)

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19
Q

Polygenic Autoinflammatory diseases

Examples

A

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

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

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20
Q

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

A

Crohns disease

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21
Q

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

A

Crohns disease

22
Q

Tx of Crohns disease

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

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

A

Mixed pattern diseases

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

24
Q

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)

A

Anklyosing Spondylitis

25
Q

Clinical presentation of Anklyosing Spondylitis

A

Low back pain and stiffness
Large joint arthritis
Enthesitis
Uveitis

26
Q

Tx of Anklyosing Spondylitis

A 
Non-steroidal anti-inflammatory drugs
Immunosuppression
	Anti-TNF alpha    
	Anti-IL17
	Anti-IL12/23
27
Q

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

A

Examples of Polygenic AI diseases

28
Q

Genetic polymorphisms of

Polygenic AI diseases

A

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

29
Q

Mechanism of AI disease

A

Autoimmune disease involves a loss of self-tolerance of Bc and Tc -> autoreactivity

Auto-antibodies are found

30
Q

Principles of Gel and Coombs

A

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

31
Q

Immediate hypersensitivity which is IgE mediated

A

Type 1

32
Q

Antibody reacts with cellular antigen

A

Type II

33
Q

Antibody reacts with soluble antigen to form an immune complex

A

Type III

34
Q

Delayed type hypersensitivity…T-cell mediated response

A

Type IV

35
Q

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

A

Ig E mediated reactions (Type I)

36
Q

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

A

Antibody driven immune reactions (Type II)

37
Q

Auto-antigen = Noncollagenous domain of basement membrane collagen type IV expressed in lung and kidneys

-> Glomerulonephritis, pulmonary hemorrhage

A

Goodpasture
disease
(Type II hypersensitivity AI disease)

38
Q

Auto-antigen = Epidermal cadherin

-> Blistering of skin

A

Pemphigus vulgaris

Type II hypersensitivity AI disease

39
Q

Auto-antigen = Thyroid stimulating
hormone (TSH) receptor

-> Hyperthyroidism

A

Graves disease

Type II hypersensitivity AI disease

40
Q

Auto-antigen =Acetylcholine receptor

-> Muscle weakness

A

Myaesthenia gravis

Type II hypersensitivity AI disease

41
Q

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

A

Type III

42
Q

Example of type III

Autoantigen = DNA, Histones, RNP

–> Rash, glomerulonephritis, arthritis

A

Systemic lupus erythematosus

43
Q

Example of type III

Autoantigen = Fc region of IgG

–> arthritis

A

Rheumatoid arthritis

44
Q

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

A

Type IV

45
Q

Examples Type IV hypersensitivity reactions

A

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)

46
Q

Which Hypersensitivity type is SLE?

A

Type III

47
Q

Which Hypersensitivity type is Eczema?

A

Type I

48
Q

Which Hypersensitivity type is Goodpasture disease?

A

Type II

49
Q

Which Hypersensitivity type is MS?

A

Type IV

50
Q

Polygenic Autoimmune diseases divided into…

A

organ-specific (e.g. Graves, Hashimotos, PA, MG, Goodpastures, T1DM) or

Organ non-specific (SLE, Sjogrens, systemic sclerosis, Dermato/polymyositis, ANCA vasculitis)

Year 5 Pathology (13 decks)

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