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Year 5 Path Immunology > Autoimmune and Autoinflammatory diseases > Flashcards

Autoimmune and Autoinflammatory diseases Flashcards

1
Q

What is an auto-inflammatory diseae?

A

Activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage

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2
Q

What is an auto-immune disease?

A

(Activation of adaptive immune-response against self)

Activation of aberrant T cell and B cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens

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3
Q

Name two examples of (rare) monogenic auto-inflammatory diseaes

A
  1. Familial Mediterranean Fever
  2. TRAPS
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4
Q

Name examples of a Mixed pattern autoimmune/auto-inflammatory disease

A
  1. Axial spondyloarthritis
  2. Psoriatic arthritis
  3. Behcet’s syndrome
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5
Q

Name 3 examples of polygenic auto-inflammatory diseases

A
  1. Crohn’s disease
  2. UC
  3. Osteoarthritis
  4. Giant Cell arthritis
  5. Takayasu’s arteritis
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6
Q

Name 3 Examples of polygenic auto-immune diseases

A
  1. Rheumatoid arthritis
  2. Myaesthenia Gravis
  3. Pernicious anaemia
  4. Graves
  5. SLE
  6. PBC (Primary Biliary Cirrhosis)
  7. ANCA associated vasculitis
  8. Goodpasture disease
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7
Q

Name examples of Monogenic auto-immune diseases (rare)

A

ALPS
IPEX

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8
Q

What signaling pathway’s are commonly abnormal in monogenic auto-inflammatory diseases?

A

Abnormal signalling via key cytokine pathways involving TNF-alpha and/or IL-1 is common

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9
Q

What are typical clinical features of monogenic auto-inflammatory diseases?

A

periodic fevers
- inflammation – eg skin/joint/serosal/CNS
- high CRP

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10
Q

What kind of disease is Familial Mediterranean Fever?

What is the epidemiology + inheritence pattern ?

A

It is a monogenic auto-inflammatory disease

Autosomal recessive

Epidemiology in those of mediterranean descent (particularly armenian + jewish, turkish), varying prevalence with 1/4 carriers (armenian 1 in 500 have diseaes)

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11
Q

What is the pathophysiology of familial mediterranean fever?

A

Generally decreased regulation of neutrophils + increased neutrophil activation

Mutation in MEFV gene
MEFV gene encodes pyrin-marenostrin
Pyrin-marenostrin expressed mainly in neutrophils

Failure to regulate cryopyrin driven activation of neutrophils

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12
Q

What is the clinical presentation of someone with familial mediterranean fever?

A

All patients experience fever attacks lasting 1–3 days that recur over weeks to months

Most patients (95%) experience abdominal pain (peritonitis) and arthralgia (75%).

Other manifestation
- rash
- arthritis
- chest pain (pleurisy and pericarditis)

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13
Q

What is the main complicaiton of Familial Mediterranean Fever?

A

Risk of AA amyloidosis (with deposition in kidneys –> renal failure)

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14
Q

What lab finidngs would you find in an individual with Familial Mediterranean fever?

A
  1. High CRP
  2. High SAA (Serum Amyloid A)

+ test for MEFV mutation

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15
Q

How would you treat Familial Mediterranean fever?
What is the effect?

A
  1. Colchicine 500ug bd - binds to tubulin in neutrophils and disrupts neutrophil functions
    including migration and chemokine secretion
  • Anakinra (Interleukin 1 receptor antagonist)
  • Etanercept (TNF alpha inhibitor)
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16
Q

What is IPEX ?

What types of disease is it
what does it stand for (abbreviation)
what is the inheritence pattern
What is the epidemiology

A

Immune dystregulation, polyendocrinopathy, enteropathy, X-linkey syndrome is a monogenic auto-immune disease with muation in the FOXP3 gene leading to disregulation of T-cell function

X-linked recessive disease

Rare (1 in 1.6 million)

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17
Q

What is the clinical presenation of IPEX?

A

Mutation in transcription factor FOXP3 → unchecked activation of T cells against host tissues

Diarrhoea, diabetes and dermatitis

Presenation in early infancy

  1. Lymphadenopathy and/or chronic lymphoid tissue hypertrophy (e.g., enlarged tonsils)
  2. Eczema (+/- other derm)
  3. Autoimmune endocrine conditions (e.g., hyperthyroidism or hypothyroidism, type 1 diabetes mellitus in male individuals)
  4. Enteropathy, manifesting as e.g., chronic diarrhea
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18
Q

How does a mutaiton in the FOXP3 gene lead to diseae?

A

FOXP3 =IPEX

Usually FOXP3 is an transcription factor improtant for development of CD25+ TREG cells

Mutation leading to
- unchecked activation of T cells against host tissue (no negaive regulation of T-cells)
- Autoreactive B-cells

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19
Q

What is ALPS?

What types of disease is it
what does it stand for (abbreviation)
what is the inheritence pattern
What is the epidemiology

A

Auto-immune lymphoproliferative syndrome is a monogenic auto-immune disease with defect in the apoptosis pathway of self-reactive lymphocytes

Autosomal Dominant disease (incomplete penetrance)

Rare (a few houndret cases worldwide)

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20
Q

What muation causes ALPS?
What is the pathophysiology?

A

Mutations within FAS pathway (E.g. TNFRSF6 -encodes FAS) →Disease is heterogeneous depending on the mutation
Leading to
Defect in apoptosis of lymphocytes → proliferation of self-reactive, antigen specific lymphocyte lineages

Autoimmune lymphoproliferative syndrome: an autosomal dominant disorder

Presentation: generalized adenopathy, hepatosplenomegaly, and autoimmunity

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21
Q

What is the clinical presenation of ALPS?

A

High lymphocyte numbers with large spleen and lymph nodes →CD4-CD8- T cells

  • Auto-immune disease→ commonly auto-immune cytopenias
  • Lymphoma
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22
Q

What role do gene mutations in HLA genes play in Polygenic auto-inflammatory vs. polygenic auto-immune diseases play?

A

Usually play a bigger role in auto-inmmune diseases, less relevant for auto-inflammatory diseases

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23
Q

Why are certain polygenic auto-inflammatory diseases (e.g. Crohn’s) are site-specific?

A

Local factors at sites predisposed to disease lead to activation of innate immune cells such
as macrophages and neutrophils, with resulting tissue damage

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24
Q

How does a mutation inthe IBD1 gene (NOD2) cause croh’s disease

A

Examply of a polygenic disease so not only factor but NOD2 mutation is present in 30% of patients

Essentially immune cells might be over-reacting to bacterial presence

  1. NOD2 is expressed in cytoplasm of myeloid cells (macrophages, neutrophils, dendritic cells)
  2. Usually NOD2 is important in detecting bacteria (recognise muramyl dipeptide) and stimmulaties NFKb –> activation
  3. Activation can induce autophagy in dendritic cells
25
Q

What role do autoantibodies play in polygenic auto-inflammatory diseases and mixed pattern diseases?

A

Usually no role

  1. not in polygenic auto-inflammatory
  2. usualyl not in mixed pattern diseases
26
Q

How do gene mutations in polygenic auto-immune diseases lead to diseases?
(Very general)

A

Aberrant B cell and T cell responses in primary and secondary lymphoid organs lead to
breaking of tolerance with development of immune reactivity towards self-antigens

27
Q

What type of auto immune/autoinflammatory disease is ankylosing spondylitis?

A

Mixed pattern disease

28
Q

What 3 gene defects are associated with the development of ankylosing sponlylitis?

29
Q

What auto-immune diseases is a polymorphism in the PTPN22 gene associated with?

Why?

A

Lymphocyte specific tyrosine phosphatase which suppresses T cell activation →

Associated development of RA, SLE and T1DM.

30
Q

What auto-immune diseases is a polymorphism in the CTLA4 gene associated with?

Why?

A

receptor for CD80/CD86 expressed by T cells which transmits inhibitory signal to
control T cell activation

→Associated with SLE, T1DM, Autoimmune thyroid disease.

31
Q

What HLA allele is Ankylsing sponylitis associated with?

How much is the risk increased by having that allele?

32
Q

What HLA allele is Goodpasture’s syndrome associated with?

How much is the risk increased by having that allele?

A

HLA DR15/DR2

33
Q

What HLA allele is Graves’ disease associated with?

How much is the risk increased by having that allele?

A

HLA-DR3 - 4-fold

34
Q

What HLA allele is SLE associated with?

How much is the risk increased by having that allele?

A

HLA DR3 - 4 fold

(mnemomic: 2,-3, S-L-E)

35
Q

What HLA allele is Type 1 diabetis associated with?

How much is the risk increased by having that allele?

A

HLA DR3/DR4

25-fold

36
Q

What HLA allele is Rheumatoid arthritis associated with?

How much is the risk increased by having that allele?

A

HLA DR4 4-fold increase

There are 4 walls in a “rheum” (room)

37
Q

What are ANA?
What part of the cell do they usually affect?

A

Anti-nuclear Antibodies
Group of antibodies against nuclear antigens (incl. DNA like anti dsDNA, anti Jo, anti La etc.)

38
Q

What conditions are increased ANA associated with?

A

Generally Multi-systemic connective tissue diseases like
1. SLE
2. Scleroderma
3. Sjögren syndrom
4. Polymyositis/dermatomyositis

39
Q

Explain the proposed aetiology/ pathophysiology of SLE

A
  1. Environmental trigger (oestrogen, medication, UV) cause apoptosis of cells –> release of nuclear antigens
  2. Nuclear parts of damaged cells are not appropriately cleared –> development of nuclear auto-antibodies
    2.Immune complexes form (ANA + nuclear antigens)
    3.Deposition of Immune complexes cuause complement activation –> Type III hypersensitivity

Additionally

  • additional antiboy formation against other cells –> Type II hypersensitivity
40
Q

Explain how renal (and other tissue damage) in SLE occurs

A

Generally via
1. Immune-complex deposition
2. Antibody-mediated complement activation

41
Q

How are antibody titre test done and how can they be interpreted?

A

Titre reported: The minimal dilution at which the antibody can be detected

Hence: high dilution: high levels of antibodies present

42
Q

The picture below shows flourescent homogenous nuclear antibody staining - what antiboies is this associated with?

A

Homogenous staining is specific for:
DNA antibodies (ds-DNA for Lupus)

43
Q

Explain the epidemiology of anti-dsDNA antibodies and their diagnosic use

A

Anti ds-DNA are

  • highly specific for SLE (95%) (false positive rare)
  • Occur in ~60-70% of SLE patients at some time in their disease
  • Very high titres are often associated with more severe disease, including renal or central nervous system involvement.
  • Useful in disease monitoring
44
Q

The picture below shows speckled nuclear antibody stainign - what antibodies is this associated with?

A

Several Nuclear antibdobies, incl. Ro, La, Sm, U1RNP –> usually ELISA done afterwards to confirm which of them are present

45
Q

What is the diagnostic significance of several nuclear auto-antibodies incl. Anti-Ro, La. Sm,

A

Antibodies may occur in SLE
Anti-Ro and La are also characteristically found in Sjogren’s syndrome
Titres not helpful in monitoring disease activity

46
Q

Explain the role of complement level monitoring in patients with SLE

A

If complements activated = higher disease activity
complement activation leads to consumption –> higher disease activity = lower complemnent levels (low C4 in moderate, Low C4 and Low C3 in severe disease activity)

Explanation:
Complement activation are part of SLE pathophysiology (activation via immune-complexed of antibody-antigens –> activate classical pathway)

Usually complements measured
C4: complement needed for activation of classical complement pathway
C3: Complement of common pathway

47
Q

What haematological complciation/ disease is associated with SLE?

A

Antiphospholipid syndrome (causes thrombophilia with recurrent miscarriage)

48
Q

Which 3 antibody tests should be done in patients with SLE or unexplained history of recurrent thrombosis/ miscarriage

A

Testing for Antiphospholipid syndrome

  1. Anti-cardiolipin antibody (AB against -ve charge phospholipids)
  2. Anti-beta 2 glycoprotein 1 antibody (glycoprotein found on -ve charged phospholipids)
  3. Lupus anti-coagulant (Antibody to phospholipids –> anti-coagulant in vitro, pro-coagulant in vivo)
49
Q

What is the clinical presentation of Sjögrens syndrome?

What is a long-term complication of it?

A

Inflammation and infiltration of exocrine glands

  • in particular of lacrimal + salivary glands (dry eyes, dry mouth)
  • Increased risk of certain lymphomas – eg MALT lymphoma
50
Q

What antibodies is primary Sjögren’s syndrome associated with?

A

ANA positive, particulary
Anti-Ro and Anti-La

–> specled staining

51
Q

What are the features of CREST syndrome?

A

Limited Cutaneous Systemic Sclerosis (CREST)
Skin involvement does not progress beyond forearms (but sometimes involves peri-oral skin)

1. Calcinosis - cutaenous depositions 
2. Raynauds
3. Oesophageal dismotility
4. Sclerodactyly (tightening of skin) 
5. Telangiectasia
52
Q

What is systemic Slerosis?

What is the difference between systemic sclerosis and CREST syndrome?

A

Diffuse Cutaneous Systemic Sclerosis
Skin involvement does progress beyond forearms –>

CREST + additional
1. More extensive GI disease
2. Pulmonary involvement
3. Renal disease
53
Q

What ANAs are associated with CREST syndrome and Systemic sclerosis respectively?

A

Both conditions have antibodies that are highly specific + usually exlusive for each other (presence of antibodies in 40-70%)
1. CREST: Anti- centromere ANA
2. Diffuse systmic: Anti-Scl-70 antibodies

54
Q

Name one example of a Cytoplasmic antibody used in testing for connective tissue disease. What condition is it associated with?

A

Jo 1 antibodies against t-RNA synthesase

–> Used for testing of Myositis

55
Q

What type of conditions are ANCA associated vasculitides?

56
Q

What are ANCA?

What conditions are they associated with?

A

ANCA = Anti-neutrophil cytoplasmic antibody

There are mainly 3 Small Vessel vasculitides associated with positive ANCA (no need to know details)

  1. Microscopic polyangiitis / Microscopic polyarteritis / MPA
  2. Granulomatosis with polyangiitis / Wegener’s granulomatosis / GPA
  3. Eosinophilic granulomatosis with polyangiitis / Churg-Strauss syndrome / eGPA

+ p-ANCA associated with PBC (Primary Biliary Cirrhosis/ UCI)

57
Q

What two different types of ANCA are there?

A

c-ANCA = cyoplasmic staining pattern
p-ANCA = perinuclear staining pattern

Generally
c-ANCA: GPA or occasionally eGPA, can be non-specific
p-ANCA: MPA or eGPA, + UC, hepato-biliary auto-immune diseases

58
Q

What HLA are associated with an increased risk of Coeliac disease?

A

HLADQ2
(Also HLA DQ8 but to a lesser extend)

Year 5 Path Immunology (6 decks)

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