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PathY5 > Autoimmune and Autoinflammatory Diseases 1 > Flashcards

Autoimmune and Autoinflammatory Diseases 1 Flashcards

1
Q

What is the damage to the host caused by an immune response to pathogens?

A

Cytokines (adaptive) may cause fever/ malaise

Neutrophilia (innate) may cause abscess formation

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2
Q

What is the damage to the host caused by an immune response to non pathogen triggered immune response?

A

Innate (cytokines)- sacroiliitis
Adaptive (Antibodies)- haemolysis

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3
Q

What immunopathology exists in the absence of infection?

A

Autoinflammatory (Innate)
Mixed (Mixed)
Autoimmune (Adaptive)

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4
Q

What are autoinflammatory diseases?

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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5
Q

What are autoimmune diseases?

A

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​

Organ-specific antibodies may predate clinical ​disease by years​

Adaptive immune response plays the ​predominant role in clinical expression of disease

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6
Q

What are the different types of non infectious immunopathologies with regard to their genetic components?

A

Innate = monogenic or polygenic

Mixed = polygenic

Adaptive = Polygenic or monogenic

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7
Q

How can genetics cause immunopathological diseases?

A

Genetics – Germline mutations affecting DNA sequence - Alteration in DNA that occurs in germ cells (sperm and ova and progenitors) and will be passed on to offspring​

Genetics – Somatic mutations affecting DNA sequence - Alteration in DNA that occurs in a single body cell after conception, does not affect germ cells and so is not inherited​

Epigenetics - (Heritable) change in gene expression ​(eg via DNA methylation)​

MicroRNA (miRNA) - Small, non-coding, single stranded RNA ​targets mRNA and regulate protein production

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8
Q

What are some rare mono genic autoinflammatory diseases?

A

Familial mediterranean fever​
TRAPS

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9
Q

What are some polygenic autoinflammatory diseases?

A

Crohns disease​

Ulcerative colitis​

Osteoarthritis​

Giant cell arteritis​

Takayasu’s arteritis

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10
Q

What are some polygenic mixed diseases?

A

Axial spondyloarthritis​

Psoriatic arthritis​

Behcet’s syndrome

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11
Q

What are some polygenic autoimmune diseases?

A

Rheumatoid arthritis Systemic lupus erythematosus​

Myaesthenia Gravis Primary biliary cirrhosis ​

Pernicious anaemia ANCA associated vasculitis​

Graves disease Goodpasture disease

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12
Q

What are some rare mono genic autoimmune diseases?

A

APS-1, APECED​

ALPS​

IPEX

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13
Q

What are monogenic auto inflammatory diseases?

A

Mutations in a gene encoding a protein involved in a pathway associated with innate immune cell function​

​

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

​

Classically present with ​

  • periodic fevers​
  • skin/joint/serosal/CNS…. inflammation​
  • high CRP
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14
Q

What is the mode of inheritence of these conditions?

A
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15
Q

What genes are affected in these conditions?

A
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16
Q

What is the inflammasome?

A
17
Q

What is the pathogenesis of familial mediterranean fever?

A

Autosomal recessive condition​

Mutation in MEFV gene ​

MEFV gene encodes pyrin-marenostrin ​

Pyrin-marenostrin expressed mainly in neutrophils​

Failure to regulate cryopyrin driven activation of neutrophils

18
Q

What is the clinical presentation of familial mediterranean fever?

A

Periodic fevers lasting 48-96 hours associated with:​

Abdominal pain due to peritonitis​

Chest pain due to pleurisy and pericarditis​

Arthritis​

Rash

19
Q

What is the complication of familial mediterranean fever?

A

Liver produces serum amyloid A as acute phase protein​

Serum amyloid A deposits in kidneys, liver, spleen

Deposition in kidney often most clinically important ,​Proteinuria - nephrotic syndrome​​, Renal failure

​

20
Q

What are the Ix and Tx for familial mediterranean fever?

A

Investigation​

High CRP, high SAA​

Blood sample to specialist genetics laboratory to identify MEFV mutation​

​

Treatment​

Colchicine 500ug bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion​

IL-1 blocker (anakinra, canukinumab)​

TNF alpha blocker​

21
Q

What are the monogenic auto immune diseases?

A

Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function​​

Abnormality of regulatory T cells - IPEX​​

Abnormality of lymphocyte apoptosis - ALPS

22
Q

What is IPEX?

A

Immune dysregulation, polyendocrinopathy, enteropathy, ​
X- linked syndrome​
IPEX

23
Q

What is IPEX caused by?

A

Mutations in Foxp3 (Forkhead box p3) which is required for development of Treg cells​

​

Failure to negatively regulate T cell responses​

Autoreactive B cells​

limited repertoire of autoreactive B cells

24
Q

What can IPEX cause?

A

Diabetes Mellitus​

Hypothyroidism ​

Enteropathy

25
Q

What causes ALPS?

A

Mutations within FAS pathway​

Eg mutations in TNFRSF6 which encodes FAS​

Disease is heterogeneous depending on the mutation​

​

Defect in apoptosis of lymphocytes​

Failure of tolerance​

Failure of lymphocyte ‘homeostasis’

26
Q

What may ALPS present with?

A

​

High lymphocyte numbers with large spleen and lymph nodes​

​

Auto-immune disease ​

commonly auto-immune cytopenias​

​

Lymphoma

27
Q

What are polygenic Auto inflammatory diseases?

A

Mutations in genes encoding proteins involved in pathways associated with innate immune cell function​

​

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

​

HLA associations are usually less strong ​

​

In general these disease are not characterised by presence of auto-antibodies​

28
Q

What are genetic polymorphisms in IBD?

A

Familial association studies and twin studies suggested genetic predisposition to disease​

15% patients have an affected family member​

50% vs <10% disease concordance in monozygotic vs dizygotic twins​

​

>200 disease susceptibility loci found

29
Q

What are the important mutations in IBD?

A

IBD1 gene on chromosome 16 identified as NOD2 (CARD-15, caspase activating recruitment domain -15). ​

​

Three different mutations of this gene have each been shown to be associated with Crohn’s disease.​

​

NOD2 gene mutations are present in 30% patients (ie not necessary)​

​

Abnormal allele of NOD2 increases risk of Crohn’s disease by 1.5-3x if one copy and 14-44x if two copies (ie not sufficient)​

​

Mutations also found in patients with Blau syndrome and some forms of sarcoidosis

30
Q

What is NOD2?

A

NOD2 expressed in cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells ​

​

Intracellular receptor for muramyl dipeptide on bacterial products and promotes their clearance

31
Q

What is the pathogenesis of Crohn’s?

A

Epigenetic factors​

microRNAs

Genetic mutations affecting innate immune response

Environmental factors​

Smoking

Intestinal microbiota

Expression of pro-inflammatory cytokines/chemokines​

Leukocyte recruitment​

Release of proteases, free radicals

Focal inflammation in/around crypts​

Formation of granulomata​

Tissue damage with mucosal ulceration

32
Q

What are the clinical features and treatment of Crohn’s?

A

Clinical features​

Abdominal pain and tenderness​

Diarrhoea (blood, pus, mucous)​

Fevers, malaise​

​

Treatment may include​

Corticosteroid​

Anti-TNF alpha antibody

33
Q

What is mixed pattern disease?

A

Mutations in genes encoding proteins involved in pathways associated with innate immune cell function​

​

And​

​

Mutations in genes encoding proteins involved in pathways associated with adaptive immune cell function​

​

HLA associations may be present​

​

Auto-antibodies are not usually a feature

34
Q

Which genes are linked to ankylosing spondylitis?

A
35
Q

Where does enhanced inflammation occur?

A

Enhanced inflammation occurs at specific sites where there are high tensile forces​

(entheses - sites of insertions of ligaments or tendons)

36
Q

What is the presentation and treatment of Ank Spon?

A

Presentation​

Low back pain and stiffness ​

Enthesitis​

Large joint arthritis​

​

​

Treatment​

Non-steroidal anti-inflammatory drugs​

Immunosuppression​

Anti-TNF alpha ​

Anti-IL17

37
Q

Which of the following is an example of a monogenic auto-inflammatory disease?

​

Familial Mediterranean fever​

​

Graves’ disease​

​

Crohn’s disease​

​

Axial spondyloarthritis​

​

IPEX syndrome due to FoxP3 mutation

A

Familial Mediterranean fever​

38
Q

Which of the following is an example of a monogenic auto-immune disease?

​

Familial Mediterranean fever​

​

Graves’ disease​

​

Crohn’s disease​

​

Axial spondyloarthritis​

​

IPEX syndrome due to FoxP3 mutation

A

IPEX syndrome due to FoxP3 mutation

39
Q

Which of the following is an example of a polygenic auto-inflammatory disease?

​

Familial Mediterranean fever​

​

Graves’ disease​

​

Crohn’s disease​

​

Axial spondyloarthritis​

​

IPEX syndrome due to FoxP3 mutation​

A

Crohn’s Disease

PathY5 (98 decks)

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