Autoimmune and Autoinflammatory Diseases 1

Question 1

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

Answer 1

Cytokines (adaptive) may cause fever/ malaise

Neutrophilia (innate) may cause abscess formation

Question 2

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

Answer 2

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

Question 3

What immunopathology exists in the absence of infection?

Answer 3

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

Question 4

What are autoinflammatory diseases?

Answer 4

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

Question 5

What are autoimmune diseases?

Answer 5

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

Question 6

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

Answer 6

Innate = monogenic or polygenic

Mixed = polygenic

Adaptive = Polygenic or monogenic

Question 7

How can genetics cause immunopathological diseases?

Answer 7

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

Question 8

What are some rare mono genic autoinflammatory diseases?

Answer 8

Familial mediterranean fever​
TRAPS

Question 9

What are some polygenic autoinflammatory diseases?

Answer 9

Crohns disease​

Ulcerative colitis​

Osteoarthritis​

Giant cell arteritis​

Takayasu’s arteritis

Question 10

What are some polygenic mixed diseases?

Answer 10

Axial spondyloarthritis​

Psoriatic arthritis​

Behcet’s syndrome

Question 11

What are some polygenic autoimmune diseases?

Answer 11

Rheumatoid arthritis Systemic lupus erythematosus​

Myaesthenia Gravis Primary biliary cirrhosis ​

Pernicious anaemia ANCA associated vasculitis​

Graves disease Goodpasture disease

Question 12

What are some rare mono genic autoimmune diseases?

Answer 12

APS-1, APECED​

ALPS​

IPEX

Question 13

What are monogenic auto inflammatory diseases?

Answer 13

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

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

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Classically present with ​

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

Question 14

What is the mode of inheritence of these conditions?

Answer 14

Question 15

What genes are affected in these conditions?

Answer 15

Question 16

What is the inflammasome?

Answer 16

Question 17

What is the pathogenesis of familial mediterranean fever?

Answer 17

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

Question 18

What is the clinical presentation of familial mediterranean fever?

Answer 18

Periodic fevers lasting 48-96 hours associated with:​

Abdominal pain due to peritonitis​

Chest pain due to pleurisy and pericarditis​

Arthritis​

Rash

Question 19

What is the complication of familial mediterranean fever?

Answer 19

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

​

Question 20

What are the Ix and Tx for familial mediterranean fever?

Answer 20

Investigation​

High CRP, high SAA​

Blood sample to specialist genetics laboratory to identify MEFV mutation​

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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​

Question 21

What are the monogenic auto immune diseases?

Answer 21

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

Question 22

What is IPEX?

Answer 22

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

Question 23

What is IPEX caused by?

Answer 23

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

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Failure to negatively regulate T cell responses​

Autoreactive B cells​

limited repertoire of autoreactive B cells

Question 24

What can IPEX cause?

Answer 24

Diabetes Mellitus​

Hypothyroidism ​

Enteropathy

Question 25

What causes ALPS?

Answer 25

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’

Question 26

What may ALPS present with?

Answer 26

​ High lymphocyte numbers with large spleen and lymph nodes​ ​ Auto-immune disease ​ commonly auto-immune cytopenias​ ​ Lymphoma

Question 27

What are polygenic Auto inflammatory diseases?

Answer 27

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​

Question 28

What are genetic polymorphisms in IBD?

Answer 28

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

Question 29

What are the important mutations in IBD?

Answer 29

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

Question 30

What is NOD2?

Answer 30

NOD2 expressed in cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells ​ ​ Intracellular receptor for muramyl dipeptide on bacterial products and promotes their clearance

Question 31

What is the pathogenesis of Crohn's?

Answer 31

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

Question 32

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

Answer 32

Clinical features​ Abdominal pain and tenderness​ Diarrhoea (blood, pus, mucous)​ Fevers, malaise​ ​ Treatment may include​ Corticosteroid​ Anti-TNF alpha antibody

Question 33

What is mixed pattern disease?

Answer 33

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

Question 34

Which genes are linked to ankylosing spondylitis?

Answer 34

Question 35

Where does enhanced inflammation occur?

Answer 35

Enhanced inflammation occurs at specific sites where there are high tensile forces​ (entheses - sites of insertions of ligaments or tendons)

Question 36

What is the presentation and treatment of Ank Spon?

Answer 36

Presentation​ Low back pain and stiffness ​ Enthesitis​ Large joint arthritis​ ​ ​ Treatment​ Non-steroidal anti-inflammatory drugs​ Immunosuppression​ Anti-TNF alpha ​ Anti-IL17

Question 37

Which of the following is an example of a monogenic auto-inflammatory disease? ## Footnote ​ Familial Mediterranean fever​ ​ Graves’ disease​ ​ Crohn’s disease​ ​ Axial spondyloarthritis​ ​ IPEX syndrome due to FoxP3 mutation

Answer 37

Familial Mediterranean fever​

Question 38

Which of the following is an example of a monogenic auto-immune disease? ## Footnote ​ Familial Mediterranean fever​ ​ Graves’ disease​ ​ Crohn’s disease​ ​ Axial spondyloarthritis​ ​ IPEX syndrome due to FoxP3 mutation

Answer 38

IPEX syndrome due to FoxP3 mutation

Question 39

Which of the following is an example of a polygenic auto-inflammatory disease? ## Footnote ​ Familial Mediterranean fever​ ​ Graves’ disease​ ​ Crohn’s disease​ ​ Axial spondyloarthritis​ ​ IPEX syndrome due to FoxP3 mutation​

Answer 39

Crohn's Disease