Auto-inflammatory and Auto-immune Disorders 1

Question 1

Describe the difference between auto-inflammatory or auto-immune disease

Answer 1

• Autoinflammatory - Innate immune response
• Auto-immune - Adaptive immune response
• Mixed - mixed innate/adaptive response

All have genetic influences

Question 2

Define auto-inflammatory diseases

Answer 2

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

Question 3

Define auto-immune disease

Answer 3

• 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
• Adaptive immune response plays the predominant role in clinical expression of disease
• Organ specific antibodies may predate clinical disease by years

Question 4

Give some examples of the following types of immunological disease:

1. Rare monogenic autoinflammatory disease
2. Polygenic auto-inflammatory disease
3. Mixed pattern diseases
4. Polygenic Auto-immune disease
5. Rare monogenic auto-immune disease

Answer 4

1. Rare monogenic auto-inflammatory disease

• Familial mediterranean fever
• TRAPS

2.Polygenic auto-inflammatory diseases

• Crohn’s disease
• UC
• Osteoarthritis
• Giant cell arteritis

3. Mixed pattern diseases

• Ankylosing spondylitis
• Psoriatic arthritis
• Bechet’s syndrome

4. Polygenic auto-immune diseases

• Rheumatoid arthritis
• Myasthenia gravis
• Pernicious anaemia
• Grave’s disease
• SLE
• Primary biliary cirrhosis
• Goodpasture disease

5. Rare monogenic auto-immune disease

• APS-1, APECED
• ALPS
• IPEX

Question 5

Describe the underlying pathophysiology of monogenic autoinflammatory diseases

Answer 5

• 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 and/o IL-1 is common

Question 6

Describe the Gene, protein involved and the mode of inheritance for the following monogenic auto-inflammatory diseases

1. Muckle Wells syndrome
2. Familial cold auto-inflammatory syndrome
3. Hyper IgD with periodic fever syndrome
4. Familial mediterranean fever

Answer 6

1. /2. Muckle Wells Syndrome/Familial cold auto-inflammatory syndrome
   
   • Gene: NLRP3 - gain of function
   • Protein: NALP3 cryopyrin
   • Inheritance: Autosomal dominant
2. Hyper IgD with periodic fever syndrome

• Gene: MK
• Protein: Mevalonate kinase
• Inheritance: Autosomal recessive

4. Familial mediterranean fever

• Gene: MEFV
• Protein: Pyrin-Marenostrin
• Inheritance: Autosomal recessive

Question 7

Describe the inflammasome complex

Answer 7

Apoptosis associated speck like protein (ASC) is:

• Inhibited by Pyrin-Mareostrin
• Stimulated Cryoprin - a protein, produced when the body is attacked by toxins, microbial pathogens or high levels of urate

ASC triggers Procaspase 1 which then:

• Releases IL-1
• NFkappaBeta - transcription factor that regulates expression of genes involved in immunity such as TNFalpha
• Apoptosis

Question 8

Describe the pathogenesis of Familial Mediterranean Fever

Answer 8

• Autosomal recessive condition
• Mutation in MEFV gene - loss of function
• Gene encodes pyrin-marenostrin (usually inhibits the innate immune system)
• Pyrin-marenostrin expressed mainly in neutrophils
• Failure to regulate cryopyrin driven activation of neutrophils (cryopyrin triggers innate immune response)

Question 9

What is the clinical presentataion of Familial Mediterranean fever?

Answer 9

• Periodic fevers lasting 46-96 hours associated with
  
  • Abdominal pain due to peritonitis
  • Chest pain due to peritonitis
  • Arthritis
  • Rash

Question 10

What do people with Familial mediterranean fever at long term risk from?

Answer 10

Long term risk of AA amyloidosis

Liver produces serum amyloid A as acute phase protein. Serum amyloid A deposits in kidney, liver, spleen. Deposition in kidney often most clinically important.

Proteinuria with development of nephrotic syndrome

Renal failure

Question 11

What is the treatment for familial mediterranean fever?

Answer 11

• Colchincine 500ug bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
• Anakinra (IL-1 receptor antagonist)
• Etanercept (TNF alpha inhibitor)

Question 12

What causes monogenic auto-immune disease?

Answer 12

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

• Abnormality in tolerance
• Abnormality of regulatory T cells
• Abnormality of lymphocyte apoptosis

Question 13

Describe the genetics of the following auto-immune diseases

1.

• Auto-immune polyendocrine syndrome type 1 (APS1)
• Auto-immune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome/ APECED

2. What are the auto-immune diseases associated?

Answer 13

• Autosomal recessive disorders
• Defect in ‘auto-immune regulator’ - AIRE
  
  • A transcription facto involved in development of T cell tolerance in the thymus.
  • Upregulates expression of self-antigens by thymic cells
  • Promotes T cell apoptosis
• Defects in AIRE leads to failure of central tolerance
  
  • Autoreactive T and B cells

2. Multiple auto-immune diseases:

• Hypoparathyroidism
• Addisons
• Hypothyroidism
• Diabetes
• Vitiligo
• Enteropathy

Huge range of autoantibodies causing a range of autoimmune endocrine disorders

Question 14

Describe the underlying pathophysiology of the following monogenic auto-immune diseases

1.

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

2. What autoimmune diseases are associated with these conditions?

Answer 14

1.

• Mutations in Foxp3 (Forkhead box p3) which is required for the development of Treg cells
• Failure to negatively regulate T cell responses - leading to autoantibody formation

2. Autoimmune conditions”

• Enteropathy (disease of the intestine)
• Diabetes mellitus
• Hypothyroidism

Question 15

Describe the underlying pathophysiology of the following monogenic auto-immune disease

• Auto-immune lymphoproliferative syndrome (ALPS)

Answer 15

ALPS

• Mutations within FAS pathway
  
  • E.g. mutations in TNFRSF6 which encodes FAS
  • Disease is heterogenous dependung on the mutation
• Defect in apoptosis of lymphocytes
  
  • Failure of tolerance
  • Failure of lymphocyte ‘homeostasis’
• High lymphocyte numbers with large spleen and lymph nodes
  
  • Double negative (CD4-CD8) T cells
• Auto-immune disease
  
  • Commonly auto-immune cytopenias
• Lymphoma

Question 16

EMQ

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

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

B) Familial Mediterranean fever

C) Auto-immune lymphoproliferative syndrome (ALPS)

Answer 16

B) Familial Mediterranean fever

Question 17

EMQ

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

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

B) Familial Mediterranean fever

C) Auto-immune lymphoproliferative syndrome (ALPS)

Answer 17

C) Auto-immune lymphoproliferative syndrome (ALPS)

Question 18

EMQ

A single gene mutation involving FOXp3 resulting in abnormality of T reg cells

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

B) Familial Mediterranean fever

C) Auto-immune lymphoproliferative syndrome (ALPS)

Answer 18

A) Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)

Question 19

What causes polygenic anti-inflammatory diseases?

Answer 19

• 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 diseases are not characterised by presence of auto-antibodies

Question 20

Describe the genetic polymorphisms associated with Crohn’s disease (a polygenic auto-inflammatory disease)

Answer 20

• Familial association and twin studies suggest a genetic predisposition
• Linkage analysis studies identified 8 regions associated with susceptibility 1BD 1-10 genes
• IBD1 gene on chromosome 16 known as NOD2
  
  • 3 different mutations of IBD-1 have each been shown to be associated with Crohn’s disease
  • NOD2 gene/IBD-1 mutations are present in 30% of patients
• Abnormal allele of NOD2 increases risk of Crohn’s disease by 1.5-3x if one copy, and 14-44x if two copies
• Mutations are also found in patients with Blau syndrome and some forms of sarcoidosis

Question 21

What is NOD2 and its relation to pathophysioloy of Crohn’s disease?

Answer 21

• NOD2 or IBD-1 gene can have mutations in leading to auto-inflammatory disease in 30% of patients
• NOD2 is expressed in cytoplasm of myeloid cells (macrophages, neutrophils, dendritic cells)
• Acts as a microbial sensor - recognises muramyl dipeptide - and stimulates NFKBeta and triggers an inflammatory response
• Some mutations associated with Crohn’s disease result in a shorter protein that fails to recognise bacteria

Question 22

1. Describe what the influences are that cause Crohn’s disease
2. What is the basic histology of Crohn’s disease?

Answer 22

1.

• Abnormal NOD2/CARD15
  
  • Affects capacity of innate immune cells to sense intracellular microbes leading to abnormal/inappropriate inflammatory response to bacteria
• Other genetic influences
  
  • Expression of pro-inflammatory cytokines/chemokines
  • Leucocyte recruitment
  • Release of proteases, free radicals
• Environmental factors
  
  • Microbes

2. Underlying histology of Crohn’s

• Focal inflammation in/around crypts
• Formation of granulomata
• Tissue damage with mucosal ulceration

Question 23

1. What are the clinical features of Crohn’s disease?
2. What are the treatments for Crohn’s disease?

Answer 23

1. Clinical features:

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

2. Treatments

• Corticosteroid
• Azathioprine
• Anti-TNF alpha antibody
• Anti-IL 12/23 antibody

Question 24

Describe the underlying causes of mixed pattern diseases

Answer 24

Mixed pattern diseases:

• Mutations in genes encoding proteins involved in pathways associated with innate immune cell function AND
• Mutations in genese encoding proteins involved in pathways associated with adaptive immune cell function
• HLA associations may be present
• Autoantibodies are not usually a feature

Question 25

Describe the different genetic polymorphisms that can lead to/increase risk of developing ankylosing spondylitis and what they affect 1. IL23R 2. ERAP1 (ARTS1) 3. ANTXR2 4. ILR2 5. HLA B27

Answer 25

1. IL23R * Affects the IL23 receptor - the receptor for IL23 whihc promotes differentiation of Th17 cells 2. ERAP1 * Affects type 1 TNF receptor shedding aminopeptidase regulator/ER aminopeptidase 1 - cleaves surface cytokine receptors and trims peptides for presentation by class 1 HLA molecules 3. ANTXR2 * Affects an Anthrax toxin receptor 2 - involved in forming capillaries and maintaining structure of basement membrane 4. ILR2 * Affects Interleukin receptor type II - acts as a decoy receptor that inhibits activity of IL-1 5. HLA-B27 (accounts for \<50% overall genetic risk) * Human leukocyte antigen B27 - presents antigen to CD8 T cells. Ligand for killer immunoglobulin receptor Genetic polymorphisms in any of these can increase the risk of developing ankylosing spondylitis

Question 26

Where do the abnormalities occur to cause Ankylosing spondylitis?

Answer 26

* Abnormalities affecting both innate and adaptive immune system resulting in increased tendency to 'inflammation * Enhanced inflammation occurs at specific sites where there are high tensile forces (entheses - sites of insertions of ligaments or tendons)

Question 27

1. What is the presentation of Ankylosing spondylitis? 2. What is the treatment of ankylosing spondylitis?

Answer 27

1. Presentation * Low back pain and stiffness * Large joint arthritis * Enthesitis * Uveitis 2. Treatment: * Non steroidal anti-inflammatory drugs * Immunosuppression * Anti-TNF alpha * Anti-IL17 * Anti-IL12/23

Question 28

Describe the underlying pathophysiology of polygenic auto-immne disease

Answer 28

* Mutations in genes encoding proteins involved in pathways associated with adaptive immune cell function * HLA associations are common * Aberrant B and T cell responses in primary and secondary lymphoid organs, lead to breaking of self tolerance with development of immune reactivity towards self-antigens * Auto-antibodies are found

Question 29

Describe the pathway in which polygenic auto-immune conditions lead to disease

Question 30

HLA presentation of antigen is required for development of T cell and B cell-dependent B cell responses Describe the susceptibility allele for each of the following polygenic autoimmune diseases 1. Goodpasture disease 2. Graves disease 3. SLE 4. Type 1 diabetes 5. Rheumatoid arthritis

Answer 30

1. Goodpasture disease - HLADR15 2. Graves disease - HLA-DR3 3. SLE - HLA-DR3 4. Type 1 diabetes - HLA DR3/DR4 5. Rheumatoid arthritis - HLA-DR4

Question 31

Describe the role of PTPN 22 in T cell activation and the role in polygenic diseases (name diseases involved)

Answer 31

PTPN 22: * Protein tyrosine phosphatase non-receptor 22 * Lymphyocyte specific tyrosine phosphatase which suppresses T cell activation. * Allelic variations (meaning T cell are not suppressed as the receptor is faulty), are found in Rheumatoid arthritis, SLE and type 1 diabetes

Question 32

Describe the role of CTLA4 in T cell activation and the role in polygenic diseases (name diseases involved)

Answer 32

CTLA4 * Cytotoxic T lymphocyte associated protein 4 * Expressed by T cells and transmits inhibitory signal to control T cell activation * Alleic variations of CTLA4 is found in SLE, Auto-immune thyroid disease, Rheumatoid arthritis and type 1 diabetes

Question 33

Describe the role of loss of self-tolerance in polygenic auto-immune disease. What is: * Central tolerance * Peripheral tolerance

Answer 33

* Autoimmune disease involves a failure of self-tolerance * Central tolerance * Deletion of auto-reactive B cells and T cells * Peripheral tolerance * Regulated expression of co-stimulatory molecules * CD40L-CD40, CD80/86-CD28 * Regulatory T cells * Tregs * Tr1 * CD8 regs * Immune privilege * Eyes, testes and CNS

Question 34

1. Describe the work done by Gel and Coombs (1960s) 2. What is the Gel and Coombs hypersensitivity classification?

Answer 34

1. * Gel and Coombs classified skin test 'hypersensitivity' reactions accordig to the type of immune response observed * Antibody or T cell mediated * Effector mechanisms for immunopathology 2. Gel and Coombs classification: * Type 1 - Immediate hypersensitivity whihc is IgE mediated * Type 2 - Antibody reacts with cellular antigen * Type 3 - Antibody reacts with soluble antigen to form an immune complex * Type 4 - Delayed type hypersensitivity - T cell mediated response

Question 35

1. Describe type 1 hypersensitivity reactions 2. What causes these reactions?

Answer 35

1. * Rapid allergic reaction * Pre-existing IgE antibodies to allergen * IgE bound to Fc epsilon receptors on mast cells and basophils * Cell degranulation occurs * Release of inflammatory mediators * Pre-formed - histamine, serotonin, proteases * Synthesised - leukotrienes, prostaglandins, bradykinin, cytokines * Increased vascular permeability * Leukocyte chemotaxis * Smooth muscle contraction 2. Type 1 hypersensitivity can be caused by * Usually foreign antigen * Pollens * Drugs * Food * Insect products

Question 36

1. Describe type 2 hypersensitivity reactions 2. What auto-immune diseases are type 2 hypersensitivity reactions and the auto-antigens involved?

Answer 36

1. * Antibody driven immune reactions (auto-immune) * Antibody binds to cell associated antigen * Antibody dependent destruction (NK cells, phagocytes and complement) * Receptor activation or blockade 2. * Goodpasture disease - autoantigen is noncollangenous domain of basement membrane collagen type 4 * Pemphigus vulgaris - autoantigen is epidermal cadherin * Graves disease - autoantigen is thyroid stimulating hormone (TSH) receptor * Myasthenia Gravis - autoantigen is acetylcholine receptor

Question 37

1. Describe type 3 hypersensitivity reactions 2. Describe the syndromes that involve type 3 hypersensitivity reactions

Answer 37

1. * Immune complex driven autoimmune disease * Antibody binds to soluble antigen to form circulating immune complex * Immune complexes deposition in blood vessels, which leads to complement activation and infiltration of macrophages and neutrophils * Cytokine and chemokine expression, granule release from neutrophils causing increased vascular permeability 2. * SLE - autoantigen is DNA, histones or RNP and causes rash, glomerulonephritis and arthritis * Rheumatoid arthritis - autoantigen is Fc region of IgG and causes arthritis

Question 38

1. Describe type 4 hypersensitivity reactions in autoimmunity CD8 T cells 2. Describe type 4 hypersensitivity reactins in autoimmunity CD4 T cells

Answer 38

1. CD8-T cells - HLA class 1 molecules present antigen to CD8 T cells * A reaction of CD8 cells to self antigen causes cytotoxic granule release from primed CD8-T cell * CD8 binding to self antigen leads to cell lysis of healthy cells 2. HLA Class II molecules present antigen to CD4 T cells * Primed T helper cell CD4 T cell binds to self peptide which causes the release of Interferon gamma, which triggers macrophage activation which causes inflammation and tissue damage

Question 39

Describe the different syndromes that are Type 4 cell mediated diseases

Answer 39

Question 40

EMQ Which of the following is Goodpastures disease? 1. Type 1 hypersensitivity reaction 2. Type 2 hypersensitivity reaction 3. Type 3 hypersensitivity reaction 4. Type 4 hypersensitivity reaction

Answer 40

2. Type 2

Question 41

EMQ Which of the following is Eczema? 1. Type 1 hypersensitivity reaction 2. Type 2 hypersensitivity reaction 3. Type 3 hypersensitivity reaction 4. Type 4 hypersensitivity reaction

Answer 41

1. Type 1

Question 42

EMQ Which of the following is SLE? 1. Type 1 hypersensitivity reaction 2. Type 2 hypersensitivity reaction 3. Type 3 hypersensitivity reaction 4. Type 4 hypersensitivity reaction

Answer 42

3. Type 3

Question 43

Which of the following is Multiple sclerosis? 1. Type 1 hypersensitivity reaction 2. Type 2 hypersensitivity reaction 3. Type 3 hypersensitivity reaction 4. Type 4 hypersensitivity reaction

Answer 43

4. Type 4