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Immunology - Path > Auto-inflammatory and Auto-immune Disorders 1 > Flashcards

Auto-inflammatory and Auto-immune Disorders 1 Flashcards

1
Q

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

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

All have genetic influences

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2
Q

Define auto-inflammatory 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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3
Q

Define auto-immune disease

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
  • Adaptive immune response plays the predominant role in clinical expression of disease
  • Organ specific antibodies may predate clinical disease by years
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4
Q

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
A
  1. Rare monogenic auto-inflammatory disease
  • Familial mediterranean fever
  • TRAPS

2.Polygenic auto-inflammatory diseases

  • Crohn’s disease
  • UC
  • Osteoarthritis
  • Giant cell arteritis
  1. Mixed pattern diseases
  • Ankylosing spondylitis
  • Psoriatic arthritis
  • Bechet’s syndrome
  1. Polygenic auto-immune diseases
  • Rheumatoid arthritis
  • Myasthenia gravis
  • Pernicious anaemia
  • Grave’s disease
  • SLE
  • Primary biliary cirrhosis
  • Goodpasture disease
  1. Rare monogenic auto-immune disease
  • APS-1, APECED
  • ALPS
  • IPEX
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5
Q

Describe the underlying pathophysiology of monogenic autoinflammatory 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 and/o IL-1 is common
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6
Q

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
A
  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
  1. Familial mediterranean fever
  • Gene: MEFV
  • Protein: Pyrin-Marenostrin
  • Inheritance: Autosomal recessive
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7
Q

Describe the inflammasome complex

A

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
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8
Q

Describe the pathogenesis of Familial Mediterranean Fever

A
  • 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)
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9
Q

What is the clinical presentataion of Familial Mediterranean fever?

A
  • Periodic fevers lasting 46-96 hours associated with
    • Abdominal pain due to peritonitis
    • Chest pain due to peritonitis
    • Arthritis
    • Rash
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10
Q

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

A

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

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11
Q

What is the treatment for familial mediterranean fever?

A
  • 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)
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12
Q

What causes monogenic auto-immune disease?

A

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
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13
Q

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
  1. What are the auto-immune diseases associated?
A
  • 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
  1. Multiple auto-immune diseases:
  • Hypoparathyroidism
  • Addisons
  • Hypothyroidism
  • Diabetes
  • Vitiligo
  • Enteropathy

Huge range of autoantibodies causing a range of autoimmune endocrine disorders

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14
Q

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

1.

  • Immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome
  • IPEX
  1. What autoimmune diseases are associated with these conditions?
A

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
  1. Autoimmune conditions”
  • Enteropathy (disease of the intestine)
  • Diabetes mellitus
  • Hypothyroidism
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15
Q

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

  • Auto-immune lymphoproliferative syndrome (ALPS)
A

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
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16
Q

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)

A

B) Familial Mediterranean fever

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17
Q

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)

A

C) Auto-immune lymphoproliferative syndrome (ALPS)

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18
Q

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)

A

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

19
Q

What causes polygenic anti-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 diseases are not characterised by presence of auto-antibodies
20
Q

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

A
  • 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
21
Q

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

A
  • 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
22
Q
  1. Describe what the influences are that cause Crohn’s disease
  2. What is the basic histology of Crohn’s disease?
A

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
  1. Underlying histology of Crohn’s
  • Focal inflammation in/around crypts
  • Formation of granulomata
  • Tissue damage with mucosal ulceration
23
Q
  1. What are the clinical features of Crohn’s disease?
  2. What are the treatments for Crohn’s disease?
A
  1. Clinical features:
  • Abdominal pain and tenderness
  • Diarrhoea (blood, pus, mucous)
  • Fevers
  • Malaise
  1. Treatments
  • Corticosteroid
  • Azathioprine
  • Anti-TNF alpha antibody
  • Anti-IL 12/23 antibody
24
Q

Describe the underlying causes of mixed pattern diseases

A

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
25
Q

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
A
  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

26
Q

Where do the abnormalities occur to cause Ankylosing spondylitis?

A
  • 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)
27
Q
  1. What is the presentation of Ankylosing spondylitis?
  2. What is the treatment of ankylosing spondylitis?
A
  1. Presentation
  • Low back pain and stiffness
  • Large joint arthritis
  • Enthesitis
  • Uveitis
  1. Treatment:
  • Non steroidal anti-inflammatory drugs
  • Immunosuppression
    • Anti-TNF alpha
    • Anti-IL17
    • Anti-IL12/23
28
Q

Describe the underlying pathophysiology of polygenic auto-immne disease

A
  • 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
29
Q

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

30
Q

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
A
  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
31
Q

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

A

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
32
Q

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

A

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
33
Q

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

  • Central tolerance
  • Peripheral tolerance
A
  • 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
34
Q
  1. Describe the work done by Gel and Coombs (1960s)
  2. What is the Gel and Coombs hypersensitivity classification?
A

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
  1. 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
35
Q
  1. Describe type 1 hypersensitivity reactions
  2. What causes these reactions?
A

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
  1. Type 1 hypersensitivity can be caused by
  • Usually foreign antigen
  • Pollens
  • Drugs
  • Food
  • Insect products
36
Q
  1. Describe type 2 hypersensitivity reactions
  2. What auto-immune diseases are type 2 hypersensitivity reactions and the auto-antigens involved?
A

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
37
Q
  1. Describe type 3 hypersensitivity reactions
  2. Describe the syndromes that involve type 3 hypersensitivity reactions
A

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
38
Q
  1. Describe type 4 hypersensitivity reactions in autoimmunity CD8 T cells
  2. Describe type 4 hypersensitivity reactins in autoimmunity CD4 T cells
A
  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
  1. 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
39
Q

Describe the different syndromes that are Type 4 cell mediated diseases

40
Q

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
41
Q

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
42
Q

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
43
Q

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

Immunology - Path (9 decks)

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