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Year 2 - T3 Theme 1 > L12 - Autoimmune diseases 1 > Flashcards

L12 - Autoimmune diseases 1 Flashcards

1
Q

What is autoimmunity

A
  • Immune responses to self-antigens
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2
Q

Autoimmune diseases

A
  • Adaptive immune responses to self-antigens which contribute to tissue damage
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3
Q

Tolerance

A
  • A state of immunological non-reactivity to an antigen

- Autoimmunity represents a failure of tolerance

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4
Q

Why are some inflammatory diseases not classified as autoimmune diseases

A
  • Diseases such as sarcoidosis and IBDs are inflammatory diseases but are not classified as autoimmune diseases because they have not been demonstrated to involve adaptive immune responses to self antigens
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5
Q

Selection of adaptive immune lymphocytes

A

Gene segments –> Naive B and T cell receptors (positive selection ensures receptors are useful, negative selection reduces autoreactivity)

Naive B and T cell receptors (small numbers of cells for each antigen, very large number of receptors overall) –infection–> expansion of best populations –resolution–> die or memory cells

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6
Q

What type of selection can lead to peripheral tolerance mechanisms

A
  • Negative selection

- Some potentially auto-reactive T cells inevitably produced

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7
Q

Effects of a rigorous adaptive immune system

A
  • Low risk of autoimmunity
  • Poor repertoire
  • Increased susceptibility to infection
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8
Q

Effects of a permissive adaptive immune system

A
  • Broad repertoire
  • Lower risk of infection
  • Higher risk of autoimmunity
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9
Q

Peripheral tolerance mechanisms

A
  • Immunological hierarchy
  • Antigen segregation
  • Peripheral anergy
  • Regulatory T cells
  • Cytokine deviation
  • Clonal exhaustion
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10
Q

What is an immunological hierarchy

A
  • CD4 T cell will not be activated unless antigen is presented in an ‘inflammatory’ context with TLR ligation
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11
Q

What is antigen segregation

A
  • Physical barriers to sequestered antigen (‘immunological privilege’)
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12
Q

What is peripheral anergy

A
  • Weak signalling between APC/CD4 T cell without co-stimulation causes T cells to become non-responsive
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13
Q

What are regulatory T cells

A
  • CD25+FoxP3 positive T cells and other types of regulatory T cells actively suppress immune responses by cytokine and juxtacrine signalling
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14
Q

What is cytokine deviation

A
  • Change in T cell phenotype eg Th1 to Th2 may reduce inflammation
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15
Q

Clonal exhaustion

A
  • Apoptosis post-activation by activation-induced cell death
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16
Q

What can failure of peripheral tolerance mechanisms cause

A
  • May allow actiation of potentially auto-reactive T cells, leading to the development of autoimmune disease
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17
Q

Examples of organ-specific autoimmune diseases

A
  • T1DM
  • Pemphigus, pemphigoid
  • Graves disease
  • Hashimotos thyroiditis
  • Autoimmune cytopenias: anaemia, thrombocytopenia
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18
Q

Examples of non organ-specific autoimmune diseases

A
  • Systemic lupus erythematosis

- Rheumatoid arthritis

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19
Q

Pathogenic mechanisms in AID: autoantibodies

A
  • Type II hypersensitivity according to Gell and coombes classification
  • Refers to diseases where an antibody is clearly pathogenic ie causes disease/tissue damage directly
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20
Q

Type II hypersensitivity criteria

A
  • Disease can be transferred between experimental animals by infusion of serum, or during gestation to cause problems in fetus/neonate
  • Removal of antibody by plasmapharesis is beneficial
  • A pathogenic antibody can be identified and characterised
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21
Q

Pathogenesis - Autoimmune haemolytic anaemia

A

Red blood cells plus anti-RBC autoantibodies leads to

  • FcR+ cells in fixed mononuclear phagocytic system –> phagocytosis and RBC destruction
  • Complement activation and intravascular hemolysis –> lysis and RBC destruction
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22
Q

What is autoimmune thrombocytopenia

A
  • Is a disorder of low blood platelet counts in which platelets are destroyed by antibodies produced by the immune system
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23
Q

Symptoms of hyperthyroidism

A
  • Tachycardia
  • Palpitations
  • Tremor
  • Anxiety
  • Heat tolerance
24
Q

What is a goitre a sign of

A
  • Goitre
25
Q

What is graves disease

A
  • Antibody-mediated autoimmune disease: autoimmune hyperthyroidism
26
Q

What is grave’s opthalmopathy caused by

A
  • Grave’s opthalmopathy due to poorly understood retro-orbital inflammation
27
Q

Why is graves disease classified as an antibody-mediated disease

A
  • Neonatal hyperthyroidism if mother is affected
  • Serum transfers disease between experimental animals
  • Antibody detected and characterised
28
Q

Pathogenesis - Grave’s thyroiditis

A
  • The pituitary gland secretes TSH which acts on the thyroid to induce the release of thyroid hormones
  • Thyroid hormones act on the pituitary to shut down production of TSH, suppressing further thyroid hormone synthesis(feedback suppression)
  • Autoimmune B cell makes antibodies against TSH receptor that also stimulate thyroid hormone production
  • Thyroid hormones shut down TSH production but have no effect on autoantibody production, which continues to cause excessive thyroid hormone production
29
Q

Antibody-mediated autoimmune disease - myasthenia gravis

A
  • Muscle weakness and fatigability
  • Eyelids, facial muscles, chewing, talking and swallowing most often affected
  • Ptosis at rest, becoming markedly worse after patient asked to close and open eyes repeatedly
30
Q

Changes in events at NMJ during myasthenia gravis

A
  • Acetylcholine receptors internalised and degraded

- So no Na+ influx and no muscle contraction

31
Q

What is spontaneous urticaria

A
  • IgG Fc epsilonR1 antibody cross-links mast cell receptor causing degranulation (Fc receptor for IgE antibody)
  • Manifests with hives and swelling
32
Q

Why aren’t auto-antibodies part of the criteria for classification of autoimmune diseases

A
  • Antibodies seemed to be produced as a by-product of the inflammatory process
  • They do not fulfil the criteria to be pathogenic
  • They are useful for diagnosis eg tissue transglutaminase antibody (coeliac), islet cell antibody (diabetes), gastric parietal cell antibody (pernicious anaemia) etc
33
Q

Pathogenic mechanisms in AID: T cells

A
  • Type IV hypersensitivity according to Gell and Coombes
  • Tissue damage is directly mediated by T cell-dependent mechanisms
  • Much more difficult to demonstrate autoreactive T cells in vitro than it is to demonstrate antibody
  • Experimental models rely on genetically susceptible animals that are sensitised, often by exposure to a self-antigen with an adjuvant
34
Q

Mechanisms via which tissue damage is mediated by T cell-dependent mechanisms

A
  • T cells activate macrophages and other elements of innate immunity
  • CD8 T cells damage tissue directly
35
Q

Features of T cell-mediated autoimmunity: autoimmune hypothyroidism (hashimotos thyroiditis)

A
  • Commonest cause of hypothyroidism in industrialised countries
  • Particularly women over 30
  • Autoimmune destruction of thyroid organ infiltrated by CD4 and CD8 T cells
36
Q

Examples of other predominantly T cell mediated autoimmune diseases

A
  • Coeliac

- Type 1 diabetes mellitus

37
Q

Genetics and autoimmunity

A
  • Rare monogenic disorders of the immune system that are associated with autoimmune diseases
  • Mouse models rely on genetically susceptible strains eg NOD mouse
  • Enrichment in families, mostly attributable to HLA associations
  • Environment clearly also important
38
Q

What is ‘APACED’ - monogenic disorders and autoimmunity

A

Autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy

39
Q

Relevance of the AIRE gene

A
  • AIRE gene regulates ectopic expression of tissue-specific antigens in thymus
40
Q

What do AIRE mutations result in

A
  • Failure of negative selection

- Strongly associated with organ-specific autoimmune diseases (T1DM, vitiligo, alopecia, autoimmune adrenal disease etc)

41
Q

What does candidiasis result from

A
  • Results from antibodies to IL-17 - this cytokine seems to be important in host defence against fungi at mucosal surfaces
42
Q

What is DiGeorge syndrome caused by

A
  • Failure migration 3rd/4th branchial arches
43
Q

Features of DiGeorge syndrome - full phenotype

A

Full phenotype:

  • Absent parathyroids (low calcium, tetany)
  • Cleft palate
  • Congenital heart defects
  • Thymic aplasia (low T cell numbers, immunodeficiency)
44
Q

Chromosome associated with DiGeorge syndrome

A

Microdeletions chromosome 22

45
Q

DiGeorge syndrome - variable presentation

A
  • Huge spectrum of immunodeficiency from mild-SCID-like

- Autommunity s also common

46
Q

What is IPEX - monogenic disorders and autoimmunity

A
  • Immune dysregulation
  • Polyendocrinopathy
  • Enteropathy
  • X-linked
  • Exceedingly rare X linked mutation affecting forkhead p3 (FoxP3) gene
  • Abrogates production of CD4+CD25+FoxP3 + regulatory T cells
  • IBD, dermatitis, organ-specific autoimmunity
47
Q

What are immune complexes cleared by

A
  • Immune complexes are cleared by phagocytes: process enhanced by Fc receptors and C3b receptors
48
Q

What can a deficiency of C1q/C2/C4 predispose

A
  • Can predispose to lupus, presumably because immune complexes cannot be cleared effectively
  • In addition to lupus, some patients may suffer from recurrent bacterial infections
49
Q

Features of the HLA system

A
  • APCs present processed peptide to T cells in combination with highly polymorphic MHC (HLA) molecules
  • Strong association between the expression of HLA molecules and autoimmune diseases
50
Q

What is the HLA system encoded by

A
  • Encoded by the HLA system on chromosome 6

Class I: A, B, C
Class II: DR, DP and DQ

51
Q

Features of coeliac disease

A

A very common inflammatory disease of the small bowel with gastrointestinal and extra-gastrointestinal features:

  • Up to 1% UK population affected
  • More common in women
  • Majority undiagnosed
  • Characteristics of an autoimmune disease, but unusually triggered by an exogenous antigen (gluten) in pre-disposed individuals
52
Q

Main manifestations of coeliac disease

A
  • Malabsorption(loose stool, weight loss, vitamin deficiency, anaemia, poor growth in children) but myriad others now recognised
53
Q

Microscopic features of coeliac disease

A
  • Total villous atrophy
  • Crypt hyperplasia
  • Lymphocyte infiltration in advanced disease
54
Q

Genes expressed in coeliac disease

A
  • HLA-DQ2

- HLA-DQ8

55
Q

What is dietary gliadin degraded by

A
  • Degraded by gut tissue transglutamine 2 enzyme during digestion to produce gliadin peptides
56
Q

What can present gliadin peptides to T cells if there are the appropriate T cell receptors present

A
  • HLA DQ2/ 8 molecules can present these gliadin peptides to T cells if the appropriate T cell receptors are present
57
Q

Coeliac pathogenesis

A
  • The damage is mediated by T cells; note that antibodies are produced, but do not contribute to tissue damage
  • Inflammation resolves with strict gluten avoidance
  • 30-50% of europeans express HLA-DQ2 and/or HLA-DQ8 - not clear which additional genetic/environmental factors are important in coeliac

Year 2 - T3 Theme 1 (15 decks)

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