L12 - Autoimmune diseases 1 Flashcards
What is autoimmunity
- Immune responses to self-antigens
Autoimmune diseases
- Adaptive immune responses to self-antigens which contribute to tissue damage
Tolerance
- A state of immunological non-reactivity to an antigen
- Autoimmunity represents a failure of tolerance
Why are some inflammatory diseases not classified as autoimmune diseases
- 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
Selection of adaptive immune lymphocytes
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
What type of selection can lead to peripheral tolerance mechanisms
- Negative selection
- Some potentially auto-reactive T cells inevitably produced
Effects of a rigorous adaptive immune system
- Low risk of autoimmunity
- Poor repertoire
- Increased susceptibility to infection
Effects of a permissive adaptive immune system
- Broad repertoire
- Lower risk of infection
- Higher risk of autoimmunity
Peripheral tolerance mechanisms
- Immunological hierarchy
- Antigen segregation
- Peripheral anergy
- Regulatory T cells
- Cytokine deviation
- Clonal exhaustion
What is an immunological hierarchy
- CD4 T cell will not be activated unless antigen is presented in an ‘inflammatory’ context with TLR ligation
What is antigen segregation
- Physical barriers to sequestered antigen (‘immunological privilege’)
What is peripheral anergy
- Weak signalling between APC/CD4 T cell without co-stimulation causes T cells to become non-responsive
What are regulatory T cells
- CD25+FoxP3 positive T cells and other types of regulatory T cells actively suppress immune responses by cytokine and juxtacrine signalling
What is cytokine deviation
- Change in T cell phenotype eg Th1 to Th2 may reduce inflammation
Clonal exhaustion
- Apoptosis post-activation by activation-induced cell death
What can failure of peripheral tolerance mechanisms cause
- May allow actiation of potentially auto-reactive T cells, leading to the development of autoimmune disease
Examples of organ-specific autoimmune diseases
- T1DM
- Pemphigus, pemphigoid
- Graves disease
- Hashimotos thyroiditis
- Autoimmune cytopenias: anaemia, thrombocytopenia
Examples of non organ-specific autoimmune diseases
- Systemic lupus erythematosis
- Rheumatoid arthritis
Pathogenic mechanisms in AID: autoantibodies
- Type II hypersensitivity according to Gell and coombes classification
- Refers to diseases where an antibody is clearly pathogenic ie causes disease/tissue damage directly
Type II hypersensitivity criteria
- 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
Pathogenesis - Autoimmune haemolytic anaemia
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
What is autoimmune thrombocytopenia
- Is a disorder of low blood platelet counts in which platelets are destroyed by antibodies produced by the immune system
Symptoms of hyperthyroidism
- Tachycardia
- Palpitations
- Tremor
- Anxiety
- Heat tolerance
What is a goitre a sign of
- Goitre
What is graves disease
- Antibody-mediated autoimmune disease: autoimmune hyperthyroidism
What is grave’s opthalmopathy caused by
- Grave’s opthalmopathy due to poorly understood retro-orbital inflammation
Why is graves disease classified as an antibody-mediated disease
- Neonatal hyperthyroidism if mother is affected
- Serum transfers disease between experimental animals
- Antibody detected and characterised
Pathogenesis - Grave’s thyroiditis
- 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
Antibody-mediated autoimmune disease - myasthenia gravis
- 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
Changes in events at NMJ during myasthenia gravis
- Acetylcholine receptors internalised and degraded
- So no Na+ influx and no muscle contraction
What is spontaneous urticaria
- IgG Fc epsilonR1 antibody cross-links mast cell receptor causing degranulation (Fc receptor for IgE antibody)
- Manifests with hives and swelling
Why aren’t auto-antibodies part of the criteria for classification of autoimmune diseases
- 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
Pathogenic mechanisms in AID: T cells
- 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
Mechanisms via which tissue damage is mediated by T cell-dependent mechanisms
- T cells activate macrophages and other elements of innate immunity
- CD8 T cells damage tissue directly
Features of T cell-mediated autoimmunity: autoimmune hypothyroidism (hashimotos thyroiditis)
- Commonest cause of hypothyroidism in industrialised countries
- Particularly women over 30
- Autoimmune destruction of thyroid organ infiltrated by CD4 and CD8 T cells
Examples of other predominantly T cell mediated autoimmune diseases
- Coeliac
- Type 1 diabetes mellitus
Genetics and autoimmunity
- 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
What is ‘APACED’ - monogenic disorders and autoimmunity
Autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy
Relevance of the AIRE gene
- AIRE gene regulates ectopic expression of tissue-specific antigens in thymus
What do AIRE mutations result in
- Failure of negative selection
- Strongly associated with organ-specific autoimmune diseases (T1DM, vitiligo, alopecia, autoimmune adrenal disease etc)
What does candidiasis result from
- Results from antibodies to IL-17 - this cytokine seems to be important in host defence against fungi at mucosal surfaces
What is DiGeorge syndrome caused by
- Failure migration 3rd/4th branchial arches
Features of DiGeorge syndrome - full phenotype
Full phenotype:
- Absent parathyroids (low calcium, tetany)
- Cleft palate
- Congenital heart defects
- Thymic aplasia (low T cell numbers, immunodeficiency)
Chromosome associated with DiGeorge syndrome
Microdeletions chromosome 22
DiGeorge syndrome - variable presentation
- Huge spectrum of immunodeficiency from mild-SCID-like
- Autommunity s also common
What is IPEX - monogenic disorders and autoimmunity
- 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
What are immune complexes cleared by
- Immune complexes are cleared by phagocytes: process enhanced by Fc receptors and C3b receptors
What can a deficiency of C1q/C2/C4 predispose
- Can predispose to lupus, presumably because immune complexes cannot be cleared effectively
- In addition to lupus, some patients may suffer from recurrent bacterial infections
Features of the HLA system
- 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
What is the HLA system encoded by
- Encoded by the HLA system on chromosome 6
Class I: A, B, C
Class II: DR, DP and DQ
Features of coeliac disease
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
Main manifestations of coeliac disease
- Malabsorption(loose stool, weight loss, vitamin deficiency, anaemia, poor growth in children) but myriad others now recognised
Microscopic features of coeliac disease
- Total villous atrophy
- Crypt hyperplasia
- Lymphocyte infiltration in advanced disease
Genes expressed in coeliac disease
- HLA-DQ2
- HLA-DQ8
What is dietary gliadin degraded by
- Degraded by gut tissue transglutamine 2 enzyme during digestion to produce gliadin peptides
What can present gliadin peptides to T cells if there are the appropriate T cell receptors present
- HLA DQ2/ 8 molecules can present these gliadin peptides to T cells if the appropriate T cell receptors are present
Coeliac pathogenesis
- 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
