12. Autoimmune diseases 1 Flashcards
Autoimmunity
= immune responses to self-antigens; can lead to autoimmune disease
failure of tolerance
Tolerance
a state of immunological non-reactivity to an antigen
what are autoimmune diseases?
adaptive immune responses to self-antigens leading to tissue damage
Selection of adaptive immune lymphocytes
Gene segments randomly give repertoir
Then positive selection (to ensure receptors are useful) and negative selection (to reduce autoreactivity) to generate naive B and T cell receptors (small number of cells for each antigen, lots of receptors overall)
clonal expansion of best populations after infection
resolution of infection then death or memory cells
Permissive negative selection result
Broad repertoire
Lower risk of infection
Higher risk of autoimmunity
Rigorous negative selection result
Low risk of autoimmunity
Poor repertoire
Increased susceptibility to infection
Negative selection ideal outcome
peripheral tolerance, but some potentially autoreactive T cells inevitable produced
Peripheral tolerance mechanisms
Immunological hierarchy Antigen segregation Peripheral anergy Regulatory T cells Cytokine deviation Clonal exhaustion
Failure of peripheral tolerance mechanisms may allow activation of potentially
Auto-reactive T cells, leading to the development of autoimmune disease
Immunological hierarchy
CD4 T cell will not be activated unless antigen is presented in an ‘inflammatory’ context with TLR ligation
Antigen segregation
Physical barriers to sequestered antigen (‘immunological privilege’)
Peripheral anergy
Weak signalling between APC/ CD4 T cell without co-stimulation causes T cells to become non-responsive
Regulatory T cells
CD25+FoxP3 positive T cells and other types of regulatory T cells actively suppress immune responses by cytokine and juxtacrine signalling
Cytokine deviation
Change in T cell phenotype eg Th1 to Th2 may reduce inflammation
Clonal exhaustion
Apoptosis post-activation by activation-induced cell death
Autoantibodies: a pathogenic mechanism in AID
Gell and Coombes Type II hypersensitivity
Diseases where an antibody is clearly pathogenic and disease/ tissue damage directly
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
Autoimmune cytopenias
E.g. 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 haemolysis -> lysis and RBC destruction
Autoimmune thrombocytopaenia
Autoimmune hyperthyroidism aka Graves Disease
Symptoms: tachycardia, palpitations, tremor, anxiety, heat intolerance etc
Goitre
Grave’s ophthalmopathy due to poorly-understood retro-orbital inflammation
Has all the characteristics of an antibody-mediated disease:
- Neonatal hyperthyroidism if mother is affected
- Serum transfers disease between experimental animals
- Antibody detected and characterised
Grave’s thyroiditis pathophysiology
Pituitary gland secretes TSH which acts on thyroid to induce release of TH, which act on pituitary in neg feedback to shutdown production of TSH to stop more TH
Autoimmune B cell makes antibodies against TSH receptor that also stimulate TH production, TH shuts down TSH production but no effect on autoantibody production, so continues to cause excess TH production
Antibody-mediated autoimmune disease: myasthenia gravis
Muscle weakness and fatigability
Eyelids, facial muscles, chewing, talking and swallowing most often affected
Myasthenia gravis pathophysiology
normally ACh binds to AChR leading to Na+ influx causes muscle contraction
In MG: autoantibodies to AChR bind them leading to AChR internalised and degraded, and no Na+ influx and no muscle contraction
Spontaneous urticaria
IgG FcεR1 antibody cross-links mast cell receptor causing degranulation. Manifests with hives and swelling
Pathogenic mechanisms in AID: T cells
Gell and Coombes Type IV hypersensitivity
Tissue damage is directly mediated by T cell-dependent mechanisms:
- T cells activate macrophages and other elements of innate immunity:
- CD8 T cells damage tissue directly
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
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
Classification of AID with a few examples
Organ specific: Type 1 diabetes mellitus Pemphigus, pemphigoid Graves disease Hashimotos thyroiditis Autoimmune cytopenias: anaemia, thrombocytopenia
Non-organ specific: systemic lupus erythematosis, rheumatoid arthritis
Do autoimmune diseases have one main pathogenic immune mechanism?
No, Multiple pathogenic immune mechanisms underlie autoimmune diseases
need T cells, B cells and APCs
This is particularly true of the chronic, multi-system autoimmune disorders such as rheumatoid arthritis (see symposium) and SLE, where multiple immune mechanisms become involved
Genetics and autoimmunity
Evidence for importance:
- 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?
A monogenic disorder leading to autoimmunity
stands for autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy
Caused by AIRE mutations resulting in failure of negative selection
AIRE gene normally regulates ectopic expression of tissue-specific antigens in thymus
APACED Strongly associated with organ-specific autoimmune diseases e.g. T1DM vitiligo, alopecia, autoimmune adrenal disease etc)
Candidiasis also a key feature of the disease
due to IL-17 autoantibodies which stops fungi at mucosa
DiGeorge Syndrome
Failure migration 3th/ 4th branchial arches
due to microdeletions chromosome 22
Full phenotype: Absent parathyroids (low calcium, tetany) Cleft palate Congenital heart defects Thymic aplasia (low T cell numbers, immunodeficiency)
Variable presentation
- May affect any of above in isolation
- Huge spectrum of immunodeficiency from mild-SCID-like
- Autoimmunity is also common
IPEX
Monogenic disorder leading to 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
Key features:
- Inflammatory bowel disease
- Dermatitis
- Organ-specific autoimmunity
Monogenic disorders and autoimmunity: classical complement deficiency
Immune complexes are cleared by phagocytes; process enhanced by phagocyte Fc receptors and C3b receptors
Deficiency of C1q/ C2/ C4 predispose to lupus, because immune complexes cannot be cleared effectively
Can also suffer from recurrent bacterial infections
The HLA system
APCs present processed peptide to T cells in combination with highly polymorphic MHC (HLA) molecules
Encoded by the HLA system on chromosome 6
Class I: A, B, C
Class II: DR, DP and DQ
Strong association between the expression of HLA molecules and some autoimmune diseases
What does HLA B27 and HLA DR2 mean
HLA B27=expresses serotype 27 at B locus of HLA class I
HLA DR2=expresses serotype 2 at locus 2 of HLA class II
Coeliac disease
A very common inflammatory disease of the small bowel with gastrointestinal and extra-gastrointestinal features
- <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 are malabsorption (loose stool, weight loss, vitamin deficiency, anaemia, poor growth in children) but myriad others now recognised
Coeliac disease 2 histology and genetics
Total villous atrophy
crypt hyperplasia
lymphocyte infiltration in advanced disease
Virtually all affected individuals express:
HLA-DQ2
HLA-DQ8
………or both
Link between HLA and coeliac
Dietary gliadin (wheat, rye and barley) is degraded by gut tissue transglutamine 2 enzyme during digestion to produce gliadin peptides
HLA DQ2/ 8 molecules can present these gliadin peptides to T cells if the appropriate T cell receptors are present
Coeliac pathogenesis
Damage is mediated by
T cells; antibodies
are produced but don’t
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
