Autoimmune diseases 1 Flashcards
What are autoimmune diseases?
Adaptive immune responses to self-antigens contribute to tissue damage. represents failure of tolerance.
What are the consequences of positive and negative selection?
Positive selection -> ensures receptors useful
Negative selection -> reduces auto reactivity
Why is the adaptive immune system prone to autoimmunity?
Negative selection -> some potentially auto-reactive T cells inevitably produced -> peripheral tolerance mechanisms.
Compromise:
Rigorous -> low risk of autoimmunity, poor repertoire,
increased susceptibility to infection.
Permissive -> broad repertoire, lower risk of infection,
higher risk of autoimmunity.
What are the peripheral tolerance mechanisms?
Immunological hierarchy -> CD4 T cell won’t be activated unless antigen is presented in ‘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 + other types of regulatory T cells actively suppress immune responses by cytokine + 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
What may failure of peripheral tolerance mechanisms allow?
Activation of potentially auto-reactive T cells -> development of autoimmune disease
Give examples of organ-specific autoimmune diseases?
Type 1 DM, pemphigus, pemphigoid, Graves disease
Hashimotos thyroiditis, autoimmune cytopenias ->
anaemia, thrombocytopenia.
Give examples of multi-system autoimmune diseases?
Systemic lupus erythematosis, rheumatoid arthritis,
Sjogrens syndrome
What is the type II hypersensitivity classification of AID and it’s criteria?
Autoantibodies.
Diseases where antibody is clearly pathogenic -> causes disease / tissue damage directly.
Can be transferred between experimental animals by infusion of serum or during gestation -> problems in foetus / neonate.
Removal of antibody by plasmapharesis is beneficial.
Pathogenic antibody can be identified + characterised.
What are the sequence of events that lead to autoimmune cytopenias?
RBCs + anti-RBC autoantibodies ->
FCR+ cells in fixed mononuclear phagocytic system -> phagocytosis + RBC destruction -> autoimmune haemolytic anaemia /
Complement activation + intravascular haemolysis -> lysis + RBC destruction -> autoimmune thrombocytopaenia
What are the characteristics of the antibody-mediated Graves’ disease?
Neonatal hyperthyroidism if mother is affected
Serum transfers disease between experimental animals
Antibody detected + characterised
What are the sequence of events that lead to Graves’ disease?
Pituitary secretes TSH -> TH release -> acts on pituitary to shut production of TSH -> suppresses further TH synthesis.
Autoimmune B cell makes antibodies against TSH receptor -> stimulates TH production -> shuts down TSH production, no effect on autoantibody production which continues to cause excessive TH production.
What are the signs and symptoms of myasthenia gravis?
Muscle weakness + fatiguability.
Eyelids, facial muscles, chewing, talking + swallowing most often affected
Ptosis at rest, becomes worse after patient closes + opens eyes repeatedly.
How does myasthenia gravis affect the neuromuscular junction?
ACh internalised + degraded, no Na influx -> no muscle contraction
What causes spontaneous urticaria?
IgG FcεR1 antibody cross-links mast cell receptor causing degranulation -> hives + swelling
What is the type IV hypersensitivity classification of AID and it’s criteria?
T cells
Tissue damage directly mediated by T cell-dependent mechanisms.
T cells activate macrophages + other elements of innate immunity.
CD8 T cells damage tissue directly.
Much more difficult to demonstrate auto-reactive T cells in vitro.
Experimental models rely on genetically susceptible animals that are sensitised by exposure to self-antigen with adjuvant.
What are the T cell mediated autoimmunity diseases?
Autoimmune hypothyroidism (Hashimotos thyroiditis).
Commonest cause of hypothyroidism in industrialised countries, esp. women >30.
Autoimmune destruction of thyroid -> organ infiltrated by CD4 + CD8 T cells.
Coeliac + T1 DM
What are the features of the monogenic disorder APACED?
Autoimmune polyglandular syndrome
candidiasis + ectodermal dystrophy
AIRE gene regulates ectopic expression of tissue-specific antigens in thymus.
AIRE mutations -> failure of negative selection. associated with organ-specific autoimmune diseases (T1DM, vitiligo, alopecia, autoimmune adrenal disease etc).
Candidiasis is key feature.
Due to antibodies to IL-17 –> important cytokine in host defence against fungi at mucosal surfaces.
What are the features of the monogenic disorder -DiGeorge syndrome?
Failure migration 3th/ 4th branchial arches.
Full phenotype: absent parathyroids (low calcium, tetany),
cleft palate, congenital heart defects, thymic aplasia (low T cell numbers, immunodeficiency), micro-deletions, chromosome 22, variable presentation -> huge spectrum of immunodeficiency from mild-SCID-like, autoimmunity is common.
What are the features of the monogenic disorder - IPEX?
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (mutation). exceedingly rare -> (FoxP3) gene.
Abrogates production of CD4, CD25, FoxP3+, regulatory T cells.
Inflammatory bowel disease, dermatitis, organ-specific autoimmunity.
Outline the HLA system
APCs present processed peptide to T cells in combination with highly polymorphic MHC (HLA) molecules.
Encoded by HLA system on chromosome 6:
Class I: A, B, C
Class II: DR, DP and DQ
Strong association between expression of HLA + some autoimmune diseases.
What are the features of coeliac disease?
Very common inflammatory disease of small bowel with GI + extra-GI features.
More common in women.
Characteristics of autoimmune disease, but unusually triggered by exogenous antigen (gluten) if pre-disposed.
Malabsorption -> loose stool, weight loss, vitamin deficiency, anaemia, poor growth in children.
Total villous atrophy, crypt hyperplasia + lymphocyte infiltration in advanced disease.
Which antigen triggers coeliac disease and what do affected patients express?
Dietary gliadin (wheat, rye + barley) degraded by gut tissue transglutamine 2 enzyme during digestion -> gliadin peptides -> fits inside groove of DQ2.
HLA DQ2/ 8 molecules can present these peptides to T cells if appropriate T cell receptors are present
HLA-DQ2, HLA-DQ8 or both.
Outline the pathogenesis of coeliac disease
Damage is mediated by T cells, antibodies produced but don’t contribute to tissue damage.
Inflammation resolves with strict gluten avoidance.
