12. Autoimmune diseases 1 Flashcards
Define autoimmune diseases
Where adaptive immune responses to self-antigens contribute to tissue damage
Tolerance
a state of immunological non-reactivity to an antigen
Autoimmunity is a failure of tolerance
Negative selection
Reduces autoreactive T cells
Can be rigorous- increasing susceptibility to infections or permissive (increasing risk of autoimmunity)
Mechanisms of peripheral tolerance [6]
Immunological hierarchy- CD4 T cell will not be activated unless antigen is presented in an ‘inflammatory’ context with TLR ligation
Antigen segregation- immune priviledge sites
Peripheral anergy- no costimulation of CD40L inhibition
Regulatory T cells
Cytokine deviation- Change in T cell phenotype eg Th1 to Th2 may reduce inflammation
Clonal exhaustion- Apoptosis post-activation by activation-induced cell death
Pathogenic mechanism of Type 2 hypersensitivity diseases [5]
diseases where an antibody is clearly pathogenic (autoantibodies)
Examples of antibody-mediated diseases
Autoimmune haemolytic anaemia
Autoimmune thrombocytopaenia
Autoimmune haemolytic anaemia
-clinical presentation
Type 2 hypersensitivty
- Anti-RBCs autoantibodies are generated and bind to RBCs
- RBCs are seen as pathogenic and are destroyed by phagocytosis and activate complement
Clinical presentation- anaemia
jaundice
Autoimmune thrombocytopaenia
-clinical presentation
pupura, rash
Give an example of antibody mediated disease affecting thyroid function
Graves disease
Symptoms of hyperthyroidism (tachycardia, palpitations, tremor, anxiety, heat intolerance etc)
Goitre
Grave’s ophthalmopathy
Graves disease immunology
Pituitary gland secretes TSH to induce release of TH
TH acts on pituitary to shut down production of TSH (neg feedback)
Autoimmune B cell makes ab against TSH receptor to also stimulate TH
TH shuts down TSH production but have no effect on autoantibody production, so XS TH
Myasthenia gravis
Type 2 hypersensitivity
Antibody-mediated autoimmune disease
ACh receptors internalised and degraded, no Na+ influx, no muscle contraction
Symptoms: Muscle weakness and fatigability
Signs: 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
Spontaneous urticaria
IgG FcεR1 antibody cross-links mast cell receptor causing degranulation.
Presents
- Hives
- Swelling
Type IV hypersensitivity
Tissue damage is directly mediated by T cell-dependent mechanisms
Autoimmune Hypothyroidism
T cell mediated
Type 4 hypersensitivity reaction
Autoimmune destruction of thyroid: organ infiltrated by CD4 and CD8 T cells
APACED
Monogenic disorder
- AIRE gene regulates ectopic expression of tissue-specific antigens in thymus
- AIRE mutations result in failure of negative selection
- Associated with organ specific autoimmune diseases
Candidiasis also a key feature of the disease
DiGeorge syndrome
22q11.2 deletion syndrome
Absent parathyroids and thymus
Deficiency of T cells
Coeliacs disease
Exogenouse gluten is considered antigenic and broke down into gliadin peptides using transglutaminase 2
IL-17
Cytokine important in host defence against fungi at mucosal surfaces
Antibodies to IL-17 can result in APACED
IPEX
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
Outline the HLA naming system
APCs present processed peptide to T cells in combination with highly polymorphic MHC (HLA) molecules
Encoded by the HLA system on chr6
Class 1: A,B,C
Class 2: DR, DP, DQ
Patients with Coeliacs disease express which tissue type
HLA-DQ2
HLA-DQ8
………or both
Pathogenesis of Coeliacs disease
The damage is mediated by
T cells; note that antibodies
are produced, but do not
contribute to tissue damage
