Autoimmune diseases 1 Flashcards
Autoimmunity
Immune response to self antigens
Autoimmune diseases
Adaptive immune responses to self antigens contribute to tissue damage
Tolerance
A state of immunological non-reactivity to an antigen
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
Organ specific autoimmune diseases
Type 1 diabetes mellitus
Pemphigus, pemphigoid
Graves disease
Hashimotos thyroiditis
Autoimmune cytopenias: anaemia, thrombocytopenia
Non-organ specific autoimmune diseases
Systemic lupus erythematosis
Rheumatoid arthritis
Type II hypersensitivity
Antibody is clearly pathogenic
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 a
identified and characterised
Autoimmune hyperthyroidism (Graves disease)
Symptoms of hyperthyroidism (tachycardia, palpitations, tremor, anxiety, heat intolerance)
Goitre
Grave’s opthalmopathy due to poorly understood retre-orbital inflammation
All the characterisitcs of an antibody mediated disease
- neonatal hyperthyroidism if mother is affected
- serum transfers disease between experimental animals
- antibody detected and characterised
Grave’s thyroiditis
Pituitary gland secretes thyroid stimulating hormones, 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
Autoimmune B cells make antibodies against TSH receptor that also stimulate thyroid hormone production
Thyroid hormones shut down TSH production
Thyroid hormones shut down TSH production but have no effect on autoantibody production, which continues to cause excessive thyroid hormone production
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
Myasthenia gravis: neuromuscular junction
Acetylcholine receptors internalised and degraded
No Na+ influx, no muscle contraction
Spontaneous urticaria
IgG FcεR1 antibody cross links mast cell receptor causing degranulation
Manifests with hives and swelling
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
Other predominantly T cell mediated autoimmune diseases
Coeliac
Type 1 diabetes mellitus
Monogenic disorders and autoimmunity: APACED (autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy)
AIRE gene regulates ectopic expression of tissue specific antigens in thymus
AIRE mutations result in failure of negative selection
Strongly associated with organ specific autoimmune disease
Candidiasis also a key feature
DiGeorge syndrome
Failure migration 3rd/ 4th branchial arches
Full phenotype:
- absent parathyroids (low calcium, tetany)
- cleft palate
- congenital heart defects
- thymic aplasia
Microdeletion chromosomes 22
Variable presentation
Monogenic disorders and autoimmunity: IPEX (immune dysregulation, polyendorcrinopathy, enteropathy, X linked)
Exceedingly rare X linked mutation affecting Forkhead p3 gene
Abrogates production of CD4 and CD25 and 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 pagocyte Fc receptors and C3b receptors
Deficiency of C1q/C2/C4 predispose to lupus, preseumably because immune complexes cannot be cleared effectively
In addition to lupus, some patients may suffer from recurrent bacterial infections
The HLA system
APCs present processed peptide to T cells in combination with highly polymorphic MHC molecules
Encoded by HLA system on chromosome 6
- class I: A, B, C
- class II: DR, DP and DQ
Complex nomenclature used to describe tissue type in an individual
Strong association between the expression of HLA molecules and some autoimmune diseases
Coeliac disease
A very common inflammatory disease of the small bowel with GI and extra-GI 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 are malabsorption (loose stool, weight loss, vitamin deficiency, anaemia, poor growth in children) but myriad others now recognised
Coeliac disease microscopy
Total villous atrophy
Crypt hyperplasia
Lymphocyte infiltration in advanced disease
Virtually all affected individuals express
- HLA-DQ2
- HLA-DQ8
HLA and coeliac
Dietary gliadin 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
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
