L12- autoiimune diseases Flashcards
define Autoimmunity
Autoimmune diseases
Tolerance
Failure of tolerance
1- Immune response to self antigens
2- in which adaptive responses to self-antigens contribute to tissue damage
3- a state of immunological non-reactivity t an antigen
4- Represented by autoimmunity
how is the adaptive immune system prone to auto immunity:
although some antibodies are negatively selected for (promoting peripheral tolerance mechanisms, although some potentially auto-reactive T cells are produced ), others are either permissively allowed or rigorously selected for.
Those that are rigorously selected for exhbit:1-lower risk of autoimmunity, 2-poor repertoire, 3- increased susceptibility to infection
Permissively-1-broad repertoire, 2- lower risk of infection, 3- higher risk of autoimmunity
list and explain some peripheral tolerance mechanisms
1-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
give 2 classifications of autoimmune antibodies and their examples
1-organ specific and 2-non-organ specific
1- T1 diabetes mellitus, graves disease, hashimotos
2- systemic lupus erythematosus, Rheumatoid arthritis
what is type 2 hypersensitivity and its criteria :
Refers to diseases where an antibody is clearly pathogenic ie causes disease/ tissue damage directly
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
describe Antibody-mediated disease: autoimmune cytopenias
1: Autoimmune haemolytic anaemia- red blood cells plus anti-RBC autoantibodies
can cause complement activation and intravascular haemolysis- leads to rbc destruction and lysis
or FCR+ cells in fixed mononuclear phagocytic system-phagocytosis and RBS destruction
2: also autoimmune thrombocytopenia
Describe graves disease
Symptoms of hyperthyroidism (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
how is graves thyroiditis caused
- TSH acts on thyroid inducing release of thyroid hormones
- Autoimmune B cells makes antibodies against TSH receptor that also stimulate thyroid hormone production
- thyroid hormones act on pituitary to shut down production of TSH, suppressing further thyroid hormone synthesis
- throid hormones shut down TSH production but have no effect on autoantibody production, which continues to cause excessive thyroid hormone production
what are the symptoms of 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
what causes myasthenia gravis
Its an antibody-mediated autoimmune disease where :
- antibodies attack the ACH receptors which result in them being internalised and degraded
- this means there is no influx of na and therefore no muscle contraction
describe spontaneous Urticaria
IgG FcεR1 antibody cross-links mast cell receptor causing degranulation. Manifests with hives and swelling
A note about antibodies and autoimmune disease
In these examples, the auto-antibody is said to be ‘pathogenic’ as it is directly leading to disease
Auto-antibodies are also found in myriad other autoimmune diseases
These antibodies seem to be produced as a by-product of the inflammatory process. They don’t fulfil the criteria to be pathogenic
They are useful for diagnosis – see next lecture, eg
Tissue transglutaminase antibody (coeliac), islet cell antibody (diabetes), gastric parietal cell antibody (pernicious anaemia) etc etc
what is type 4 hypersensitivity according to Gell and coombes
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
describe 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
name some other T cell mediated autoimmune diseases
Coeliac: see later slides
Type 1 diabetes mellitus: see later slides
what are the evidence that genetics is importance in regards to 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
evidence of genetics importance in autoimmunity for mice studies
Littermates in this group of non-obese diabetic mice have an identical genetic background and a very similar environment, but even so there is variability in the development of type 1 diabetes mellitus. Note also that female mice are more susceptible.
describe 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 auutoimmune diseases (type 1 diabetes, vitiligo, alopecia, autoimmune adrenal disease etc)
Results from antibodies to IL-17 – this cytokine seems to be important in host defence against fungi at mucosal surfaces
describe DiGeorge syndromes
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)
Microdeletions chromosome 22
Variable presentation
- May affect any of above in isolation
- Huge spectrum of immunodeficiency from mild-SCID-like
- Autoimmunity is also common
describe Monogenic disorders and autoimmunity: 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
describe 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, presumably because immune complexes cannot be cleared effectively (see Professor Davies lecture)
In addition to lupus, some patients may suffer from recurrent bacterial infections
what IS THE 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
Complex nomenclature used to describe ‘tissue type’ in an individual Eg HLA B27=expresses serotype 27 at B locus of HLA class I EG HLA DR2=expresses serotype 2 at locus 2 of HLA class II
Strong association between the expression of HLA molecules and some autoimmune diseases
describe 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 are malabsorption (loose stool, weight loss, vitamin deficiency, anaemia, poor growth in children) but myriad others now recognised
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
what occurs to the Villi in coeliac disease
Total villous atrophy, crypt hyperplasia and lymphocyte infiltration in advanced disease
