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= immune responses to self-antigens; can lead to autoimmune disease

failure of 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

- 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
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



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