Lecture 18: Immunology of the Endocrine System Flashcards
Central immunological tolerance mechanisms
- self-tolerance may be induced in immature self-reactive lymphocytes in the generative lymphoid organs.
- the thymus plays an important role in eliminating T cells with high affinity to self-antigens.
- bone marrow is important in B cell tolerance.
what happens to mature lymphocytes that recognise self-antigens in peripheral tissues?
in normal health
- mature lymphocytes that recognise self-antigens in peripheral tissues become incapable of activation by re-exposure to that antigen or die by apoptosis.
mechanisms of peripheral tolerance
- anergy (functional unresponsiveness)
- Treg suppression
- Deletion (cell death)
how can peripheral tolerance be overcome (leading to autoimmune disease)?
- inappropriate access of self-antigens
- inappropriate or increased local expression of co-stimulatory molecules
- alterations in the way self-molecules are presented to the immune system
The structures of self-peptides may be altered by viruses, free-radicals, or ionising radiation, thus bypassing previously established tolerance.
epidemiology of autoimmune disease
- it is estimated that 3% of the population have some sort of autoimmune disease.
- show clustering within families.
- peak onset of 15-65 years (exception; type 1 diabetes mellitus)
- almost all types of autoimmune diseases are more common in women (except ankolysing spondylitis).
list the aetiology of autoimmune disease
Genetic factors:
- clusters within families
- alleles of MHC
Infections:
- molecular mimicry
- up-regulation of co-stimulation
- antigen breakdown and presentation changes
Drugs:
- molecular mimicry
- genetic variation in drug metabolism
UV radiation:
- trigger for skin inflammation
- modification of self-antigen
describe molecular mimicry and give an example
- structural similarity between self-proteins and microbial antigens may trigger an autoimmune response.
- In systemic infection, this cross-reactivity will cause expansion of the responsive T-cell population recognising the self-peptide if local conditions allow.
Example:
- microbial antigen: Coxsackie B4 nuclear protein, has a similar structure to
- self-antigen: pancreatic islet cell glutamaye decarboxylase
- consequential molecular mimicry may play a role in developing insulin-dependent diabetes mellitus
Aims of autoimmune disease treatment
Suppression of the damaging immune response:
- before irreversible tissue damage
- early detection is a challenge
- problem with specificity of treatments and toxicity
Replacement of the function of the damaged organ:
- e.g. thyroxine for hypothyroidism
- e.g. insulin for insulin dependent diabetes mellitus
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aetiology of type 1 diabetes
- autoimmune destruction
- genetic factors: association with certain HLA types
- viral infection: viruses may act as triggers for autoimmune destruction e.g. coxsackie B and mumps
list some causes of hyperthyroidism
- graves thyroiditis
- functioning adenoma
- toxic nodular goitre
- exogenous thyroid hormone (rare)
- ectopic secretion by ectopic thyroid tissue or tumours
which two autoantibodies can be detected in the serum of most patients with Hashimoto thyroidits?
- one reacting with thyroid peroxidase
- the other reacting with thyroglobulin
describe autoimmune polyendocrine syndrome type 1 (APS-1)
- APS-1 is a rare autosomal recessive disease caused by mutations in the autoimmune regulator gene (AIRE).
- The estimates prevalence is roughly 1:100,000 in most countries, with a higher prevalence in some counties.
clinical features of APS-1
At least 2 of the 3 cardinal components during childhood:
- chronic mucocutaneous candidiasis
- hypoparathyroidism
- primary adrenal insufficiency (Addison’s disease)
Other typical components:
- enamel hypoplasia
- enteropathy with chronic diarrhoea or constipation
- primary ovarian insufficiency (approx 60% of women with APS-1 before they reach 30 years of age).
list the less frequenct and rare clinical features of APS-1
Less frequent:
- bilateral keratitis (accompanied by severe photophobia)
- periodic fever with rash
- autoimmunity-induced hepatitis, pneuomonitis, nephritis, exocrine pancreatitis and functional asplenia.
Rare:
- retinitis
- metaphyseal dysplasia
- pure red-cell aplasia
- polyarthritis
describe autoimmune polyendocrine syndrome type 2 (APS-2)
- APS-2 is more common than APS-1 (estimated prevalence 1:1000).
- Patients with APS-2 have at least two of the following three endocrinopaties:
> type 1 diabetes
> autoimmune thyroid disease
> Addison’s disease - in many affected patients other autoimmune conditions develop.
- the onset of APS-2 typically occurs in young adulthood, later than the onset of APS-1.
in APS-2, which other autoimmune conditions can commonly develop?
- coeliac disease
- alopecia, vitiligo
- primary ovarian insufficiency
- pernicious anaemia
describe X-linked immunodysregulation, polyendocrinopathy and enteropathy (IPEX)
An extremely rare inherited syndrome (1:1000000) characterised by:
- early onset type 1 diabetes
- autoimmune enteropathy with intractable diarrheal and malabsorption
- dermatitis that may be eczematiform, ichthyosiform, or psoriasiform.
- IPEX is frequently fatal in the first few years of life unless patients are promptly treated with immunosuppressive agents or, if possible, with allogeneic bone marrow transplantation, which can cure the disease.
