Lecture 18: Immunology of the Endocrine System

Question 1

Central immunological tolerance mechanisms

Answer 1

• 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.

Question 2

what happens to mature lymphocytes that recognise self-antigens in peripheral tissues?

in normal health

Answer 2

• mature lymphocytes that recognise self-antigens in peripheral tissues become incapable of activation by re-exposure to that antigen or die by apoptosis.

Question 3

mechanisms of peripheral tolerance

Answer 3

• anergy (functional unresponsiveness)
• Treg suppression
• Deletion (cell death)

Question 4

how can peripheral tolerance be overcome (leading to autoimmune disease)?

Answer 4

• 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.

Question 5

epidemiology of autoimmune disease

Answer 5

• 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).

Question 6

list the aetiology of autoimmune disease

Answer 6

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

Question 7

describe molecular mimicry and give an example

Answer 7

• 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

Question 8

Aims of autoimmune disease treatment

Answer 8

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

Question 9

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Answer 9

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Question 10

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Answer 10

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Question 11

aetiology of type 1 diabetes

Answer 11

• 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

Question 12

list some causes of hyperthyroidism

Answer 12

• graves thyroiditis
• functioning adenoma
• toxic nodular goitre
• exogenous thyroid hormone (rare)
• ectopic secretion by ectopic thyroid tissue or tumours

Question 13

which two autoantibodies can be detected in the serum of most patients with Hashimoto thyroidits?

Answer 13

• one reacting with thyroid peroxidase
• the other reacting with thyroglobulin

Question 14

describe autoimmune polyendocrine syndrome type 1 (APS-1)

Answer 14

• 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.

Question 15

clinical features of APS-1

Answer 15

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).

Question 16

list the less frequenct and rare clinical features of APS-1

Answer 16

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

Question 17

describe autoimmune polyendocrine syndrome type 2 (APS-2)

Answer 17

• 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.

Question 18

in APS-2, which other autoimmune conditions can commonly develop?

Answer 18

• coeliac disease
• alopecia, vitiligo
• primary ovarian insufficiency
• pernicious anaemia

Question 19

describe X-linked immunodysregulation, polyendocrinopathy and enteropathy (IPEX)

Answer 19

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.