Immunological aspects of endocrine disease

Autoimmune disease is the most frequent cause of overactivity and underactivity of endocrine organs; common in apparently healthy people, especially females.

Iceberg model of endocrine autoimmunity:

Genetic polymorphism

(Environment & other factors)



Autoimmunity

(Autoantibodies & autoreactive T cells)



Autoimmune disease

(Tropic hormone changes)



Organ dysfunction / failure

Autoantibodies:

• Detection of endocrine auto-antibodies is useful to predict autoimmune endocrine failure and to distinguish autoimmune endocrine disease from other types

• May bind to:

  • Cell surface: C’ activation, cytotoxicity

  • Receptors: mimic ligand and stimulate; or block ligand effect; or bind elsewhere and cause down regulation or destruction of receptor

  • Intracellular structures: marker of destructive response e.g. T-cells

  • Secreted protein: inhibit function or effect of protein

Autoreactive lymphocytes: effects on tissues and cells…

• Cytotoxic T-cells and NK cells: killing of tissue cells

• Helper T-cells: release of IL and cytokines, induction of Fas expression and apoptosis

At present, treatment is usually not directed at control of the autoimmunity, rather organ failure is accepted and hormone replacement therapy is given. IDDM and hypothyroidism can now be predicted by genetic polymorphisms, auto-antibodies and hormone measurements; making early intervention and prevention more possible.

Autoimmune thyroid failure:

Grave’s disease: hyperthyroidism caused by stimulating receptor autoantibodies.

Genetics link:

• Incidence in general population (1%): Monozygotic twin concordance (30-60%)

• HLA-DR3 relative risk increased3: incidence in HLA identical siblings (7%)

Autoantibodies to the TSH receptor:

• Long acting thyroid stimulator (LATS)

• Thyroid stimulating immunoglobulin (TSI)

• IgG (in 80-90%): transfer of disease from mother to foetus

Bind receptors -> stimulate activity and growth (hypertrophy and hyperplasia) of the thyroid gland.

Laboratory diagnosis:

• High T3/T4 and low TSH (general primary hyperthyroidism)

• Anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) confirm autoimmunity and predict thyroid failure

• Anti-TSH-R confirms Grave’s disease and predict relapse

Atrophic thyroiditis: chronic autoimmune destructive inflammation that may result in thyroid failure (primary hypothyroidism) associated with anti-TPO and anti-TG.

Thyroid antibodies:

• Occur in apparently healthy people

• Associated with diagnosed hypothyroidism

• (Microsomal) predicts development of thyroid failure

Insulin dependent diabetes mellitus: (IDDM or type 1) autoimmune destruction of islet b-cells causing insulin deficiency.

Genetic link: HLA most significant:

• General population (0.3-0.6%): siblings (6%): monozygotic twins (>20%)

• Markers of risk: e.g. DR3/4, DQB1 show marked increase in relative risk

Autoantibodies against particular antigens predictive of IDDM:

• Islet cell antibodies e.g. ICA, GAD, IA2

• >4 units  40% IDDM within 10 years

• >80 units  100% IDDM within 10 years

• Auto-antigen e.g. Insulin B chain, GAD65

Other related autoimmune conditions include:

• Insulin autoimmune syndrome: (rare – Japanese)

• Autoantibodies bind to insulin --> act as a buffer or reservoir for insulin

• Prolonged insulin action --> delayed hypoglycaemia

• Autoimmune (Type B) insulin resistance: autoantibodies bind insulin receptor  block insulin binding  insulin resistance

Category: Pathology Notes