Immunology of Endocrine Disease Flashcards
Describe common organ specific and non-organ specific autoimmune disease.
Organ-specific;
- Graves thyroiditis
- Hashimoto thyroiditis
Illustrate the multifactorial aetiology of autoimmune disease.
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Describe the immunopathological mechanisms involved in causation of autoimmune disease.
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Illustrate the roles of cell-mediated and humoral immune mechanisms in autoimmune thyroid disease (as an illustration of all autoimmune endocrine disorders).
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Define and classify autoimmune polyendocrine syndromes.
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Illustrate the importance of endocrine autoantibodies as primary pathogenic agents or as secondary non-pathogenic markers of disease.
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Define ‘autoimmunity’.
A immune response against a self-antigen.
Define ‘autoimmune diseease’.
Tissue damage or disturbed function resulting from an autoimmune response.
Define ‘organ-specific’.
Disease may be restricted to a single organ, usually an endocrine gland.
Define ‘non organ-specific’.
- Affect multiple organs
- Associated with autoimmune responses against self-molecules, which are widely distributed throughout the body
- Intracellular molecules involved in transcription and translation
Define ‘immunologic tolerance’.
Unresponsiveness to an antigen that is induced by previous exposure to that antigen.
Define ‘tolerogens’ (or tolerogenic antigens).
Antigens that induce tolerance.
Describe the mechanism of immunological tolerance.
The immune system can generate a diversity of T-cell antigen receptors and immunoglobulin molecules by differential genetic recombination.
This produces many antigen-specific receptors capable of binding to self-molecules.
To avoid autoimmune disease, the T and B cells bearing these self-reactive molecules must be either eliminated or downregulated so that the immune system is made specifically tolerant to self-antigens.
Several mechanisms are involved (central and peripheral tolerance).
A break down of any of the immunological tolerance mechanisms results in autoimmune responses.
Describe central tolerance.
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.
Describe peripheral tolerance.
Mature lymphocytes that recognise self-antigens in peripheral tissues become incapable of activation by re-exposure to that antigen or die by apoptosis.
An important mechanism for the induction of peripheral tolerance is antigen recognition without co-stimulation or “second signals”.
Peripheral tolerance is also maintained by regulatory T cells (Tregs) that actively suppress the activation of lymphocytes specific for self- and other antigens.
Some self-antigens are sequestered from the immune system, and other antigens are ignored.
—> Antigens may be sequestered from the immune system by anatomic barriers, e.g. in testes and eyes, and thus cannot engage antigen receptors.
Name the three mechanisms of peripheral tolerance.
- Anergy (functional unresponsiveness)
- Treg Suppression
- Deletion (cell death)
Overcoming peripheral tolerance can result from…
- Inappropriate access of self-antigens
- Inappropriate or increased local expression of co-stimulatory molecules
- Alterations in the ways in which self-molecules are presented to the immune system
Describe overcoming peripheral tolerance.
More likely to happen when inflammation or tissue damage is present due to the increased activity of proteolytic enzymes –> intra- and extracellular proteins broken down –> high concentrations of peptides (cryptic epitopes) being presented to responsive T cells.
The structures of self-peptides may be altered by viruses, free radicals or ionising radiation, thus bypassing previously established tolerance.
Describe the epidemiology of autoimmune disease.
- 3% of the population
- Clustering within families
- Peak onset: 15-65 years (except type 1 DM)
- Almost all types are more common in women (except ankylosing spondylitis)
Describe the aetiology of autoimmune disease.
Genetic factors;
- Clusters within families
- Alleles of MHC
Environmental factors
Infections;
- Molecular mimicry
- Upregulation of co-stimulation
- Antigen breakdown and presentation changes
- ?Increased incidence in animals held in germ free conditions
Drugs;
- Molecular mimicry
- Genetic variation in drug metabolism
UV radiation;
- Triggers skin inflammation
- Modification of self-antigen
Describe the treatment of autoimmune diseases.
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;
- Hypothyroidism
- Insulin-dependent diabetes mellitus
Describe the classification of diabetes.
Type 1 (Juvenile-onset, insulin-dependent diabetes);
- Ketoacidosis
- Inadequate insulin secretion
- Lymphocytic infiltration of the islets of Langerhans with specific destruction of beta cells
- Aetiology: Autoimmune destruction, genetic factors, viral infections
Type 2 (maturity onset, noninsulin-dependent diabetes);
- More common
- Middle age
- Non-ketotic coma (occasional)
- Normal or increased insulin secretion
- Reduction of cell surface receptors to insulin
- Genetic factors
- Evidence against autoimmunity
Describe the aetiology of type 1 diabetes.
Autoimmune destruction;
- Circulatory antibodies to islet cells
- Patients prone to develop other organ specific autoimmune diseases
Genetic factors;
- Association with certain HLA types
- Environmental factors play a role too (40% concordance in twins in comparison to 100% in Type 2)
Viral infection;
- Antibodies to certain viruses are high in patients
- Viruses may act as triggers for autoimmune destruction e.g. coxsackie B, mumps
Describe the complications of diabetes.
Large blood vessels;
- Accelerates atheroma leading to MI, CVS disease, ischaemic limbs
Small blood vessels;
- Endothelial cells and basal lamina damage
- Retinopathy
- Nephropathy
Peripheral nerves;
- Neuropathy
Neutrophils;
- Susceptibility to infection
Pregnancy;
- Preeclamptic toxaemia
- Large babies
- Neonatal hypoglycaemia
Skin;
- Necrobiosis lipoidica diabeticorum
- Granumolma annulare
- Gangrene of extremities
Describe the structure and secretion of the thyroid gland.
- Follicles lines by cuboidal cells
- Proteinaceous stores secretions
- Synthesis of T3 and T4 under negative feedback by TSH (anterior pituitary)
- C-cells scattered throughout the gland that secrete calcitonin
Name the diseases of the thyroid gland.
Secretory malfunction;
- Hyperthyroidism
- Hypothyroidism
Swelling of the entire gland = goitre
Solitary masses;
- Nodular goitre
- Adenoma
- Carcinoma
Name the causes of hyperthyroidism.
- Graves thyroiditis
- Functioning adenoma
- Toxic nodular goitre
- Exogenous thyroid hormone (rare)
- Ectopic secretion by ectopic thyroid tissue or tumours
Briefly describe Graves thyroiditis and its histology.
- Most common cause of thyrotoxicosis
- Usually associated with a diffuse goitre
- Increased vascularity
Histologically;
- Hyperplasia of the acinar epithelium
- Reduction of stored colloid
- Local accumulations of lymphocytes with lymphoid follicle formation
Describe the pathophysiology of Graves thyroiditis.
- Organ-specific autoimmune disease
- Autoantibody (IgG) (LATS) binds to thethyroidepithelial cells and mimics the action of TSH
- LATS stimulates the function and growth ofthyroidfollicular epithelium
Describe the signs of Graves thyroiditis.
- Diffuse goitre
- Exophthalmos
- Pretibial myxoedema (accumulation of mucopolysaccharides in the deep dermis of the skin)
- Finger clubbing
Describe cretinism.
If hypothyroidism is present in the new-born, physical growth and mental development are impaired, sometimes irreversibly (cretinism).
Cretinism may be endemic in geographical areas where the diet contains insufficient iodine for thyroid hormone synthesis.
Sporadic cases are usually due to a congenital absence of thyroid tissue, or to enzyme defects blocking hormone synthesis.
Briefly describe Hashimoto thyroiditis and its histology.
- Most common cause of acquired hypothyroidism in adults
- Female preponderance
- Certain HLAs are commonly found in affected individuals
- May initially cause thyroid enlargement but later atrophy and fibrosis
- In early stages: damage to thyroid follicles –> release of thyroglobulin –> transient thyrotoxicosis
Histologically:
- Dense infiltration by lymphocytes and plasma cells, with lymphoid follicle formation
- Colloid content is reduced
- Thyroid epithelial cells show a characteristic change in which they enlarge and develop eosinophilic granular cytoplasm due to proliferation of mitochondria (called Askanazy cells, Hürthle cells or oncocytes)
- In advanced cases, there may be fibrosis
What two antibodies are found in the serum of patients with Hashimoto thyroiditis, and what are their origin?
- One reacting with thyroid peroxidase
- The other reacting with thyroglobulin
These autoantibodies are probably formed locally by the plasma cells infiltrating the thyroid, and are possibly the result of a loss of specific suppressor T-lymphocytes.
Define ‘autoimmune polyendocrine syndromes’,
A diverse group of clinical conditions characterised by functional impairment of multiple endocrine glands due to loss of immune tolerance.
Frequently include conditions such as alopecia, vitiligo, celiac disease, and autoimmune gastritis with vitamin B12deficiency that affect non-endocrine organs.
Describe the aetiology and pathophysiology of autoimmune polyendocrine syndromes.
Aetiology;
- Can occur in patients from early infancy to old age
- new components of a given syndrome can appear throughout life
- Variation in the frequencies and patterns of autoimmunity in affected patients and their families
- Combination of genetic susceptibility and environmental factors
Pathophysiology;
- Circulating autoantibodies and lymphocytic infiltration of the affected tissues or organs
- Eventually leading to organ failure
Describe autoimmune polyendocrine syndrome type 1.
- APS-1, AKA autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy
- Rare autosomal recessive disease
- Caused by mutations in the autoimmune regulator gene (AIRE).
Describe the epidemiology of autoimmune polyendocrine syndrome type 1.
1:100,000 in most countries, with a higher prevalence in some countries.
Describe the clinical features of autoimmune polyendocrine syndrome type 1.
At least two of three cardinal components during childhood;
- Chronic mucocutaneous candidiasis
- Hypoparathyroidism
- Primary adrenal insufficiency (Addison’s disease)
Other typical components;
- Enamel hypoplasia
- Enteropathy with chronic diarrhea or constipation
- Primary ovarian insufficiency (approximately 60% of women with APS-1 before they reach 30 years of age)
Less frequent components;
- Bilateral keratitis (accompanied by severe photophobia)
- Periodic fever with rash
- Autoimmunity-induced hepatitis, pneumonitis, nephritis, exocrine pancreatitis, and functional asplenia
Rare findings;
- Retinitis
- Metaphyseal dysplasia
- Pure red-cell aplasia
- Polyarthritis
