Immunology of Endocrine Disorders Flashcards
Immunologic tolerance
unresponsiveness to an antigen that is induced by
previous exposure to that antigen
When lymphocytes encounter antigens what might happen?
they may be activated, leading to
immune responses, or inactivated or eliminated, leading to tolerance.
what might an antigen producing an immune response or tolerance depend on?
depending on the conditions of exposure and the presence or absence of other stimuli
what are antigens that induce tolerance called?
tolerogens or tolerogenic antigens
what is tolerance to self antigens?
self-tolerance, is a fundamental property of the normal immune system, and failure of self-tolerance results in immune
reactions against self (autologous) antigens.
what are reactions against self (autologous) antigens?
autoimmunity
what are the diseases reactions against self (autologous) antigens cause called?
autoimmune diseases
what is the immune system capable of generating?
a diversity of T-cell antigen receptors and immunoglobulin molecules by differential genetic recombination.
what does the immune system generate?
produces many antigen-specific receptors capable of binding to selfmolecules.
how does the immune system 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.
what mechanisms are involved in avoiding autoimmune disease?
Several mechanisms are involved (central and peripheral tolerance)
what does a breakdown of any immunological tolerarance mechanism result in?
A break down of any of the immunological tolerance mechanisms results in
autoimmune responses
what is 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
what is peripheral tolerance?
Mature lymphocytes that recognize 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.
what is an important mechanism for the induction of peripheral tolerance?
An important mechanism for the induction of peripheral tolerance is antigen
recognition without co-stimulation or “second signals.”
what is peripheral tolerance also maintained by?
regulatory T cells (Tregs) that
actively suppress the activation of lymphocytes specific for self and other antigens.
what happens to some self antigens?
Some self antigens are sequestered from the immune system (immune privileged sites), and other antigens are ignored.
how might antigens be sequestered from the immune system?
Antigens may be sequestered from the immune system by anatomic
barriers, such as in the CNS, testes and eyes, and thus cannot engage
antigen receptors.
what are the three mechanisms of peripheral tolerance?
Anergy (functional unresponsiveness)
Treg Suppression
Deletion (cell death)
how can peripheral tolerance be overcome?
- 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.
when is peripheral tolerance more likely to be overcome?
More likely to happen when inflammation or tissue damage is present due to
the increased activity of proteolytic enzymes which can cause intra- and extracellular proteins to be broken down, leading to high concentrations of
peptides (cryptic epitopes) being presented to responsive T cells.
what might the structures of self peptides be altered by?
The structures of self-peptides may be altered by viruses, free radicals or ionising radiation, thus bypassing previously established tolerance.
when does autoimmunity happen?
when normal tolerance breaks down
describe the epidemiology of autoimmune disease?
It is estimated that 3% of the population have some sort of autoimmune
disease.
- Autoimmune diseases show clustering within families.
- Peak years of onset 15-65 years (exception; Type 1 Diabetes mellitus)
- Almost all types of autoimmune diseases are more common in women
(Exception, ankylosing spondylitis).
what are non organ specific autoimmune diseases?
They affect multiple organs
- Associated with autoimmune responses against self-molecules which are
widely distributed throughout the body - Intracellular molecules involved in transcription and translation
what are organ specific autoimmune diseases?
Restricted to one organ
Endocrine glands
describe effect of autoimmune disease targetting the TSH receptor?
describe effect of autoimmune disease targetting the insulin receptor?
describe effect of autoimmune disease targetting the acetylcholine receptor?
describe effect of autoimmune disease on other self antigens?
what genetic factors are responsible for the aetiology of autoimmune disease?
describe the environmental factors that may be resposible for autoimmune disease?
Infections
* Molecular mimicry
* Upregulation 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
what is molecular mimicary?
how is autoimmune disease treated?
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 your knowledge of diabetes mellitus?
what makes up the endocrine pancreas?
Islets of Langerhans
- About a million islets scattered within the exocrine tissue of the pancreas
- 1% of the total pancreas mass
- Clusters of compact cells
- Four different types according to hormone content
what four different types of islets of langerhans cellls are there?
what are the characteristics of type 1 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
what is the aetiology of type one diabetes?
autoimmune destruction, genetic factors, viral infections
what are the characteristic features of type 2 diabetes?
- More common
- Middle age
- Non-ketoic coma (occasional)
- Normal or increased insulin secretion
- Reduction of cell surface receptors to insulin
- Genetic factors
- Evidence against autoimmunity
describe autoimmune destruction in type one diabetes?
Circulatory antibodies to islet cells
Patients prone to develop other organ specific autoimmune diseases
describe genetic factors in type 1 diabetes?
- Association with certain HLA types
- Environmental factors play a role too (40% concordance in twins in
comparison to 100% in Type 2)
describe viral infection in type 1 diabetes?
- Antibodies to certain viruses are high in patients.
- Viruses may act as triggers for autoimmune destruction
- Coxsackie B
- Mumps
what are complications of type 1 diabetes?
describe 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
what does secretory dysfunction of the thyroid result in?
Hyperthyroidism
Hypothyroidism
what does swelling of the entire thyroid gland result in?
goitre
what are examples of solitary masses of the thyroid?
- Nodular goitre
- Adenoma
- Carcinoma
what is the cause of hyperthyroidism?
- Excess T3 and T4
- Very rarely due to excess TSH
what conditions may hyoerthyroidism result from?
- Graves thyroiditis
- Functioning adenoma
- Toxic nodular goitre
- Exogenous thyroid hormone (rare)
- Ectopic secretion by ectopic
thyroid tissue or tumours
what is graves thyroidititis the most common cause of?
thyrotoxicosis
what is graves thyroiditis usually associated with?
diffuse goitre
what is shown histologically in graves thyroiditis?
Increased vascularity.
- Histologically:
- hyperplasia of the acinar epithelium
- reduction of stored colloid
- local accumulations of lymphocytes with lymphoid follicle formation
what is graves thyroiditis?
- Graves thyroiditis is an ‘organ-specific’ autoimmune diseases.\
- Autoantibody (IgG), long-acting thyroid stimulator (LATS) which binds to
the thyroid epithelial cells and mimics the action of TSH. - LATS stimulates the function and growth of thyroid follicular epithelium.
- Exophthalmos, pretibial myxoedema (accumulation of mucopolysaccharides in
the deep dermis of the skin) and finger clubbing.
what is exopthalmos?
common and results from infiltration of the orbital tissues by
fat, mucopolysaccharides and lymphocytes, and may be due to an additional
autoantibody reacting with these tissues.
what is the cause of hypothyroidism?
- Insufficient circulating T3 and T4
- When congenital, causes
cretinism - Most common cause is
Hashimoto thyroiditis, an
autoimmune disorder - The metabolic rate is lowered
what is 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.
when might there be sporadic cases of cretinism?
- Sporadic cases are usually due to a congenital absence of thyroid
tissue, or to enzyme defects blocking hormone synthesis
what is hashimoto thyroiditis the most common cause of?
The most common cause of acquired hypothyroidism in adults is Hashimoto thyroiditis.
what are the effects of hashimoto thyroiditis?
- Hashimoto thyroiditis may initially cause thyroid enlargement, but later there may be
atrophy and fibrosis. - In the early stages of Hashimoto thyroiditis, the damage to the thyroid follicles may
lead to release of thyroglobulin causing a transient phase of thyrotoxicosis.
what is shown histologically in hashimoto thyroiditis?
- Densely 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;
they are then termed Askanazy cells, Hürthle cells or oncocytes.
In advanced cases, there may be fibrosis.
what is hashimoto thyroiditis?
- Hashimoto thyroiditis is an ‘organ-specific’ autoimmune diseases.
- Two autoantibodies can be detected in the serum of most patients:
- 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. - Female preponderance
- Certain HLAs are commonly found in affected individuals
what are polyendocrine syndromes?
- A diverse group of clinical conditions
characterized by functional
impairment of multiple endocrine
glands due to loss of immune
tolerance.
what do autoimmune polyendocrine frequenly include conditions wise
- Frequently include conditions such as
alopecia, vitiligo, celiac disease, and
autoimmune gastritis with vitamin B12 deficiency that affect
nonendocrine organs.
what are autoimmune polyendocrine syndromes?
- Circulating autoantibodies and lymphocytic infiltration of the
affected tissues or organs - Eventually leading to organ failure.
when can autoimmune polyendocrine syndromes affect a patient?
- The syndromes can occur in patients from early infancy to old age,
and 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.
what is autoimmune polyendocrine syndrome type 1?
- APS-1, also named autoimmune
polyendocrinopathy–
candidiasis–ectodermal
dystrophy is a rare autosomal
recessive disease caused by
mutations in the autoimmune
regulator gene (AIRE).
what is the prevalence of autoimmune polyendocrine syndrome?
- The estimated prevalence is
roughly 1:100,000 in most
countries, with a higher
prevalence in some countries
what are clinical features of APS-1 during childhood?
- At least two of three cardinal components during childhood:
- Chronic mucocutaneous candidiasis
- Hypoparathyroidism
- Primary adrenal insufficiency (Addison’s
disease)
what are other typical clinical componenets of APS-1?
- Enamel hypoplasia * Enteropathy with chronic diarrhoea or
constipation. - Primary ovarian insufficiency
(approximately 60% of women with APS - 1 before they reach 30 years of age).
what are less frequent clinical components of APS-1?
- Bilateral keratitis (accompanied by severe photophobia)
- Periodic fever with rash
- Autoimmunity-induced hepatitis,
pneumonitis, nephritis, exocrine
pancreatitis, and functional asplenia
what are rare findings of clinical features of APS-1?
- Retinitis
- Metaphyseal dysplasia
- Pure red-cell aplasia
- Polyarthritis
what is the prevalance of autoimmune polyendocrine syndrome type 2?
- APS-2 is more common than APS-1 (estimated prevalence 1:1000).
- Women predominate among patients with APS-2
what do patients with APS-2 have?
Patients with APS-2 have at least two of the following three endocrinopathies:
- Type 1 diabetes
- Autoimmune thyroid disease
- Addison’s disease
what other autoimmune conditions often develop in affected patients?
- Celiac disease
- Alopecia, vitiligo
- Primary ovarian insufficiency
- Pernicious anaemia
when is the typical onset of APS-2 in patients?
- The onset of APS-2 typically occurs in young adulthood, later than the onset of APS-1
what is X-Linked Immunodysregulation, Polyendocrinopathy, and Enteropathy (IPEX), and what is it characterised by?
An extremely rare inherited syndrome (1:1000000) characterized by:
- Early-onset type 1 diabetes
- Autoimmune enteropathy with intractable diarrheal and malabsorption.
- Dermatitis that may be eczematiform, ichthyosiform, or psoriasiform.
what levels are elevated in X-Linked Immunodysregulation, Polyendocrinopathy, and Enteropathy (IPEX)?
Eosinophilia and elevated IgE levels are frequently present
what disease develops in some patients with X-Linked Immunodysregulation, Polyendocrinopathy, and Enteropathy (IPEX)?
Kidney disease, most often membranous glomerulonephritis or interstitial nephritis, develops
in some patients
what are later manifestations of X-Linked Immunodysregulation, Polyendocrinopathy, and Enteropathy (IPEX)?
- Autoimmune thyroid disease
- Alopecia
- Various autoimmune cytopenias
- Hepatitis
- Exocrine pancreatitis.
when is IPEX 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.
when does IPEX usually develop?
- Many features overlap with APS-1, but they usually develop much earlier in life than in APS-1.
summarise the classification and characteristics of autoimmune polyendocrine syndromes?
