Immunology of Endocrine Disease Flashcards
autoimmunity is an immune response against a ____ ______
autoimmunity is an immune response against a self antigen
autoimmune disease is tissue damage or disturbed function resulting form an __________ reposnse
autoimmune disease is tissue damage or disturbed function resulting form an autoimmune reposnse
disease may be restricted to a single ____ (organ specific), usually an ________ gland, or involve autoantigens widely distributed throughout the body (nonorgan specific)
disease may be restricted to a single organ (organ specific), usually an endocrine gland, or involve autoantigens widely distributed throughout the body (nonorgan specific)
most, but not all, autoimmune diseases are most ocmmon in _______
most, but not all, autoimmune diseases are most ocmmon in females
the immune system is normally specifically _________ (tolerant) to self-antigens: autoimmune disease occurs when __________ breaks down
the immune system is normally specifically unreactive (tolerant) to self-antigens: autoimmune disease occurs when tolerance breaks down
What is immunologic tolerance?
Immunologic tolerance: unresponsiveness to an antigen that is induced by previous exposure to that antigen.
What may happen when a lymphocyte encounters an antigen?
When lymphocytes encounter antigens, they may be activated, leading to immune responses, or inactivated or eliminated, leading to tolerance
can the same antigen produce an immune response and tolerance?
The same antigen may induce an immune response or tolerance, depending on the conditions of exposure and the presence or absence of other stimuli
What are antigens that induce tolerance called?
Antigens that induce tolerance are called tolerogens, or tolerogenic antigens
what is the importance of tolerance to self antigens?
Tolerance to self antigens, also called self-tolerance, is a fundamental property of the normal immune system, and failure of self-tolerance results in immune reactions against self (autologous) antigens
Such reactions are called autoimmunity, and the diseases they cause are called autoimmune diseases
how are antigen-specific receptors made?
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
How do you avoid autoimmune diseases?
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
what is the idfference between central and peripheral tolerance?
in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral)
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
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, such as in the testes and eyes, and thus cannot engage antigen receptors
what are the different mechanisms of peripheral tolerance?
- Anergy (functional unresponsiveness) - If there is not a co-stimulus then there is anergy which is when the cells are not highly reactive then there is not a reaction again self-antigens
- Treg Suppression
- Deletion (cell death)
what happens to lymphocytes specific for self antigens?
how can overcoming peripheral resistance occur?
This 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
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
The structures of self-peptides may be altered by viruses, free radicals or ionising radiation, thus bypassing previously established tolerance
what does a breakdown of tolerance cause?
autoimmune disease
do autoimmune diseases run in families?
Often will run in families but doesn’t have to be the same autoimmune disease
are autoimmune diseases more common in men or women?
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).
autoimmune diseases can be _____ specific or ___-_____ specifc
organ
non-organ
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
e.g. thyroid disease, type 1 diabetes is an organ-specific autoimmune disease caused by the autoimmune response against pancreatic β cells
a
hyperthyroidism
hypothyroidism
b
hyperglycaemia
hypoglycaemia
c
myasthenia gravis
d
thyoiditis
hpyothyroidism
(extra shwon below)
what is one aetiology of autoimmune diseases?
Genetic factors:
- Clusters within families
- Alleles of MHC (The major histocompatibility complex (MHC) is a set of genes that code for cell surface proteins essential for the acquired immune system to recognize foreign molecules in vertebrates, which in turn determines histocompatibility. HLA codes for MHC which codes for antigen variation)
Aetiology of Autoimmune Disease - what are some environmental factors that may cause autoimmune diseases?
Infections:
- Molecular mimicry - Some virus or bacteria can have antigens a lot like self antigens and the immune system will respond to these viral antigens and at the same time respond to the bodies antigen aswell
- 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:
- Trigger for skin inflammation
- Modification of self-antigen
What is molecular mimicry?
summary diagram showing the aetiology of autoimmune disease
what is the treatment of autoimmune disease?
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
- If permanent damage due to autoimmune disease then you need to replace damage = e.g. type 1 diabetes B cells destroyed so need to replace this with insulin
what is diabetes mellitus?
abnormal metabolic state characterised by glucose intolerace due to inadequate insulin action
type 1 (juvenile onset) due to destruction of beta-cells (probably a result of virus infection and genetic factors); insulin-dependant
type 2 (maturity onset) due to defective insulin action; treatment by weight reduction and oral hypoglycaemic agents
complications inculde accelerated atherosclerosis, susceptibility to infection, and microangiopathy affecting many organs
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
is diabetes increasing or decreasing aorund the world?
increasing
what is the classification of type 1 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
what is the classification of type 2 diabetes?
- Type 2 (maturity onset, noninsulin-dependent 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
what is 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
what are some complications of diabetes?
what ar ethe features 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
what types of thyroid disease may occur?
Secretory malfunction - Hyperthyroidism and Hypothyroidism
Swelling of the entire gland - Goitre
Solitary masses - Nodular goitre, Adenoma, Carcinoma
what is hyperthyroidism?
what may hyperthyroidism result from?
Graves thyroiditis
Functioning adenoma
Toxic nodular goitre
Exogenous thyroid hormone (rare)
Ectopic secretion by ectopic thyroid tissue or tumours
Ectopic – thyroid tissue somewhere else in the body making excessive thyroid tissue
Starts to develop in back of tongue and you may get lingual thyroid and this is when parts of the thyroid remains in the tongue, may be functional thyroid tissue and need to check there is more where it is meant to be before you remove it
what does graves thyroiditis cause?
The most common cause of thyrotoxicosis (excess of thyroid hormone in the body)
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
What is Graves thyroiditis?
Graves thyroiditis is an ‘organ-specific’ autoimmune diseases
Autoantibody (IgG) (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 (a bulging of the eye anteriorly out of the orbit), pretibial myxoedema (accumulation of mucopolysaccharides in the deep dermis of the skin) and finger clubbing
Exophthalmos is 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 hypothyroidism?
- Inadequate levels of circulating T3 and T4
- The metabolic rate is lowered
goitre is caused in hypo or hyperthyroidism?
both
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
Sporadic cases are usually due to a congenital absence of thyroid tissue, or to enzyme defects blocking hormone synthesis
The most common cause of acquired hypothyroidism in adults is what?
Hashimoto thyroiditis
What does hashimoto thyroiditis cause?
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
Histologically what is seen 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
Is Hashimoto thyroiditis organ specific?
yes
Two autoantibodies can be detected in the serum of most patients with hashimoto thyroiditis, what are they?
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
Hashimoto thyroiditis - more common in males or females?
Female preponderance
Certain _____ are commonly found in affected individuals with hasimoto thyroiditis
Certain HLAs are commonly found in affected individuals with hasimoto thyroiditis
What are autoimmune polyendocrine syndromes?
A diverse group of clinical conditions characterized 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 B12 deficiency that affect nonendocrine organs
a rare, inherited disease in which the immune system mistakenly attacks many of the body’s tissues and organs
can run in families
How is autoimmune polyendocrine syndromes caused?
Circulating autoantibodies and lymphocytic infiltration of the affected tissues or organs, eventually leading to organ failure
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 are the types of autoimmune polyendocrine syndromes?
APS-1
APS-2
IPEX
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)
The estimated prevalence is roughly 1:100,000 in most countries, with a higher prevalence in some countries
Autoimmune polyglandular syndrome type 1 is an inherited autoimmune condition that affects many of the body’s organs
what are the clinical features of APS-1
At least two of three cardinal components during childhood:
- Chronic mucocutaneous candidiasis (immune disorder of T cells, it is characterized by chronic infections with Candida that are limited to mucosal surfaces, skin, and nails)
- Hypoparathyroidism
- Primary adrenal insufficiency (Addison’s disease)
what are other typical components of APS-1?
- Enamel hypoplasia
- Enteropathy with chronic diarrhea or constipation (a disease of the intestine, especially the small intestin)
- Primary ovarian insufficiency (approximately 60% of women with APS-1 before they reach 30 years of age)
what are some less frequent components of APS-1?
- Bilateral keratitis (accompanied by severe photophobia) (condition in which the eye’s cornea, the clear dome on the front surface of the eye, becomes inflamed)
- Periodic fever with rash
- Autoimmunity-induced hepatitis, pneumonitis, nephritis, exocrine pancreatitis, and functional asplenia (Asplenia refers to the absence of normal spleen function and is associated with some serious infection risks)
what are some rare findings in APS-1
- Retinitis
- Metaphyseal dysplasia
- Pure red-cell aplasia (the failure of an organ or tissue to develop or to function normally)
- Polyarthritis
APS-_ is far more common than APS-_
APS-2 is far more common than APS-1
Patients with APS-2 have courses characterized by at least two of the following three endocrinopathies:
- Type 1 diabetes
- Autoimmune thyroid disease
- Addison’s disease
_______ predominate among patients with APS-2
Women
In many affected patients, other autoimmune conditions develop such as what?
- Celiac disease
- Alopecia, vitiligo
- Primary ovarian insufficiency
- Pernicious anemia
The onset of APS-2 typically occurs when and how does this compare to APS-1?
The onset of APS-2 typically occurs in young adulthood, later than the onset of APS-1
APS-_ needs to be distinguished from the unrelated but more common APS-_ which is characterized by type-_ diabetes and ________ _______ ______
APS-1 needs to be distinguished from the unrelated but more common APS-2 which is characterized by type-1 diabetes and autoimmune thyroid diseases
What is IPEX?
X-Linked Immunodysregulation, Polyendocrinopathy, and Enteropathy (IPEX)
a rare disease linked to the dysfunction of the transcription factor FOXP3, widely considered to be the master regulator of the regulatory T cell lineage. It leads to the dysfunction of regulatory T-cells and the subsequent autoimmunity
IPEX is an extremely rare inherited syndrome characterized by what?
- Early-onset type 1 diabetes
- Autoimmune enteropathy with intractable diarrhea and malabsorption
- Dermatitis that may be eczematiform, ichthyosiform, or psoriasiform
Eosinophilia and elevated IgE levels are frequently present in patients with IPEX
Kidney disease, most often membranous glomerulonephritis or interstitial nephritis, develops in some patients
Later manifestations of the syndrome (IPEX) may include what?
- Autoimmune thyroid disease
- Alopecia
- Various autoimmune cytopenias
- Hepatitis
- Exocrine pancreatitis
Many features overlap with APS-_, but they usually develop much earlier in life than in APS_
Many features overlap with APS-1, but they usually develop much earlier in life than in APS-1
Is IPEX dangerous and what is the treatment?
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
a
APS-1
b
APS-2
c
IPEX
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