Immunology of Endocrine Disorders Flashcards
What is autoimmunity?
An immune response against self-antigens
What are antigens?
Structures bound to cell surface of antibodies
What is autoimmune disease?
Tissue damage or disturbed function due to an autoimmune response
What is organ specific autoimmune disease?
Restricted to single organ, usually an endocrine gland
What is non-organ specific autoimmune disease?
Invovle autoantigens widely distributed throughout the body
What is an autoantigen?
Normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by the immune system of patients suffering from a specific autoimmune disease
Are most autoimmune diseases more common in males or females?
Females
When does autoimmunity occur?
When tolerance to self-antigens breaks down
What is immunological tolerance?
Unresponsiveness to an antigen that is induced by previous exposure to that antigen
Explain what happens when a lymphocyte encounters an antigen?
- When lymphocytes encounter antigens they are activated
- Leading to immune responses, or inactivated, or eliminated, leading to tolerance
- 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 tolerogens?
Antigens that induce tolerance
What is self-tolerance?
Tolerance to self-antigens
What does failure of self-tolerance result in?
An immune reaction against self-antigens, called autoimmunity cand causing autoimmune diseases
The immune system can generate a diversity of T-cell antigen receptors and immunoglobulin molecules by different genetic recombination, what does this produce?
Many antigen-specific receptors capable of binding to self-molcules
Immune system can generate a diversity of T-cell antigen receptors and immunoglobulin molecules, how is autoimmune disease avoided?
- T and B cells bearing those self-reactive molecules must be either eliminated or downregulated so that immune system is made tolerant to self-antigens
What are the different type of tolerance?
Central and peripheral tolerance
What happens in central tolerance?
Induced in immature self-reactive lymphocytes in the generative lymphoid organs:
- thymus plays important role in eliminating T cells with high affinity for self-antigens
- bone marrow is important in B cell tolerance
For central tolerance, what organ plays an important role in eliminating T cells with high affinity to self-antigens?
Thymus
In central tolerance, what organ plays an important role in B cells tolerance?
Bone marrow
What is central tolerance also known as?
Negative selection
What is central tolerance?
Process of eliminating any developing T or B cells that are reactive to self-antigens
Does central tolerance deal with mature or immature lymphocytes?
Immature
Does peripheral tolerance deal with mature or immature lymphocytes?
Mature
What is peripheral tolerance?
Mature lymphocytes that recognise self-antigens in peripheral tissues become incapable of activation by re-exposure to that antigens or die by apoptosis
Explain how peripheral tolerance works?
- An important mechanism for the induction of peripheral tolerance is antigen recognise without co-stimulation or “second signals”
- Also maintained by regulatory T cells (Tregs) that actively suppress activation of lymphocytes specific for self and other antigens
- Some self-antigens are sequestered from immune system, and other antigens are ignored
- Antigens may be sequestered from immune system by anatomic barriers, such as in testes and eyes, and this cannot engage antigen receptors
What are some organs where antigens may be sequestered from the immune system?
By anatomical barriers in testes and eyes so cannot engage antigen receptors
What are some mechanisms of peripheral tolerance?
- Anergy (functional unresponsiveness)
- Treg suppression
- Deletion (cell death)
What is anergy in peripheral tolerance?
Functional unresponsiveness
What is deletion in peripheral tolerance?
Cell death (apoptosis)
What cell is responsible for performing peripheral tolerance?
Dendritic cell
What happens in central tolerance?
- Immature lymphocytes specific for self antigens may encounter these antigens in generative (central) lymphoid organs and are
- Deleted, change their specificity (B cells only) or develop into regulatory lymphocytes called Tregs (only CD4+ T cells can do this)
What happens in peripheral tolerance?
- Some self-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by encounter with self-antigens in these tissues or are suppressed by regulatory T cells (Tregs)
- Note that T cells recognise antigens presented by antigen-presenting cells (APCs)
In central tolerance, what are the only cells that can develop into regulatory lymphocytes called Tregs?
Helper T cells (CD4+ T cells)
What are helper T cells also known as?
CD4+ T cells
What are cytotoxic T cells also known as?
CD8+ T cells
In central tolerance, what are the only cells that can have their specificity changed?
B cells
How can peripheral tolerance be overcome?
- Inappropriate access of self-antigens
- Inappropriate or increased local expression of co-stimulatory molecules
- Alternations in the ways in which self-molecules are presented to the immune system
When is peripheral tolerance more likely to be overcome?
When inflammation or tissue damage is present due to increased activity of proteolytic enzymes which can cause intra and extra-cellular proteins to be broken down
Why is peripheral tolerance more likely to be overcome when inflammation or tissue damage is present?
Increased activity of proteolytic enzymes causes intra and extra-cellular proteins to be broken down:
- leading to high concentrations of peptides being presented to responsive T cells
- structures of self-peptides may be altered by viruses, free radicals or ionising radiation thus bypassing previously established tolerance
Almost all types of autoimmune disease are more prevalent in woman, what is an example of one that is more prevalent in en?
Ankylosing spondylitis
What are the 2 types of autoimmune disease?
Non-organ specific autoimmune disease
Organ-specific autoimmune disease
How does non-organ and organ specific autoimmune disease differ?
Non-organ specific affects multiple organs, being associated with autoimmune responses against self-molecules that are widely distributed throughout the body
Organ specific is restricted to one organ, which is usually an endocrine gland
What molecules does non-organ specific autoimmune disease affect?
Intracellular molecules involved in transcription and translation
What are some genetic factors of autoimmune disease?
Clusters within familes
Alleles of MHC (major histocompatibility complex)
What is the major histocompatible complex (MHC)?
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
What are some environmental factors of autoimmune disease?
- Infections
- Molecular mimicry
- Upregulation of co-stimulation
- Antigen breakdown and presentation changes
- Drugs
- Molecule mimicry
- Genetic variation in drug metabolism
- UV radiation
- Trigger for skin inflammation
- Modification of self-antigen
How does infection cause autoimmune disease?
- Molecular mimicry
- Upregulation of co-stimulation
- Antigen breakdown and presentation changes
How do drugs cause autoimmune disease?
- Molecule mimicry
- Genetic variation in drug metabolism
How does UV radiation cause autoimmune disease?
- Trigger for skin inflammation
- Modification of self-antigen
What is molecular mimicry?
Possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides
What is co-stimulation?
Secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response.
What does DC stand for?
Dendritic cell
Describe the role of infection in development of autoimmunity?
Microbes may activate the APC to express co-stimulators, and when these APCs present self-antigens the self reative T cells are activated rather than rendering tolerance
or some microbial antigens may cross-ract with self antigens (molecular mimicry), initiating an immune response that may activate T cells specific for self antigens
What are some examples of microbial antigens that can cause molecular mimicry?
Explain the genetic susceptibility to autoimmunity?
What does APC stand for?
Antigen presenting cell
What are some general treatments of autoimmune disease?
- Suppression of the damaging immune response
- Before irreversible tissue damage
- Early detection is the challenge
- Problem with specificity of treatments and toxicity
- Replacement of the function of the damaged organ
- Used for hypothyroidism and insulin dependent diabetes mellitus
What is diabetes?
Abnormal metabolic state characterised by glucose intolerance due to inadequate insulin access
What are the 2 main types of diabetes?
Type 1 diabetes
Type 2 diabetes
Does T1 and T2 diabetes have a juvenile onset or a mature onset?
T1 - juvenile
T2 - mature
What pathology causes T1 diabetes?
Destruction of beta cells (probably due to viral infection and genetic factors)
What pathology causes T2 diabetes?
Defective insulin access
What are some examples of complications of diabetes?
Accelerated atherosclerosis
Susceptability to infection
Microangiopathy affecting many organs
What part of the pancreas forms the endocrine pancreas?
Islet of Langerhans
What percentage of the total pancreas mass is composed of the endocrine pancreas (Islet of Langerhans)?
1%
What are the 4 cell types present in Islet of Langerhans?
What cell type is most prevalent in Islet of Langerhans?
Beta cells
What do beta cells secrete?
Insulin
What do alpha cells secrete?
Glucagon
What do delta cells secrete?
Somatostatin
What do pancreatic polypeptide cells secrete?
Pancreatic polypeptide
What are the actions of insulin?
What are the actions of glucagon?
What are the actions of somatostatin?
What is the function of pancreatic polypeptide?
Is the prevalence of diabetes increasing or decreasing?
Increasing
What is type 1 diabetes also known as?
Insulin dependent diabetes
What is type 2 diabetes also known as?
Insulin independent diabetes
Explain the aetiology of T1 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 to
Viral infection:
- Antibodies to certain viruses are high in patients
- Viruses may act as triggers for autoimmune destruction
- Coxsackie B
- Mumps
What genetic factors impact the aetiology of T1 diabetes?
Association with certain HLA types
What viruses may trigger T1 diabetes?
Coxsackie B
Mumps
What are some complications of T1 diabetes?
What does the thyroid gland synthesis?
T3 and T4
What is the production of T3 and T4 under the negative feedback off?
TSH (from anterior pituitary)
What are some examples of thyroid diseases?
- Secretory malfunction
- Hyperthyroidism
- Hypothyroidism
- Swelling of the entire gland
- Goitre
- Solitary masses
- Nodular goitre
- Adenoma
- Carcinoma
What do C-cells in the thyroid gland secrete?
Calcitonin
What are the follicles of the thyroid gland lined by?
Cuboidal cells
In terms of T3, T4 and TSH, what is hyperthyroidism due to?
Excess T3 and T4, very rarely due to excess TSH
What is the most common cause of hyperthyroidism?
Grave’s disease
Could also be due to functioning adneoma, but not as likely
What can cause hyperthyroidism?
- Graves thyroiditis
- Functioning adenoma
- Toxic nodular goitre
- Exogenous thyroid hormone (rare)
- Ectopic secretion by ectopic thyroid tissue or tumours
What are the signs and symptoms of hyperthyroidism?
What is the most common cause of thyrotoxicosis?
Grave’s thyroiditis
What is grave’s thyroiditis usually associated with?
Diffuse goitre
What are 2 kinds of goitre?
Diffuse goitre
Nodular goitre
What is diffuse goitre?
Entire thyroid gland swells up and is smooth to touch
What is nodular goitre?
Lumps called nodules develop in the thyroid
Histologically, what is observed in Grave’s thyroiditis?
- Hyperplasia of the acinar epithelium
- Reduction of stored colloid
- Local accumulation of lymphocytes with lymphoid follicle formation
Explain the pathogenesis of Grave’s thyroiditis being an organ specific autoimmune disease?
- 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, pretibial myxoedema (accumulation of mucopolysaccharides in the deep dermis of skin) and finger clubbing
What autoantibody is responsibly for Grave’s thyroiditis?
Long acting thyroid stimulating immunoglobin (LATS)
What is the most common cause of hypothyroidism?
Hashimoto thyroiditis which is an autoimmune disorder
What is a congenital cause of hypothyroidism?
Cretinism
What is the clinical presentation of hypothyroidism?
What is cretinism?
When hypothyroidism is present in new-born, physical growth and mental development is impaired, sometimes irreversibly
What is the cause of cretinism when its endemic in areas and when it is sporadic?
Endemic - insufficient iodine for thyroid hormone synthesis
Sporadic - congenital absence of thyroid tissue, or to enzyme defects blocking hormone synthesis
What does Hashimoto’s thyroiditis cause?
May initially cause thyroid enlargement, but later there may be atrophy and fibrosis
Cause hypothyroidism (most common cause)
What can happen in the early stages of Hashimoto’s thyroiditis that contradicts it causing hypothyroidism?
Damage to thyroid follicles may lead to release of thyroglobulin causing a transient phase of thyrotoxicosis
Explain the histology of Hashimoto’s 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 mitochondira (termed Askanazy cells, Hurthle cells or oncocytes)
- In advanced cases, may be fibrosis
Is Hashimoto’s thyroiditis an organ specific or non-organ specific autoimmune disease?
Organ specific autoimmune disease
What are the two antibodies that can be detected in the serum of most patients with Hashimoto’s thyroiditis?
One reacting with thyroid peroxidase
Other reacting with thyroglobulin
What is the genetic link to Hashimoto’s thyroiditis?
HLA genes
Does Hashimoto’s thyroiditis affect more males or females?
Females
What are autoimmune polyendocrine syndromes?
Diverse group of conditions characterised by functional impairment of multiple endocrine glands due to loss of immune tolerance
What are examples of conditions frequently included in autoimmune polyendocrine syndromes?
Alopecia
Celiac disease
Autoimmune gastritis with vitamin B12 deficiency that affects nonendocrine organs
What is the pathophysiology of autoimmune polyendocrine syndromes?
- Circulating autoantibodies and lymphocytic infiltration of the affected tissues or organs
- Eventually leading to organ failure
How do the components of autonomic polyendocrine syndrome change throughout life?
Can occur in patients from early infancy to old age
New components to a syndrome can appear throughout life
What is the aetiology of autoimmune polyendocrine syndromes?
Combination of genetic susceptibility and environmental factors
What are the different autoimmune polyendocrine syndromes?
APS-1
APS-2
IPEX
What does APS stand for?
Autoimmune polyendocrine syndrome
What is APS-1 also known as?
Autoimmune polyendocrinopathy-candidiasis
What is APS-1?
Rare autosomal recessive disease caused by mutations in the autoimmune regulatory gene (AIRE)
What is the estimated prevalence of APS-1?
1:100000
What are the clinical features of APS-1?
- At least 2 of 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
- Less frequent components
- Bilateral keratitis
- Periodic fever with rash
- Autoimmunity induced hepatitis, pneumonitis, nephritis, exocrine pancreatitis and functional asplenia
- Rare findings
- Retinitis
- Metaphyseal dysplasia
- Pure red cell aplasia
- Plyarthritis
APS-1 must have at least 2 of what 3 components during childhood?
- Chronic mucocutaneous candidiasis
- Hypoparathyroidism
- Primary adrenal insufficiency (Addison’s disease)
Is APS1 or APS2 more common?
APS-2
APS-2 is characterised by 2 of what 3 components?
- Type 1 diabetes
- Autoimmune thyroid disease
- Addison’s disease
Is APS-2 more common in men or woman?
Woman
APS-2 is characterised by at least 2 of type 1 diabetes, autoimmune thyroid disease and Addison’s disease. What are some other autoimmune conditions that can develop?
- Celiac disease
- Alopecia, vitiligo
- Primary ovarian insufficiency
- Pernicious anaemia
When does the onset of APS-2 usually occur?
Young adulthood, later than APS-1
Which of APS1 and APS2 usually has the later onset?
APS-2, which occurs in early adulthood
What does IPEX stand for?
X-linked immunodysregulation, polyendocrinopathy and enteropathy
What is IPEX characterised by?
- Early onset type 1 diabetes
- Autoimmune enteropathy with intractable diarrhoea and malabsorption
- Dermatitis that may be eczematiform, icthyosiform or psoriasiform
What are the different manifestations of dermatitis in IPEX?
Eczematiform, icthyosiform or psoriasiform
What in the blood is frequently elevated in IPEX?
Eosinophils and IgE levels
What are some later manifestations of IPEX?
- Autoimmune thyroid disease
- Alopecia
- Various autoimmune cytopenias
- Hepatitis
- Exocrine pancreatitis
What is the treatment of IPEX?
If often fatal in first few years unless treated with immunosuppresive agent or if possible, with allogeneic bone marrow transplantation which can cure the disease
