Immunology of Endocrine Disorders Flashcards
Describe autoimmunity
Immune response against a self antigen
Tissue damage or disrupted function resulting from autoimmune response
Commoner in females
What is immunologic tolerance?
Unresponsiveness to an antigen that is induced by previous exposure to that antigen When lymphocytes encounter antigens they may be activated or eliminated/ inactivated leading to tolerance
What are antigens which induce tolerance called?
Tolerogens
How is autoimmune disease avoided - immunological tolerance?
T and B cells bearing these self reactive molecules must be eliminated or downregulated so immune system is made specifically tolerant to self antigens
Describe central tolerance
Bone marrow is important in B cell tolerance
Thymus plays important role in eliminating T cells with high affinity to self antigens
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
What is an important mechanism for the induction of peripheral tolerance?
Antigen recognition without co-stimulation or second signals
How does regulatory T cells help peripheral tolerance?
Actively suppress the activation of lymphocytes specific for self and other antigens
How are antigens sequestered from immune system?
Anatomic barriers like in the CNS, testes and eyes
So cannot engage antigen receptors
What are the 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 ways in which self molecules are presented to immune system
What causes a breakdown of tolerance?
Genes
Infections
Environmental factors
Describe the epidemiology of autoimmune diseases
Show clustering in families
Peak onset 15-65 yrs
More common in females except ankylosing spondylitis
What is the difference between organ and non organ specific diseases?
Non - affect multiple, autoimmune response against self molecules widespread through body and intracellular molecules involved in transcription and translation
Organ - one organ and usually endocrine
What are the genetic factors of autoimmune disease?
Cluster in families
Alleles of MHC
HLA association
What is the aetiology of autoimmune diseases?
Susceptible genes and failure of self tolerance leads to tissue injury and inflammation
Activation of tissues APCs
Then activation of self reactive lymphocytes
What are some environmental factors leading to autoimmune disease?
Infections - molecular mimicry, upregulation of co-stimulation and antigen breakdown
Drugs - molecular mimicry and genetic variation
UV radiation - trigger of skin inflammation and modification of self antigen
Explain molecular mimicry
Structural similarity between self proteins and microbial antigens may trigger autoimmune response
Cross reactivity will cause expansion of responsive T cell population recognising self peptise
Describe treatment of autoimmune disease
Suppression of damaging immune response
Replacement of the function of damaged organ
What is the aetiology of type I diabetes?
Autoimmune destruction, genetic factors (HLA types) and viral infections
What viruses can trigger autoimmune destruction?
Coxsackie B
Mumps
Describe the thyroid gland
Follicles lined by cuboidal cells and c cells scattered throughout gland - secrete calcitonin
Synthesis of T3 and T4
Negative feedback by TSH
Describe graves thyroiditis
Organ specific
Autoantibody, long acting thyroid stimulator which binds to epithelial cells and mimics actions of TSH
Stimulates function and growth of follicular epithelium
Exophthalmos, pretibial myxoedema and finger clubbing
Describe cretinism
If hypothyroidism is present in new born - physical and mental development are impaired
In areas where diet is insufficient in iodine
Sporadic - congenital absence of thyroid tissue or enzyme defect
Describe Hashimoto thyroiditis
Most common cause of acquired hypothyroidism in adults
May initially cause thyroid enlargement - later can be atrophy and fibrosis
Damage of follicles leads to release of thyroglobulin causing thyrotoxicosis
What is Hashimoto thyroiditis histologically?
Densely infiltration by lymphocytes and plasma cells - lymphoid follicle formation
Colloid content is reduced
Thyroid epithelium enlarges - eosinophilic cytoplasm
May be fibrosis
What autoantibodies are detected in serum of patient with Hashimoto thyroiditis?
One reacting thyroid peroxidase
Other reacting with thyroglobulin
These are formed by plasma cells infiltrating thyroid as loss of specific suppressor T lymphocytes
What are autoimmune polyendocrine syndromes?
Diverse group of conditions characterised by functional impairment of multiple endocrine glands due to loss of immune tolerance
Ex. alopecia, coeliac disease, autoimmune gastritis
What does autoimmune polyendocrine syndrome lead to?
Circulating autoantibodies and lymphocytic infiltration of affected tissues or organs
Eventually leading to organ failure
Describe autoimmune polyendocrine syndrome type I
Ectodermal dystrophy - rare autosomal recessive disease caused by mutations in autoimmune regulator gene - AIRE
What are 3 cardinal components during childhood of APS-1?
Chronic mucocutaneous candidiasis
Hypoparathyroidism
Primary adrenal insufficiency
What are some other findings of APS-1?
Enamel hypoplasia
Enteropathy with chronic diarrhoea or constipation
Primary ovarian insufficiency
Describe APS-2
More common
Have 2/3 of - type I diabetes, autoimmune thyroid disease and Addison’s disease
Women mainly
Typically younger onset than APS-1
What other autoimmune conditions develop in affected APS-2 patients?
Coeliac disease, alopecia, vitiligo, primary ovarian insufficiency and pernicious anaemia
Describe IPEX (immunodysregulation, polyendocrinopathy ad enteropathy)
An extremely rare inherited syndrome characterised by type I diabetes, autoimmune enteropathy with diarrhoea and malabsorption and dermatitis
Early development
Fatal in first few years of life - immunosuppressive agents or bone marrow transplant
What are some manifestation of IPEX?
Autoimmune thyroid disease
Alopecia
Various autoimmune cytopenia
Hepatitis
Exocrine pancreatitis
