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 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 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 is hyperthyroidism?
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 hypothyroidism?
- Inadequate levels of circulating T3 and T4
- The metabolic rate is lowered
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
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 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
a
APS-1
b
APS-2
c
IPEX
study this image
