Immunology Flashcards
How does immunologic tolerance to an antigen happen?
When a lymphocyte encounters an antigen it is inactivated or eliminated, leading to tolerance - future exposure to that antigen causes no response
What are antigens that induce tolerance called?
Tolerogens
What is meant by the term self-tolerance
Tolerance to self antigens
It’s a fundamental property of the normal immune system, and failure of self-tolerance results in immune reactions against self (autologous) antigens.
If reactions occur against self antigens what is this called?
Autoimmunity reactions - cause autoimmune diseases
How is autoimmune disease avoided?
T and B cells bearing 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 making sure the body is tolerant of self-antigens
Central (also known as negative selection)
Peripheral
What does a breakdown in any of the immunological tolerance mechanisms cause?
Autoimmune responses
By what method can the immune system generate a diversity of T-cell antigen receptors?
Differential genetic recombination
Process of central tolerance/negative selection
Central tolerance, also known as negative selection, is the process of eliminating any immature T or B lymphocytes that are self-reactive.
3 things happen - apoptosis (deletion), change in receptors or development of Tregs
The thymus plays an important role in eliminating T cells with high affinity to self-antigens
What is important in B cell tolerance?
Bone marrow
What is peripheral tolerance
Peripheral tolerance is the 2nd branch of immunological tolerance
Comes after central tolerance.
It takes place in the peripheral tissues - some self-reactive mature lymphocytes may enter peripheral tissues and are either inactivated or deleted by encounter with self antigens in these tissues or are suppressed by tregs
What regulates peripheral tolerance? How do they regulate it?
regulatory T cells (Tregs)
They actively suppress the activation of lymphocytes specific for self and other antigens
Mechanisms of peripheral tolerance
Anergy (functional unresponsiveness)
Treg suppression
Deletion (cell death)
How can you overcome peripheral tolerance/ pre-established tolerance
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 - structures of self-peptides may be altered by viruses, free radicals or ionising radiation, thus bypassing previously established tolerance.
State 3 factors of tolerance breakdown that may result in autoimmune disease
Genes
Infections
Environmental factors
Which gender are almost all types of autoimmune diseases more common in?
Females
Non-specific autoimmune diseases
They affect multiple organs
Associated with autoimmune responses against self-antigens which are widely distributed throughout the body
Intracellular molecules involved in transcription and translation
Organ specific autoimmune diseases
Restricted to one organ
Endocrine glands
Self-Antigens binding to TSH receptors or insulin receptors cause what?
Hyper or hypo thyroidism
Hyper or hypoglycaemia
Self-Antigens binding to acetylcholine receptors causes which disease
Myasthenia gravis
Epidermal cell adhesion molecules (self-antigens) cause what disease?
Blistering skin diseases
Self-antigens that are intracellular enzymes and their diseases
Thyroid peroxidase - thyroiditis, hypothyroidism
Steroid 21-hydroxylase - adrenocortical failure (addison’s)
Glutamate decarboxylase (beta-cells of pancreatic islets) - autoimmune diabetes
Name some intracellular molecules involved in transcription and translation
Double stranded DNA
Histones
Amino-acyl t-RNA synthases
Centromere proteins
Genetic factors of autoimmune disease
Clusters within families
Alleles of MHC
Which HLA allele is associated with diseases such as Sicca syndrome, Addison’s, Hashimoto thyroiditis and Myasthenia gravis disease?
DR3
Environmental factors causing autoimmune disease
Infection - molecular mimicry, antigen breakdown and presentation changes, upregulation of co-stimulation
Drugs - molecular mimicry, genetic variation in drug metabolism
UV radiation - trigger for skin inflammation
What is molecular mimicry
a structural similarity between self-proteins and microbial antigens that may trigger an autoimmune response
In systemic infection, the cross-reactivity will cause expansion of the responsive T-cell population recognising the self peptide
Which microbial antigen is similar to a self antigen found in cardiac muscle which results in rheumatic fever
Group A streptococcal M protein
Aim of treatment of autoimmune diseases (2)
Suppression of the damaging immune response - before irreversible damage to tissue, early detection is a challenge
Replacement of the function of the damaged organ - hypothyroidism, insulin dependent DM
Type 1 diabetes mellitus cause
Juvenile onset
Destruction of pancreatic beta cells probably as a result of viral infection and genetic factors
Inadequate insulin secretion
What are the 4 different types of pancreatic cells
Beta
Alpha
Delta
PP
Aetiology of Type 1 Diabetes mention
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
Viral infection
- Antibodies to certain viruses are high in patients.
Viruses may act as triggers for autoimmune destruction e.g Coxsackie B or Mumps
What can Hyperthyroidism result from? (6)
Graves thyroiditis Functioning adenoma Toxic nodular goitre Exogenous thyroid hormone (rare) Ectopic secretion by ectopic thyroid tissue or tumours
Grave’s thyroiditis
The most common cause of thyrotoxicosis.
Autoantibody (IgG) (LATS) which binds to thethyroidepithelial cells and mimics the action of TSH. LATS stimulates the function and growth ofthyroidfollicular epithelium.
It is an ‘organ specific’ autoimmune disease.
Usually associated with a diffuse goitre.
Increased vascularity.
What is Cretinism
Caused by congenital thyroid deficiency
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.
Hashimoto Thyroiditis
The most common cause of acquired hypothyroidism in adults.
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.
Hashimoto thyroiditis may initially cause thyroid enlargement, but later there may be atrophy and fibrosis.
What do the 2 autoantibodies detectable in Hashimoto thyroiditis react with?
thyroid peroxidase
Thyroglobulin
What are Autoimmune polyendocrine syndromes
A diverse group of clinical conditions characterised by functional impairment of multiple endocrine glands due to loss of immune tolerance.
Circulating autoantibodies and lymphocytic infiltration of the affected tissues or organs - eventually leads 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.
Give examples of autoimmune polyendocrine syndromes
Frequently include conditions such as alopecia, vitiligo, celiac disease, and autoimmune gastritis with vitamin B12deficiency that affect nonendocrine organs.
What is Autoimmune Polyendocrine Syndrome Type 1? what causes it?
Also named autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy is a rare autosomal recessive disease caused by mutations in the autoimmune regulator gene (AIRE).
Clinical features of APS-1
At least two of three cardinal components during childhood:
Chronic mucocutaneous candidiasis
Hypoparathyroidism
Primary adrenal insufficiency (Addison’s disease)
Other typical features: enamel hypoplasia (teeth), Enteropathy with chronic diarrhea or constipation or primary ovarian insufficiency
Autoimmune Polyendocrine Syndrome Type 2
Much more common than APS-1
Patients with APS-2 have at least 2 of the following endocrinopathies:
Type 1 diabetes
Autoimmune thyroid disease
Addison’s disease
The onset of APS-2 typically occurs in young adulthood, later than the onset of APS-1.
X-Linked Immunodysregulation, Polyendocrinopathy, and Enteropathy (IPEX)
Extremely rare inherited syndrome
characterised by:
Early onset type 1 DM
Autoimmune enteropathy with diarrhoea and malabsorption
Dermatitis that may be eczematiform, ichthyosiform or psoriasiform
Eosinophilia and elevated IgE levels are frequently present in patients with IPEX.
Later manifestations of the syndrome may include: Autoimmune thyroid disease Alopecia Various autoimmune cytopenias Hepatitis Exocrine pancreatitis.
Many features overlap with APS-1, but they usually develop much earlier in life than in APS-1.
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.
