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Autoimmunity
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Autoimmunity
Autoimmunity
- When the immune system loses sense of self and attacks and destroys healthy body tissue
- A destructive immune response against self antigens
- Once started, difficult to stop
- Severity ranges from minor to lethal
- Affects 5-7% of the population
- Can affect any organ or organ system in the body
- Autoantibodies can be passed from mothers to their babies
Autoimmunity vs. hypersensitivity
- Immunogen in hypersensitivity is an allergen, in autoimmunity it's an autoantigen
- Hypersensitivity causes a clinical allergy, autoimmunity causes an immune disorder
- 10% of the population experience hypersensitivity, 5% experience autoimmunity
- Mortality by hypersensitivity is rare, but in autoimmunity it is high
- Mechanisms in hypersensitivity include type I, II, III and IV, in autoimmunity type II, III and IV
What causes autoimmunity?
- Failure to maintain self-tolerance
- Risk factors
- Genetic susceptibility
- Presence of susceptible genes
- Being female
- Could be due to imbalance in hormone levels
- Rise in hormones associated with pregnancy may cause abortion of the foetus
- Endometriosis and preeclampsia are thought to be autoimmune in nature
- ORE: oestrogen response elements
- There isn't a single pin-pointable gene
- Numerous genes involved in susceptibility
- Environmental triggers
- Infections
- Injury
- Drugs, toxins, UV radiation
- Stress, poor diet, lack of exercise, lack of sleep, abuse of alcohol and use of tobacco
- Genetic susceptibility
Exceptions to the rule: simple genetic autoimmune illnesses
- Autoimmune polyglandular syndrome type I (APS-1)
- Gene: AIRE
- Knockout causes decreased expression of self antigens in the thymus, resulting in defective selection of self reactive T cells
- Mechanism: decreased expression of self antigens in the thymus resulting in a defect in negative selection
- Gene: AIRE
- Immunodysregulation polyendocrinopathy enteropathy,X linked (IPEX)
- Gene: FOXP3
- Knockout causes decreased function of CD4 CD25 regulatory T cells
- Decreased generation of regulatory T cells
- Gene: FOXP3
- Autoimmune lymphoproliferative syndrome (ALPS)
- Gene: FAS
- Knockout causes failure of apoptotic death of self reactive B and T cells
- Failure of apoptotic death of self reactive T or B cells
- Gene: FAS
- Autoimmune polyglandular syndrome type I (APS-1)
MHC association
- Mechanisms underlying the association of MHC alleles with various autoimmune diseases are still not clear
- Association with MHC class II genes
- MHC may present a self peptide and activate pathogenic T cells
- MHC may influence negative selection of developing T cells
Genetics of autoimmunity
- NOD2
- Polymorphism associated with 25% of Crohn's disease
- Microbial sensor
- PTPN22
- Most common autoimmunity associated gene
- Phosphatase
- CD25
- Associated with MS
- Role in regulatory T cells
- NOD2
Injury
- Sympathetic opthalamaia
- Physical trauma in one eye can initiate autoimmune response to both eyes
- Eye anterior chamber is an immune privileged site
- Normally autoimmune antigens in this site are not exposed to the immune system
- Trauma to one eye results in the release of sequestered introcular protein antigens
- Released intraocular antigens are carried to the lymph node and activate T cells
- Effector T cells return via bloodstream and attack antigen in both eyes
- On occasion this causes blindness in both damaged and undamaged eyes
- Effector T cells return via bloodstream and attack antigen in both eyes
- Released intraocular antigens are carried to the lymph node and activate T cells
- Sympathetic opthalamaia
Superantigens
- Several infectious agents contain antigens with the ability to polyclonally activate a subset of CD4+ T cells bearing particular VB TCR families
- Hypothesis: this may activate auto antibodies
- This would increase VB in autoimmune lesions
- Isolated reports in rheumatoid arthritis and diabetes
- No strong evidence
- Polyclonal activation
- Viruses and bacteria can induce non-specific polyclonal B cell activation leading to autoantibodies
- Gram negative bacteria, cytomegalovirus and EBV are polyclonal activtors
- SLE patients produce large quantities of IgM polyclonal antibodies
- Systemic Lupus Erythematosus (SLE) can attack any part of the body resulting in inflammation or tissue damage
- Hypothesis: this may activate auto antibodies
- Several infectious agents contain antigens with the ability to polyclonally activate a subset of CD4+ T cells bearing particular VB TCR families
Local infections
- Induces inflammation which results in activation of non-professional APC
- Thyroid cells do not normally express MHC class II
- IFN-gamma produced during infection or non-specific inflammation induces MHC class II expression on thyroid cells
- Activated T cells recognise peptides presented by MHC class II and induce autoimmune thyroid disease
- IFN-gamma produced during infection or non-specific inflammation induces MHC class II expression on thyroid cells
- Hashimoto thyroiditis
- Follicular cells of the thyroid
- Type I diabetes
- beta cells of islets of Langerhans
Molecular mimicry
- Some viruses and bacteria possess antigenic determinants that are identical or similar to normal host cell components
- The same MHC molecule presents both a pathogen peptide and a self peptide that mimics it
- Naive T cell is activated by the pathogen peptide present by the MHC molecule
- Effector Th1 cells responds to the self peptide mimic and activates the macrophage causing inflammation
- Naive T cell is activated by the pathogen peptide present by the MHC molecule
- Examples
- Rheumatic fever
- Multiple sclerosis
- Type I diabetes
- Systemic Lupus erythematosus
- Post rabies encephalitis
- Used to develop in individuals that had the rabies vaccine
- Rabies virus was grown in rabbit cell culture that contained antigens from rabbit brains
- In vaccinated people these antigens would induce formation of antibodies and activated T cells which would cross react with the recipient's own brain cells causing encephalitis
Epitope spreading
- Once autoimmune diseases begin they tend to be progressive with remissions and exacerbations
- A mechanism for chronic progression
- In a persistent microbial infection and tissue damage, initial response to one self epitope expands to involve additional epitopes on the same molecule as well as additional self proteins
- Explains how one epitope can mature into full blown autoimmune response
- Release of sequestered antigen
- APC with cross reacting Ag (molecular mimicry)
- Inappropriate MHC expression on non-APCs
- Activated macrophages from activated T helper cells cause inflammation and local Delayed Type Hypersensitivity (IV) resulting in tissue damage
- Activated Th cell produces B cells which produce plasma cells by polyclonal activation that produce Abs to self antigens resulting in tissue damage
- Inappropriate MHC expression on non-APCs
- APC with cross reacting Ag (molecular mimicry)
Autoimmunity classification
- Organ specific autoimmune diseases
- Type I diabetes
- Goodpasture's syndrome
- Autoantibodies specific for antigens in the basement membranes of the kidney and the alveoli of the lungs
- Leads to complement activation and direct cellular damage as well inflammatory response mediated by the build up of complement split products
- Tissue damage leads to kidney damage and pulmonary haemorrhage
- Smoking can be the trigger because it damages alveoli and exposes collagen
- Multiple sclerosis
- Grave's disease
- Hashimoto's thryoiditis
- Systemic autoimmune diseases
- Rheumatoid arthritis
- Scleroderma
- Systemic lupus erythematosus
- Organ specific autoimmune diseases
Autoimmune diseases of the endocrine glands
- Insulin dependent diabetes mellitus
- Type 1
- T cells attack and destroy insulin producing cells (beta cells) located in the islets of Langerhans
- The pancreas does not produce or properly use insulin and consequently increased levels of blood glucose
- Islets of Langerhans contain several cell types secreting distinct hormones, each cell expresses different tissue specific proteins
- In IDDM an effector T cell recognises peptides from the beta cell specific protein and kills the beta cell
- Glucagon and somatostatin are still produced by the alpha and delta cells but no insulin can be made
- In IDDM an effector T cell recognises peptides from the beta cell specific protein and kills the beta cell
- Treated with daily insulin injections
- Factors involves in the destruction of beta cells
- Activated CTLs migrate to the islets and begin to attack the beta cells
- Cytokine production released during response: IFN-y, TNF-a and IL-1
- Coxasckie virus group B- direct destruction of the beta cells by the virus as a result of molecular mimicry
- Chronic thyroiditis: Hasimoto's disease
- Production of autoantibodies and sensitised to Th1 cells specific for thyroid antigens
- Intense infiltration of the thyroid gland by lymphocytes, macrophages and plasma cells
- Binding of autoantibodies against thyroid tissue proteins interferes with the iodine uptake and leads to decreased production of thyroid hormones
- Treatment: oral administration of thyroid hormone
- Hyperthyroidism: Graves' disease
- Autoantibodies produced against the thyroid gland
- Long acting thyroid stimulating antibody causes unregulated overproduction of thyroid hormones
- Symptoms
- Heat intolerance
- Nervousness
- Irritability
- Warm, most skin
- Thyroid enlargement
- Treatment
- Thyroidectomy
- Destruction of thyroid by radioactive 131I
- Autoantibodies can be passed from mothers to their babies
- Mother with Graves disease makes anti-TSHR antibodies
- During pregnancy antibodies cross the placenta into the foetus
- Newborn infant also suffers from Graves' disease
- Plasmapheresis removes maternal anti-TSHR antibodies and cures the infant's disease
- Newborn infant also suffers from Graves' disease
- During pregnancy antibodies cross the placenta into the foetus
- Mother with Graves disease makes anti-TSHR antibodies
- Insulin dependent diabetes mellitus
Myasthenia Gravis
- Blocks normal binding of acetylcholine and mediates complement mediated degradation of receptors
- Binding autoantibodies to the acetylcholine receptors on the motor end plates of muscles
- Progressive weakening of the skeletal muscles and loss of muscle control
- Symptoms
- Drooping eyelids
- Inability to retract the corners of the mouth
- Blocks normal binding of acetylcholine and mediates complement mediated degradation of receptors
Systemic autoimmune diseases
- Defects in immune regulation
- Response is directed towards a broad range of target antigens and involves a number of organs
- Tissue damage is widespread by...
- Cell mediated immune responses
- Direct cellular damage caused by autoantibodies
- Accumulation of immune complexes
- Celiac disease
- Wheat flour gluten peptide specific CD4 T cells
- Gluten is degraded in the gut lumen to give a resistant fragment
- Gluten fragment enters the gut tissue and is deaminated by transglutaminase
- Naive CD4 T cells respond to deaminated peptides presented by MHC II
- Inflammatory effector T cells cause villous atrophy
- Naive CD4 T cells respond to deaminated peptides presented by MHC II
- Gluten fragment enters the gut tissue and is deaminated by transglutaminase
- Systemic Lupus Erythematosus (SLE)
- Appears in women age 20-40
- More prevalent in females
- Symptoms
- Low grade fever
- Ulcers
- Aching muscles
- Arthritis
- Fatigue
- Loss of appetite
- Butterfly rash on face
- Poor circulation
- Antinuclear antibodies directed against DNA, nucleoprotein, histones and nucleolar RNA
- IgG against a wide variety of cellular constituents (defect in maintenance of B cell self tolerance
- Binding of antibodies to cell surface antigens causes inflammatory responses leading to cell and tissue destructon
- Immune complexes, deposited in blood vessels, kidney, joints and other tissues cause tissue inflammation and destruction
- Binding of antibodies to cell surface antigens causes inflammatory responses leading to cell and tissue destructon
- IgG against a wide variety of cellular constituents (defect in maintenance of B cell self tolerance
- Damage occurs by...
- Formation of immune complexes
- Type III hypersensitivity
- Antibody mediated injury to blood cells
- Type II hypersensitivity
- Formation of immune complexes
- Gene: C1q
- Knockout causes defective clearance of immune complexes and apoptotic cells
- Rheumatoid arthritis
- Mostly affects women age 40-60
- Major symptom: chronic inflammation of joints
- B cells in joints produce IgM autoantibodies called rheumatoid factors
- This binds to Fc region of normal circulating IgG, forming IgM-IgG complexes that are deposited in the joints and activate the complement cascade
- Type III hypersensitivity reaction which leads to chronic inflammation of the joints
- This binds to Fc region of normal circulating IgG, forming IgM-IgG complexes that are deposited in the joints and activate the complement cascade
- Multiple sclerosis
- Autoimmune neurological disease
- Symptoms may be mild such as numbess in the limbs or severe such as paralysis and loss of vision
- Most people are diagnosed between the ages of 20 and 40
- Autoreactive Th1 cells in the cerebrospinal fluid induce expression of chemokines and cytokines that recruit inflammatory cells
- Inflammatory lesions along the myelin sheath of nerve fibres
- Treated with immunosuppressive drugs
- Inflammatory lesions along the myelin sheath of nerve fibres
- Possible environmental influence and genetic infleunce
- Cause unknown, possibly a virus
Information
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- Immunology Mind Map on Autoimmunity, created by sophie_connor on 23/05/2013.
- Created by
- sophie_connor · May 2013
- Updated
- Mar 16, 2016
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