Autoimmunity Flashcards
(32 cards)
What is autoimmune disease? Give example.
A specific and sustained adaptive immune response directed against self which causes damage to host. Example: In SLE, antibodies are formed against self DNA, histones and other nuclear components.
Example of physiologic or regulatory autoimmunity
Body removes aged RBCs by rxn of IgG autoantibodies with senescent cell antigen
What is tolerance?
It is the acquired and specific lack of immunological activity to a particular antigen.
What is autoimmunity?
The immune system responds against self causing destruction of normal cells and tissues d/t a failure of mechanisms of tolerance to self antigens. Can be caused by inheritance of susceptibility genes, hormonal milieu and/or environmental factors (heavy metals or infection)
Diseases with MHC associated genetic predispositions
RA, myasthenia gravis, Type I diabetes, Goodpasture’s syndrome, SLE, ankylosing spondylitis, Grave’s disease, Multiple sclerosis
What is molecular mimicry?
Infectious pathogen bears peptides that mimic AA sequence of self antigens. An APC presents pathogen peptide to CD4+ Th cell => activates macrophages and B-cells that mount immune response against self tissues.
How do protein changes in self cells and cryptic antigens cause a immune response?
Tissue injury, cell death or reparative changes can make self proteins unrecognizable to immune system and induce autoimmune response. Cryptic antigens are proteins normally sequestered or shielded from immune recognition that can become immunogenic when exposed to the immune system
What are superantigens and how do they mount an immune response?
Superantigens are proteins produced by bacteria or mycoplasmae or virus that bind TCR irrespective of its antigenic specificity causing activation of a large number of T lymphocytes of different antigenic specificity.
How is tolerance normally effected?
Self reactive, immature B-cells are deleted in the bone marrow; self reactive DP T-cells are deleted at the CM junction in the thymus
Are all self-reactive lymphocytes deleted? Why or why not?
Only strongly self reactive B and T cells are deleted during positive and negative selection. Not all self antigens are expressed in the thymus and bone marrow so some self-reactive lymphocytes do escape to the periphery.
What are central tolerance mechanisms?
Immature lymphocytes specific for self antigens are deleted. B lymphocytes change their specificity by receptor editing. Some T lymphocytes develop into regulatory T cells.
What are peripheral tolerance mechanisms?
Some mature self reactive lymphocytes in peripheral tissues may be inactivated or deleted by encounter with self antigens or suppressed by regulatory T cells.
What are examples of autoimmune diseases with mendelian inheritance?
Multiple sclerosis, rheumatoid arthritis, lupus
What is the mechanism of genetic susceptibility resulting in autoimmune disease?
Susceptible genes result in failure of self tolerance. Self reactive lymphocytes interact with APCs during an infection. Influx of self reactive lymphocytes into tissues causes tissue injury.
What is the mechanism bystander activation?
During an infection or tissue damage, activated APC presents epitope spread from microbial to self peptides to self-reactive T cells that cause self-tissue destruction.
What is the microbial mechanism of induction of costimulators?
Microbes activate APCs to express co-stimulators (B7-1, B&-2) so that when self antigens are presented to self-reactive T cells they become activated instead of being rendered tolerant (become anergic or apoptose).
What is the mechanism of cross-reactivity in autoimmune disease?
An infectious agent causes disease. Recovery from disease d/t T cell and Ab response. A portion of antigenic protein mimics self protein. D/t the MHC composition, T-cells specific for antigenic protein also cross-reacts with self protein. T-cell responds to self protein and recruits immune cells causing tissue destruction.
Which autoimmune diseases do Th17 cells appear to be intimately involved?
Crohn’s, psoriasis, inflammatory bowel disease and rheumatoid arthritis. Deficiencies in Th17 or its receptor result in chronic mucocutaneous candidiasis syndrome.
What are some factors contributing to autoimmune disease?
- Estrogen - induces IFN-gamma production => ^ HLA expression on APCs; may also push Th2 autoimmune response toward Th1
- Infections - superantigenic effect of Staph or Mycoplasma may activate T-cells causing them to secrete cytokines and/or expand autopathogenic T-cell pop. d/t prolonged inflammatory response
- Stress - stimulation of hypothalamus and pituitary may lead to ^ cytokine secretion => inflammation
What are important cytokines in autoimmunity?
TNF-a, IL-1, IL-6 => begin acute phase response
IL-2 => induces T-cell, NK and B-cell proliferation (minor)
IL-4, IL-5 => induces IgG1, IgE and IgA, eosinophil production (IL-5)
IL-7, GM-CSF => hematopoiesis
IL-10 => suppresses Th1 response
IFN-gamma => upregulates MHC class I and II expression
What is systemic autoimmunity?
Autoimmune pathology is evident in a number of organ systems. Examples include SLE, Sjogren’s and scleroderma
What is organ-specific autoimmunity?
Autoimmunity is exhibited in specific tissues in which the target antigen is found. Examples are thyroiditis (thyroid), diabetes (islets), Addison’s (steroid producing cells of adrenals and ovary)
What are treatments for autoimmune disease?
1) corticosteroids - prednisone
2) NSAIDs - ASA, ibuprofen, tylenol
3) cyclosporin A, Tacrolimus, Rapamycin
4) monoclonal antibodies (anti-CTLA-4)
5) TCR peptide immunization
6) anti-TNF-a biologicals - infliximab, etanercept, adalimumab
How does the hygiene hypothesis cause autoimmune disease?
The hygiene hypothesis suggests that exposure to microbes early in life is associated with the prevention of asthma and certain autoimmune diseases. This observation may be d/t the levels of T-regs and iNKT cells stimulated by the presence or absence of microbes.
