Overview of Autoimmune Disease Flashcards
1
Q
Overview of Autoimmune Diseases
A
- affect 5% of the population- incidence is increased in women and in developed countries
- self antigen is recognized as foreign as foreign by immune system and there is a failure of regulatory mechanisms
- effector mechanisms include types II, III, IV hypersensitivity reactions
- may be organ-specific, affecting only a few select cells or organs or systemic, affecting multiple organs
- most autoimmune diseases have no known cause or cure and treatment is aimed at controlling symptoms
2
Q
Factors contributing to development of autoimmune diseases
A
- immune factors- all autoimmune diseases involve the breakdown of T and B cell tolerance and the production of autoantibody and/or inflammatory autoreactive T cells
- genetic factors- there is a genetic predisposition to develop autoimmune diseases
- environmental factors modulate and/or trigger autoimmune diseases
3
Q
How do contributing factors develop to autoimmune disease
A
- trigger (infection?) seems to be required- bacterial products required to induce autoimmune response to injected self proteins
- also increases in disease incidence supports a role for environmental factors
- susceptibility genes -> failure of self tolerance -> influx of self-reactive lymphocytes into tissues
- tissue injury: autoimmune disease
4
Q
Breakdown in B cell tolerance
A
- central B cell tolerance- clonal deletion of self-reactive B cells in the bone marrow (but not all are deleted)
- peripheral B cell tolerance- without cognate T cell help, antigen-activated B cells in the T cell zone of a lymph node die by apoptosis
- B cells may also become anergic after encounter with soluble antigen, and then will be eliminated by antigen-specific T cell through Fas signaling
5
Q
Breakdown in T cell tolerance
A
- normally T cells that bind to self peptides presented by MHC on the thymic cells are deleted
- defects in AIRE leads to the production of a variety of autoimmune B and T cell responses and autoimmune polyglandular disease
- even if negative selection works properly, some autoreactive cells do escape- controlled by peripheral tolerance
6
Q
Insufficient control of T-cell costimulation
A
- activation of naive T cells require both antigen presentation and costimulation (B-7/CD28) -> most cells producing tissue-specific antigens do not express costimulatory molecules
- autoreactive T cells may lower threshold for activation
- allelic variants of CTLA-4 (soluble and membrane CTLA-4 compete for binding to B-7
- CD40, CD40L varients
7
Q
Lack of Regulatory T cells (Treg) may contribute to autoimmune disease
A
- CD4+, CD25+, CTLA-4+ producing IL-4, IL-10, and TGFB (TH2)
- require cell contact and CTLA-4 for activity
- suppression of autoreactive T cells by regulatory T cells requires them to interact with the same antigen-presenting cell
- defects in FoxP3, a transcription repressor gene uniqueto Treg results in autoimmune disease, mainly in bodys
8
Q
Inflammatory Th17 cells in autoimmune disease
A
- helper CD4+ T cells that secrete IL-17
- pro-inflammatory binds to IL-17 receptor on fibroblasts epithelial cells and keratinocytes, leading to secretion of cytokines and recruitment of inflammatory cells
- may accumulate in affected tissues in Crohn’s diseae, RA, psoriasis, allergic asthma
- link between infection and autoimmunity?
9
Q
Genetic factor affecting autoimmune disease
A
- genes located in the MHC region
- different combinations of HLA II allotypes confer susceptibility and resistance to some autoimmune diseases
- variants of complement (complotypes)
- variants of CTLA-4
- variants of AIRE
- variants of Fas and Fas L
10
Q
Other Factors- Release of sequestered antigens
A
- trauma to sites of immune privilege- normally entry of naive lymphocytes is prevented but self antigens may be exposed to circulation by wound or infection, and effector cells can gain access
- sympthetic ophthalmia
- also UV damage to skin in lupus, chemicals in cigarette smoke damage lung alveoli, brain trauma
11
Q
Self proteins may be modified to appear foreign
A
- celiac disease
- gluten is degraded in the gut lumen to give a resistant fragment
- gluten fragment enters gut tissue and is deaminated by transglutaminase
- naive CD4 T cell responds to deaminated peptides presented by HLA-DQ
- inflammatory effector T cells cause villous atrophy
- result-> diarrhea, malabsorption of nutrients
- IgG or IgA antibodies to tissue transglutaminase may also be produced
12
Q
Associations of infection with autoimmunity
A
- Group A Strep- rheumatic fever
- Chlamydia teachomatis- HLA-B27- Reiter’s syndrome
- Shigella, Salmonella, Yersinia, Campylobacter jejuni, HLA-B27, reactive arthritis
- Borrelia Burgdorferi- HLA-DR2, DR4- chronic arthrtis in lyme disease-
- Coxsackies and rubella- Type I diabetes
13
Q
Molecular mimicry
A
- pathogen-derived peptides structurally similar to a self-antigen stimulate a TH1 cell response directed against the self-antigen
- other possible mechanism(s) include infection of APC, inflammatory tissue damage leading to bystander effect, polyclonal activation of autoreactive cells (superantigen, LPS), creation of neoantigens
14
Q
infection may also lead to increased antigen presentation
A
- during infection class I and class II expression may be induced or increased due to interferon gamma production
- Hashimoto’s disease- thyroid gland resembles secondary lymphoid tissue, with B and T cells present
15
Q
Additional factors may contribute to disease mechanisms in genetically susceptible individuals
A
- chemicals (pesticides, solvents, industrial pollutants, drugs)
- metals (mercury, lead)
- hormones (estrogen, phytoestrogens)- 90% of all autoimmune diseases occur in women
- stress
- diet
- age
