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
16
Q
Antibody-mediated autoimmune diseases
A
- a single type of cell (organ) is targeted by autoantibodies, thus this type of autoimmune disease is organ-specific. The effector mechanisms correspond to Type II hypersensitivity reactions
- Autoimmune hemolytic anemia- destruction of RBCs
- Autoimmune thrombocytopenia-abnormal bleeding
- Goodpasture’s syndrome-glomerulonephritis
- Grave’s Disease- hyperthyroidism
- Myasthenia gravis- antibodies to AChR
- Insulin-resistant diabetes
- Hashimotos’ disease- hypothryoidism
17
Q
Hemolytic Anemia
A
-IgG autoantibodies bound to Rh or I antigens may promote antibody-dependent cell-mediated cytotoxicity (ADCC) or complement fixation
18
Q
Graves’ disease
A
- normally, thyroid-stimulating hormone (TSH) induces the breakdown of iodinated thyroglobulin, releasing T3 and T4 signaling the pituitary to stop releasing TSH
- in Graves’ disease autoantibodies bind to the TSH receptor of thyroid cells, mimicking the action of TSH so more thyroid hormones are released
- incidence 1 in 100
19
Q
Myasthenia gravis
A
- acetylcholine binds to Ach receptors on muscle cells, causing an inflow of sodium ions that indirectly causes muscle contraction (left)
- in Myasthenia gravis, anti-acetylchloline receptor Ig binds to the receptors lead to decreased sensitivity to stimulation, and progressive muscle weakening
20
Q
IgG-mediated diseases may be transfered in utero
A
- mother with Graves’ disease makes anti-TSHR antibodies
- during pregnancy, antibodies cross the placenta into the fetus
- newborn infant also suffers from Graves’ disease
- plasmapheresis removed maternal anti-TSHR antibodies and cures the infant’s disease
- other examples: Hemolytic disease of the newborn, Myasthenia gravis, Thrombocytopenia purpura, Neonatal lupus
- lymphocytes cannot pass from mother to fetus so babies born to mothers with T cell mediated autoimmune diseases do not show disease symptoms
21
Q
Immune complex-mediated autoimmune disease
A
- type II hypersensitivity effector mechanisms
- directed at multiple cells of the body, resulting in a systemic autoimmune response
- fix in tissues, fix complement, leading to the influx of inflammatory cells, resulting in tissue damage
22
Q
Systemic Lupus Erythematous (SLE)
A
- chronic systemic autoimune disease, with flares and remissions
- immune complexes contain anti-DNA, anti-nucleosome antibodies, among others
- anti-dsDNA titer is diagnostic
- specificity of response broadens over time- epitope spreading
- incidence is about 1 in 200 with more women than men affected; also more prevalent in females of African and Asian dscent
- symptoms may include butterfly-shaped rash on face, fatigue, headaches among others
23
Q
T cell-mediated autoimmune disease
A
- Type IV hypersensitivity effector mechanisms (DTH)
- antigen-specific T cells activated by antigen, as well as other immune cells (macrophages, mast cells) lead to inflammatory response
- insulin-dependent diabetes mellitus
- rheumatoid arthritis
- multiple sclerosis
- systemic lupus erythematosus
24
Q
Juvenile diabetes
A
- incidence 1 in 800with diagnosis usually before age 30
- also known as type I diabetes or insulin dependent diabetes
- beta cells in the pancreas produce little or no insulin due to destruction by inflammatory cytotoxic CD8+ T cells
- symptoms include increase thirst and urination, weight loss, nausea, fatigue
25
Q
Rheumatoid arthritis
A
- incidence is about 1 in 100 with onset most often between the ages of 25-55; women 4 times more likely to develop
- caused by the production of antibodies that react with constant regions of other antibodies (rheumatoid factor) and infiltration of the joint synvium by inflammatory CD4+ and CD8+ T cells
- classified variably as immune complex-mediated or T cell mediated
- secretion of TNFalpha, IL-1, IL-6, IL-7 leads to recruitment of effector cells
- symptoms include weakness, fatigue and joint pain
26
Q
Multiple Sclerosis
A
- chronic organ-specific disease- may be mild or severe
- affects 1 in 700 people, 60% of the cases occur in women
- inflammation of brain leads to permeability of blood brain barrier
- myelin sheath covering cells of spinal cord and brain destroyed due to TH1 CD4+ T cells which secrete IFNgamma and activation
- autoantibodies to myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein
- symptoms may disappear and recur over time and include weakness, tremors or paralysis of one or more extremities, numbness, decreased memory and attention span
27
Q
Treatment for autoimmune diseases
A
- physical removal of antigen, antibody or immune complexes-splenectomy
- IV Ig
- anti-inflammatories
- depletion of immune cells
- blocking interaction and/or activation of immune cells, bind cytokines or block second signals
- replacement therapy-insulin
- hormones, diet, exercise
