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Flashcards in Overview of Autoimmune Disease Deck (27)
1

Overview of Autoimmune Diseases

-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

Factors contributing to development of autoimmune diseases

-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

How do contributing factors develop to autoimmune disease

-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

Breakdown in B cell tolerance

-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

Breakdown in T cell tolerance

-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

Insufficient control of T-cell costimulation

-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

Lack of Regulatory T cells (Treg) may contribute to autoimmune disease

-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

Inflammatory Th17 cells in autoimmune disease

-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

Genetic factor affecting autoimmune disease

-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

Other Factors- Release of sequestered antigens

-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

Self proteins may be modified to appear foreign

-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

Associations of infection with autoimmunity

-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

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Molecular mimicry

-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

infection may also lead to increased antigen presentation

-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

Additional factors may contribute to disease mechanisms in genetically susceptible individuals

-chemicals (pesticides, solvents, industrial pollutants, drugs)
-metals (mercury, lead)
-hormones (estrogen, phytoestrogens)- 90% of all autoimmune diseases occur in women
-stress
-diet
-age

16

Antibody-mediated autoimmune diseases

-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

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Hemolytic Anemia

-IgG autoantibodies bound to Rh or I antigens may promote antibody-dependent cell-mediated cytotoxicity (ADCC) or complement fixation

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Graves' disease

-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

Myasthenia gravis

-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

IgG-mediated diseases may be transfered in utero

-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

Immune complex-mediated autoimmune disease

-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

Systemic Lupus Erythematous (SLE)

-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

T cell-mediated autoimmune disease

-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

Juvenile diabetes

-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

Rheumatoid arthritis

-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

Multiple Sclerosis

-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

Treatment for autoimmune diseases

-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