Autoimmune Diseases Flashcards
AI disease
- affect 5% of pop-incidence increased in women and developed countries
- self antigen is recognized as foreign by immune system and there is a failure of regulation
- effector mechanisms include types II, III, IV
- may be organ specific, affecting only a few cells or systemic, multiple organs
- no known cause or cure and treatment is aimed at controlling symptoms
factors contributing to development of AI diseases
- immune factors-breakdown of T and B cell tolerance and the production of autoantibody/ IF autoreactive T cells
- genetic factors
- environmental factors
development of AI
- trigger infection seems to be required- bacterial products required to induce autoimmune responses to injected self proteins
- also increase in disease incidence with industrialization supports role for environmental factors
breakdown in B cell tolerance
- central B cell tolerance-clonal deletion of self reactive cells in marrow-not all deleted
- peripheral B cell tolerance-without T cell help, antigen activated B cells in the T cell zone die by apoptosis
- B cells may also become anergic after encounter with soluble (self) antigen, then will be eliminated by T cell via Fas
**this all doesn’t happen in AI-or at least some of it
Breakdown in central T cell tolerance
- normally T cells that bind to self peptides presented by MHC on thymic cells are deleted
- defects in AIRE lead to the production of a variety of autoimmune B and T cell responses, and AI polyglandular disease
-even if negative selection works properly, some autoreactive cells do escape, theyre controlled by peripheral tolerance
breakdown in peripheral T cell tolerance
- insufficient control of T cell costimulation
- need 2 signals, self signal usually no co stim and anergy develops
- autoreactive t cells may have low threshold for activation
- allelic variants of CTLA4 can cause AI
- CD40 of CD40L variants can mess up activation
breakdown in peripheral 2
- lack of Tregs
- Tregs have CD4, CD25, CTLA4, produce IL4, IL 1- and TGFb
- require cell contact and CTLA4 to work
- defects in Foxp3 can cause AI mainly in boys
TH17
- helper CD4 cells secrete
- activates fibroblasts, epithelial cells, keratinocytes, leads to secretion of cytokines and recruitment of IF cells
- may accumulate in affected tissues in crohns disease, RA, psoriasis, allergic asthma
- link between infection and AI?
HLA
- dominant genetic factor affecting susceptibility to AI
- RR >150 down to 2 depending on HLA variations
- B27 big one
- also variants in AIRE, Fas, FasL, bcl2 (resistant to apoptosis) TNF, FoxP3, signalling molecules
release of sequestered antigens
- trauma to sites of immune privilege, normally entry of naive lymphocytes prevented but self antigens exposed by wound or infection and effector cells can get in
- injury to eye releases eye antigens to blood, go to lymph nodes and activate T cells, effector cells come back and hurt other eye
self protein modification
- gluten degraded to resistant fragment
- then deaminated
- then cd4 cell responds to peptide presented by HLA DQ
- IF effector cells cause villous atrophy
- leads to diarrhea and malabsorption
lyme disease
-HLA DR2,4 can lead to chronic arthritis
molecular mimicry
- self peptide looks enough like antigen than immune system gets confused and attacks
- T cell activated by actual antigen then thinks our protein is antigen
- also infection of APC, IF tissue damage/bystander, superantigens/LPS,
- neoantigens (penicillin)
infection and antigen presentation
- thyroid cells don’t normally have HLA II (some of them)
- IFN gamma produced during infection or nonspecific IF induced HLA class II
- activated T cells recognize this and cause AI disease
hashimoto’s disease
-thyroid gland resembles secondary lymphoid tissue with T and B cells present
additional factors that can contribute to disease mechanism
- chemicals
- metals
- hormones-estrogen- 90% in women
- sunlight
- stress
- diet
- age
antibody mediated AI
single type of organ targeted by autoantibodies
- organ specific
- type II hypersensitivity
hemolytic anemia
- loss of RBCs after fixation of complement by IgG and IgM on RBCs
- lysis or clearance via binding to Fc and complement receptors on phagocytes in the spleen and liver
thrombocytopenia
-platelet antigens are the target of autoantibodies
goodpastures syndome
antibody mediated
- IgG against type IV collagen
- IF in renal tissue
grave’s disease
antibody mediated
-antibodies binds to TSH receptor and act as agonists so thyroid hormones overproduced
myasthenia gravis
antibody mediated
- antibodies to Ach receptors on muscles induce their endocytosis
- antibodies also compete with Ach for binding with the receptors that are there, progressive muscle weakening
- cholera toxin stabilizes receptors that are there
insulin resistant diabetes
antibody mediated
-insulin binding to receptor is blocked by antibody so that insulin accumulates, hyperglycemia, resistance to insulin
NOT TYPE 1
-in some patients agonist antibodies for insulin deplete glucose resulting in hypoglycemia
IgG passed through placenta
- mom can pass IgG for TSH receptor to baby
- baby makes too much thyroid hormone, but can be corrected
immune complex mediated AI disease
- AI response is directed at multiple cells of the body, systemic
- Type III response
SLE
immune complex regulated
- chronic systemic AI disease, flares and remissions
- immune complexes have anti DNA, anti nucleosome
- anti dsDNA diagnostic
- specificity of response broadens over time
- incidence is 1/200 with more women, african and asian
- butterfly shaped rash, fatigue, headaches
T cell mediated AI
antigens in tissue are targeted by TH1 cells
-type IV reaction
insulin dependent DM
T cell mediated
-CD8 cells cytotoxic to pancreatic beta cells so that insulin production is low
1/800
-thirst and urination, weight loss, nausea, fatigue
RA
T cell mediated
- 1/1– 22-55
- caused by production of antibodies that react with constant regions of other antibodies (rheumatoid factor) and infiltration of the joint synovium by IF cd4 and 8 cells
- classified variably as immune complex mediated or t cell mediated
- secretion of TNF a, IL1, IL6,7 leads to recruitment of effector cells
- weakness, fatigue, joint pain
- proteases and collagenases produced in joint cause damage to cartilage and erosion of supporting structures
MS
t cell mediated
- chronic organ specific disease
- 1/700, 60% women
- inflammation of brain (trigger?) leads to permeability of blood brain barrier
- myelin sheath cover cells of spinal cord and brain destroyed due to TH1 CD4 cells which secrete IFN gamma and activate macrophages, also mast cell and complement activation
- autoantibodies to myelin basic protein, proteolipid protein, MOG
- symptoms may disappear and recur over time and include weakness, tremors, paralysis of one or more extremities, numbness, decreased memory and attention span
treatments for AI
- physical removal of the antigen, antibody, or immune complexes- splenectomy
- IVIG
- anti IF drugs
- depletion of immune cells
- blocking interaction/activation of immune cells (antiTNF, TNF antagonist, soluble CTLA4)
- replacement therapy- insulin for diabetes
- hormones, diet exercise
