CH. 16 Autoimmune Diseases Flashcards
What is central tolerance?
-deletion of lymphocytes in primary lymphoid organs before they mature; limits development of autoreactive T- and B-cells
During central tolerance, B cells have been shown to undergo
receptor editing
Peripheral tolerance
either renders self-reactive lymphocytes nonresponsive (anergic) or actively generates inhibiting lymphocytes outside the BM and thymus; regulates autoreactive cells in circulation
Dependent mechanisms of CD4+ T cells
- occur as TREG cells express high levels of inhibitory CTLA-4 molecules
- CTLA-4 blocks CD28 activation through CD80/86, inhibiting APC activation/licensing
Independent mechanisms of CD4+ T cells
rely upon secretion of cytokines (IL-10, TGF-B, IL-35) into the surrounding area, shutting down nearby cell responses
-these mechanisms halt costimulation and activate indoleamine 2,3-dioxygenase, responsible for cleaving tryptophan, creates kynurenines, which inhibits T cells
In what ways do CD4+ T cells maintain tolerance?
work via contact dependent and independent mechanisms
What current mechanisms are anticipated to allow regulatory CD8+ T cells to maintain tolerance?
- not likely generated in the thymus, but instead in the periphery during CD8+ T-cell activation induction events (appear after Ag-MHC class I stimulation in the presence of TGF-B)
- Most likely use a range of mechanisms to suppress activity (lysis of APCs, inhibition of APC function, regulation of effector cells that bind the same Ag)
What factors can predispose an individual for tolerance rather than stimulation?
- high doses of antigen
- long-term persistence of antigen in the host
- intravenous or oral introduction
- absence of adjuvants
- low levels of costimulation
- presentation of antigen by immature or unactivated APCs
What percentage of people in industrialized countries are estimated to have an autoimmune disease?
3-8%
- caused by failure of tolerance processes
- may be organ-specific or systemic
- may involve antibodies, T cells, immune complexes, or any combination of elements
What factors predispose an individual for developing an autoimmune disease?
- studies have linked sex hormones to gene expression changes that could help explain why women experience autoimmune diseases more frequently
- intrinsic and extrinsic factors can favor susceptibility to autoimmune disease
- The roles of genes in susceptibility to autoimmunity (certain MHC genes linked to specific autoimmune disorders)
In most organ-specific autoimmunities, what four areas are treatments aimed at?
- increasing levels of missing, required gene products (thyroid hormone, insulin, acetylcholine)
- decreasing antibody production (B cell inhibitors)
- decreasing inflammatory mediators (TNA, IL inhibitors)
- decreasing costimulatory signals (CD80/86 inhibitors)
What potential side effects are affiliated with long-term use?
- general toxicity, often to rapidly dividing cells (hair follicles, intestinal lining, blood cells)
- also predisposes individuals to uncontrolled infections
- can promote development of cancer by removing anti-tumor T and NK cells
What is the holy grail of immunotherapy in treating autoimmunity?
Antigen-specific immunotherapy
stimulate tolerance to the auto-Ag, restoring balance
What is an example of the holy grail of immunotherapy in treating autoimmunity?
glatiramer acetate has been used to treat MS
- four basic AAs found in mylein basic protein
- selectively increases TREG cells, modulating APC function
- although shifts T cell populations, it has shown only modest improvement over standard therapies
What are the four types of tissue transplantations?
- autograft
- isograft
- allograft
- xenograft
Autograft
transplant from the same individual
Isograft
tissue transplant from genetically identical sibling or clone
Allograft
transplant from genetically different member of the same species
Xenograft
transplant from different species
First-set rejection
complete by 12-14 days, but memory of the anti-graft response is generated; first exposure
Second-set rejection
occurs much faster, completing within only 5-6 days; secondary immune iresponse
What is the role of T cells in graft rejection
T cells mediate graft rejection
Which type of T cells facilitate rejection?
-CD4+ more important, but CD8+ does too
Histocompatible
tissues that are antigenically similar
How do you determine MHC compatibility?
Cross-matching
What allows organ transplant between completely mismatched people?
anti-rejection drugs (immunosuppressants)
Sensitization Stage of Graft Rejection
CD4 and CD8 cells recognize alloantigens expressed on foreign graft cells
- T cells proliferate in response
- May recognize donor MHC molecules directly
- may recognize peptides from donor MHCs presented in the recipient’s own APC MHC molecules (indirect)
- Memory T cells generated
Effector Stage of Graft Rejection
- generally involves heavy infiltration of recipient cells into graft tissue (similar to DTH reaction)
- can rarely involve production of Abs against donor HLA molecules or endothelial Ag
Hyperacute rejection
- by preexisting antibodies
- occurs before grafted tissue ever revascularizes
- antibodies bind to graft cells and activate complement
- complete rejection may occur in as few as 24 hours
Acute rejection
- mediated by T-cell responses
- begin 7-10 days post-transplantation
- induce massive infiltration of lymphocytes and macrophages
- rejection occurs through mechanisms described for effector stage of graft rejection
Chronic rejection
- develops months or years after acute rejection reactions have subsided
- mechanisms include humoral and cell-mediated recipient responses
- anti-rejection drugs help, but are not perfect
Total lymphoid irradiation
-used to eliminate lymphocytes
-lymphocytes extremely sensitive to x-rays
often used in bone marrow transplants or to treat GvHD
-repeated x-ray exposures to the thymus, spleen, and lymph nodes
-effectively wipes out the recipient’s own immune cells, creating a situation where donor stem cells can engraft and form a “new” immune system safely
Azathioprine
- mitotic inhibitor that diminishes B- and T-cell proliferation
- can dramatically increase survival rates of allografts by inhibiting proliferation of these cells
- often prescribed with corticosteroids to prevent inflammation
Cyclophosphamide
inserts into DNA helix, disrupting it
Cyclosporin A (CsA)
- fungal metabolite
- acts to decrease synthesis of inflammatory cytokines by preventing the activation of key transcription factors
- not without side effects, including kidney toxicity
In Hashimoto’s Thyroiditis, what is produced?
autoantibodies and sensitized TH1 cells specific for thyroid antigen
What do autoantibodies produced in Hashimoto’s Thyroiditis do?
interfere with iodine uptake by thyroid, which decreases production of thyroid hormone. This results in hypothyroidism
In Hashimoto’s Thyroiditis, a delayed-type hypersensitivity reaction occurs which results in:
inflammation –> goiter
Functions of thyroid hormone
- controls basal metabolic rate
- protein synthesis
- sensitivity to other hormones
What causes Type 1 Diabetes?
autoimmune attack against insulin-producing Beta cells in the pancreas
Type 1 Diabetes: After CTLs infiltrate the pancreas and activate macrophages, what happens?
Followed by cytokine release and production of autoantibodies, which may activate complement or antibody-dependent cell-mediated toxicity activities by NK cells
In Myasthenia Gravis, what do autoantibodies do?
bind acetylcholiine receptors on motor end plates of muscles
In Myasthenia Gravis, the binding of autoantibodies on acetylcholine receptors induces:
complement-mediated lysis of cells
In SLE, what kinds of autoantibodies are produced?
autoantibodies against DNA, histones, platelets, and other self structures
symptoms of SLE
- fever
- weakness
- kidney dysfunction
- frequent skin rashes
in SLE, autoantibodies against RBCs and platelets induce
complement-mediated lysis
In SLE, autoantibodies against nuclear antibodies can deposit on walls of small blood vessels resulting in:
type III hypersensitivity reaction
In MS, autoreactive T cells form:
inflammatory lesions along myelin sheaths around nerve fibers in the brain and spinal cord
Breakdown of myelin sheaths around nerves leads to a range of symptoms:
numbness to paralysis and loss of vision
What virus may predispose a person to MS?
Epstein-Barr virus
What factors may predispose a person to MS?
- Epstein-Barr virus
- hygiene hypothesis
- sunlight exposure
_______ is a known immune modulator that promotes anti-nflammatory response.
Vitamin D
What is the major symptom of Rheumatorid arthritis?
chronic inflammation in joints
In rheumatoid arthritis, autoantibodies are reactive with:
determinants in the Fc region of IgG
Rehumatoid factos are often produced in rheumatoid arthritis and form _____ complexes and activate complement cascades.
immune
