Download Autoimmune Diseases

Lecture Notes for Med. Tech. Class
Oct. 2006
C.K. Shieh
Immunological Tolerance
• Tolerance is one of the central characters of the immune system (along with memory,
specificity).
• Location: Central tolerance and peripheral tolerance
• Cell type: T cell tolerance and B cell tolerance
• Mechanisms: deletion, anergy, immune deviation (ignorance)
Owen’s “Experiment of Nature”-1945
Neonatal exposure leads to life-long tolerance to the otherwise foreign cells.
Medawar’s Experiment of Neonatal Tolerance Induction
• Neonatal exposure of allogeneic blood cells causes tolerance to the skin grafts from
the blood donor.
Central and Peripheral Immunological Tolerance
• Theoretically, most endogenous antigens can tolerize the immune cells during their
maturation in the “central” lymphoid organs. #Exeptions?
2. Exogenous antigens usually are encountered in the peripheral tissues. e.g. food
antigens, air allergens
Positive and Negative Selection of Thymocytes
• Negative selection is important for the central tolerization of T cells.
• Avidity is determined by TCR-MHC-peptide affinity, expression levels of these
receptors and other co-receptors
• Aire as a promoter of organ specific genes in medullary thymic epithelial cells
Synthetic Peptides Were Used to Prove the Role of TCR Affinity in Thymic
Selection
TCR and CD4/8 signaling for lineage determination: The ratio of Lck and TCR
signals determines the T cell lineage in an “instructional model”
Two kinds of T-cell death: AICD and PCD –Fig.19.12
TCR Induced Cell Death in the Thymus
Cell Death (Apoptosis) for Auto-reactive Lymphocytes
• Cell deletion in the thymus due to negative selection
• Cell deletion in the periphery (activation induced cell death)
Mechanism of Peripheral Tolerance
• Cell death (apoptosis)
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Anergy
Ignorance ?
Immune deviation
Regulatory T cells: CD25+CD4+ T cells, working in a cytokine dependent and
cytokine independent manner.
Anergy: Antigen Stimulation Without Co-stimulations
• Costimulation receptor on T cells: CD28
• B7-1 and B7-2 in APC provide the necessary stimulations for CD28
• Anergy: a state of lymphocyte inactivation marked by lack of cell proliferation after
proper antigen stimulation.
T Cell Tolerance Prevents B cell Autoimmunity
• T cell help is necessary for most B cell immune responses.
• Cross reactive T epitope may break B cell tolerance.
• Some B cell antigen do not require T cell help.
Location and importance of mircroenvironments for B cell tolerance:Exclusion of
self-reactive cells from B cell follicles
Regulatory T cells
• Treg are CD4+CD25+ subpopulation of T cells which mature through positive and
negative selections
• Treg mediate antigen-specific suppression through cell-cell contact and soluble factors
• A nuclear factor, FOXP3, is very important for the development of Treg.
Artificially induced Tolerance
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Immune chimerism
Soluble antigen induced tolerance
Oral tolerance
Tolerance by clonal activation
Anti-coreceptor induced tolerance
Thymic central tolerance induction
B cell central tolerance induction
Lecture Notes for Med. Tech Class
Autoimmune Diseases
Oct 2006 C.K.Shieh
Spectrum of Autoimmune Diseases
HLA Association of Autoimmune Diseases
Depletion of Autoreactive T Cells in the Thymus
How does autoantibody cause diseases
• Direct binding to target cells
thyrotoxicosis
Myasthenia gravis
Goodpasture’s syndrome
• Immune complex deposition
SLE (systemic lupus erythematosus)
Rheumatoid arthritis
* SLE is a disease best known for dysregulation of B cells and hence the production of
autoantibodies. Different from organ specific autoimmune diseases, various
autoantibodies found in other antibody-mediated autoimmune diseases may be found in
SLE patients. Self-damage caused by type II and type III hypersensitivity mechanisms
thus may be found in SLE patients.
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Cell Mediated cytotoxicity
Diabetes mellitus (DM): CMI targets beta cells in the pancreas
Hashimoto’s thyroiditis: CMI targets thyroid gland
Experimental allergic encephalitis (EAE): CMI targets myelin in CNS, an animal
model of the human disease multiple sclerosis.
A spectrum of autoimmunity to thyroid gland is apparent clinically
On the one end of the spectrum is the antibody mediated stimulation (non-goitrous
hyperthyroidism), on the other end is the cell mediated thyroid gland destruction
(Hashimoto’s (橋本) thyroiditis)
Autoimmunity Is Antigen driven
Anti-thyroid autoantibody disappears after thyroidectoy in OS chicken
Rheumatoid factor: anti-antibody antibody found in patients with seropositive
rheumatoid arthritis
Breaking Self Tolerance
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Direct stimulation of autoimmune cells e.g. EBV
Molecular mimickry e.g. rheumatic fever
Cross-reactive microbial antigens (T Cell Antigen)
Cross-reactive B cell antigen (not protected by T Cell tolerance)
•Cytokine dysregulation
Breaking of ignorance by changed cytokine in the tissue milieu (Immune Deviation)
•Breaking of tolerance by disturbed central tolerance machinery:
e.g. myasthenia gravis in patients with thymoma
•Regulatory T cells play a crucial in controlling autoimmune responses:
CD25+FoxP3+ CD4+T cells block the effect of autoimmune responses mediated by
autoreactive T cells. This blocking may or may not require the secretion of suppressive
cytokines such as TGF and IL-10. Some autoimmune diseases appear to correlate with
the compromised function of regulatory T cells. Successful treatment of the
autoimmune disease can restore the compromised regulatory function.
How to Treat Autoimmune Reactions
By trying to restore homeostasis in the immune system, various approaches have been
employed to treat autoimmunity. Cytokines, anti-cytokines, and immunosuppressive
agents are in use for treating patients with autoimmune diseases.
自體免疫疾病是免疫控制基轉失調的最終表現，所以經常表現出複
雜的免疫反應。在已經發生的自體免疫疾病中，找出引起疾病的元凶經
常是很困難的。學習自體免疫疾病的致病機轉，重點在於了解引發這些
自體免疫疾病的免疫控制機轉失調的原因和起始點。近十多年來基因轉
殖動物的研究對這個問題提供了全新的觀點。
本節課的另外一個重點是熟悉這些自體免疫疾病的名稱和表現。請
各位將 20.3 圖多看幾遍。