自身免疫
• 自身免疫与自身免疫病： 自身免疫：抗自身抗原的免疫应答。 自身免疫病：自身免疫应答对机体造成病理 性损伤。此种疾病通常被分类为“免疫介导的炎 症性疾病”。 • 总体特点: –发生机制: 易感基因 + 环境诱发 –全身性和器官特异性
Central and peripheral tolerance
Immune responses against self tissues
Genetics of autoimmunity
• Human autoimmune diseases are complex polygenic traits
– Identified by genome-wide association mapping – Single gene mutations are useful for pathway analysis
Pathogenesis of autoimmunity
Susceptibility genes Failure of self-tolerance Persistence of functional self-reactive lymphocytes Activation of self-reactive lymphocytes Environmental trigger (e.g. infections, tissue injury)
• What factors determine the balance of effector cells and Treg?
Signals for the generation and maintenance of regulatory T cells
• Antigen recognition, with or without inflammation? • TGF- (source?) • Interleukin-2 (originally identified as T cell growth factor; major function is to control immune responses by maintaining functional Treg; works via Stat5) • Low levels of B7: CD28 costimulation • Transcription factor Foxp3
Immune-mediated inflammatory diseases
• Chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation
– RA, IBD, MS, psoriasis, many others – Affect 2-5% of people, incidence increasing
自身耐受和免疫调节异 常与免疫介导的炎症性 疾病
吕昌龙 中国医科大学免疫研究所
Balancing lymphocyte activation and control
Activation Effector T cells Tolerance Regulatory T cells
Normal: reactions against pathogens Inflammatory disease, e.g. reactions against self
From Abbas and Lichtman. Basic Immunology 2nd ed, 2006
Both pathways cooperate to prevent reactions against self
Regulatory T cells
From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007
Apoptosis (activation-induced cell death)
Suppression
APC
Block in activation
Regulatory T cell
T cell anergy
“Activation-induced cell death”: death of mature T cells upon recognition of self antigens
– May influence end-organ damage
Genetics of autoimmunity: recent successes of genomics
• NOD2: polymorphism associated with ~25% of Crohn’s disease • PTPN22: commonest autoimmunityassociated gene; polymorphism in RA, SLE, others
Target Cells CD28 Involvement in vivo Role
Effector T Cells Unnecessary for development or function Mucosal immunity, inflammatory response CD3, IL-10, Retinoic Acid
The principal fate of lymphocytes that recognize self antigens in the generative organs is death (deletion), BUT: Some B cells may change their specificity (called “receptor editing”) Some CD4 T cells may differentiate into regulatory (suppressive) T lymphocytes
Induced Treg (iTreg) Tr1
Periphery (MALT) CD4+CD25CD45RBlowFoxp3-
Induced Treg (iTreg) Th3
Periphery (MALT) CD4+CD25+ from CD25- precursors CD25lowvariableCD45RBlow F
From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007
Consequences of self antigen recognition in thymus
From: Abbas & Lichtman, Cellular & Molecular Immunology 5th ed 2003
– Many activated T cells (not only Treg) may transiently express Foxp3
cellular therapy with Regulatory T cells? • Some autoimmune diseases are associated with defective generation or function of Tregs or resistance of effector cells to suppression by Tregs • Will cellular therapy with ex vivo expanded Treg become a reality? Therapeutic goal: selective induction or activation of Treg in immune diseases
Unknown Unnecessary for development or function Mucosal immunity, inflammatory response CD3, TGF beta
in vitro Expansion
Peripheral (adaptive, inducible) regulatory T cells
• CD25 (IL-2R): associated with MS, others; genome-wide association mapping
• Develop from mature CD4 T cells that are exposed to persistent antigen in the periphery • May be generated in all immune responses, to limit collateral damage • Can be induced in vitro (stimulation of CD4 T-cells in presence of TGF + IL-2)
Peripheral tolerance
Normal T cell response
CD28 APC TCR
T cell
Activated T cells
Anergy
APCBiblioteka TCROff signals
Functional unresponsiveness
Deletion
APC
Activated T cell
• May result from immune responses against self antigens (autoimmunity) or microbial antigens (Crohn’s disease?)
• May be caused by T cells and antibodies • May be systemic or organ-specific