Antigen
APC cell
Activated macrophage
TNF-
APC cell
IL-12
CD4
T cell
Activated T cell
IFN- Th1 cell
TNF-
Gately MK et al. Annu Rev Immunol. 1998;16:495-521; Podolsky DK. N Engl J Med. 2002;347:417-429
• NOD2突变破坏了细胞对细菌的天然(先天性) 免疫反应
• 特异性获得性免疫反应增强引起CD的组织损 伤
• 编码蛋白在单核细胞表达可使NF-κB活化，对 LPS反应
免疫异常
• 细胞中介免疫反应异常
• T细胞中心地位，激活后产生各种细胞因子、 炎性介质，引起和放大粘膜炎症--Th1类型免 疫反应
CD4
T cell
IL-12
Activated T cell
IFN- Th1 cell
TNF-
Gately MK et al. Annu Rev Immunol. 1998;16:495-521; Podolsky DK. N Engl J Med. 2002;347:417-429
Interleukin 12 (IL-12) Promotes Th1 Responses in CD
↑ density/frequency of TNF-–positive cells
↑ TNF- mRNA expression
Lamina propria cells ―
Colonoscopic
―
biopsies
Braegger CP al. Lancet. 1992;339:89-91. Reinecker HC et al. Clin Exp Immunol. 1993; 94:174-181 Murch SH et al. Gut. 1993;34:1705-1709.
Genetic Linkages and CD
Chr. 16q12 6p
- IBD1 NOD2 - IBD3 MHC Ⅰ和Ⅱ
14q
- IBD4 TCR α/β复合体
5q
- IBD5 IL-3,IL-4,IL-5
19p
- IBD6 TB4H,C3
Others:- Chr 1, 2, 3, 7, X
NOD2 基因
Antigen APC cell
Activated macrophage
TND4
T cell
Activated T cell
IFN- Th1 cell
TNF-
Gately MK et al. Annu Rev Immunol. 1998;16:495-521; Podolsky DK. N Engl J Med. 2002;347:417-429
Additional Mechanisms for IL-12-induced Th1 Reponses
IL-12
Naïve T cells
Differentiation
Th1 cell
Resting memory T cells
Gately MK et al. Annu Rev Immunol. 1998;16:495-521
Th1 cell
Inflammatory cells
TNF-
Coagulation (increased production
of thrombin)
Adapted from Holtmann et al. Z Gastroenterol. 2002;40:587-600.
Clinical Evidence of Increased Expression of TNF in CD
IFN
Clinical Evidence of Increased Expression of IL-12 in CD
Clinical Evidence
↑ IL-12 expression
Clustered IL-12-positive cells
↑ IL-12-containing
macrophages
Lamina propria and CD4+ T cells
Kakazu T et al. Am J Gastroenterol. 1999;94: 2149-2155. Parronchi P et al. Am J Pathol. 1997;150:823-832.
Colpaert S et al. Eur Cytokine Netw. 2002;13: 431-437. Monteleone G et al. Gastroenterology. 1997;112: 1169-1178.
IL-12 TNF- IFN-
Th1 cell
Inflammation
Genetic factors
Th1 cell
Normal controlled inflammation via apoptosis of Th1 cells (programmed cell death)
Normal state
Gately MK et al. Annu Rev Immunol. 1998;16:495-521; Ina K et al. J Immunol. 1999;163:1081-1090; Podolsky DK. N Engl J Med. 2002;347:417-429
Cytokine Imbalance in Chronic Inflammation
• 遗传决定因素使普通肠菌抗原引起上调的Ｔ细 胞免疫反应
Th1
IFN-γ
巨噬 IL－12 幼稚的
细胞
CD4细胞
IL-4
Th2
凋亡
IFN-γ TNF IL-2
IL-4 IL-5 IL-10
延迟超敏反 应肉芽肿
体液免疫 变态反应
克罗恩病的粘膜免疫反应
Role for Targeted Biologic Therapy in Crohn’s Disease (CD)
Current Concepts in Crohn’s Disease (CD)
• Disease Mechanisms: Chronic Immune Activation • Natural History of Crohn’s Disease: Chronic Progression • Monoclonal Antibodies for the Treatment of CD
↑ IL-12 mRNA expression
Location/Cell Type Mononuclear cells in actively inflamed tissue Ileal lamina propria and gastric mucosa Lamina/muscularis propria
Crohn’s disease state
Environmental factors
Macrophage
IL-12
IFN-
Th1
T cell
cell
Chronic uncontrolled inflammation due to Th1
cell apoptotic defect
TNF- Th1 cell
• NOD2/CARD15基因——CD相关基因 • Hugot等1996年发现在IBD1位点 • 仅见于CD而非UC，约20%-30%的CD患者 • 欧美澳三洲12个研究组613个家庭研究证实
• NOD2基因产物是一种细胞内的内毒素结合蛋白 ,野生 型能清除入侵病原体.
• NOD2突变可引起肠道菌群改变导致的免疫激活异常 • NOD2突变还可使细胞凋亡机制失常 • 导致CD慢性炎症和组织破坏 • 突变杂合子患病危险性增加3倍,纯合子增加23倍.
Breese EJ et al. Gastroenterology. 1994;106:1455-1466. MacDonald TT et al. Clin Exp Immunol. 1990;81: 301-305. Cappello M et al. Gut. 1992;33:1214-1219.
adapted from Papachristou G et al. Pract Gastroenterol. 2004;28:18-30.
Key Inflammatory Mediators in CD
Antigen
APC cell
Activated macrophage
TNF-
APC cell
TNF Promotes CD Activity and Pathogenesis Through Multiple Pathways
Tissue destruction & inflammation
Macrophage
TNF-
Inflammation Ulcer
TNF-
IL-12
IFN-
Activated T cell
克罗恩病研究进展
彭孝纬
福建省立医院 福建省胃肠病研究所
流行病学研究概况
• 发病率分别为 4-12/105 • 近20年来CD增加明显 • 欧美多见,中国和亚洲国家少见, • 青壮年多见,儿童和老年人少见
流行病学研究概况
• 经济发达地区的发病危险性高于落后地区 • 城市地区高于农村 • 当人群从疾病低发区移居到高发区后,发病率也
Disease Mechanisms: Chronic Immune Activation
Natural History of Crohn’s Disease: Chronic Progression