克罗恩病研究进展
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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.
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
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
stricturing
10
0
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months
• 增加CD的发病率 • 饮用热水成为习惯：OR 5.0 (95%CI1.4-17.3) • 不再使用公共浴室：OR 3.3 (95%CI1.3–8.3) • 儿童期胃肠道感染可能是 CD的保护因素?
Gent Lancet 1994
克罗恩病
• 病因、发病机制迄今未明。
• 主要集中在环境、遗传和免疫异常 等方面。
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
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
IL-12 TNF- IFN-
Th1 cell
Inflammation
Genetic factors
Th1 cell
Normal controlled inflammation via apoptosis of Th1 cells (programmed cell death)
Normal state
↑ 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.
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
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
The Likelihood for Disease Complications in CD Increases Over Time
• Occurrence of a stricturing and/or penetrating complication was assessed retrospectively in 2,002 consecutive CD patients (1974–2000)
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.
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
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
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
• 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
• 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)
会上升
亚洲国家克罗恩病发病率在上升
国家
报告时间
CD
1965
0.01
1979
0.78
日本
1986
0.60
1991
0.51
1998
1.2
新加坡
Hale Waihona Puke Baidu
1956 - 1970
0.04
1992
1.3
国内近15年克罗恩病病例数
年代
89-93 94-98 99-03
小计
CD
236 1041 1633
2910
提高城市化：公共卫生水平
• The estimated risks for penetrating CD at 5 and 20 years after diagnosis are 40% and 70%
100
Cumulative probability %
90
80
70
penetrating
60
50
40
30
20
inflammatory
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
Berrebi D et al. Am J Pathol. 1998;152:667-672.
Nielsen OH et al. Scand J Gastroenterol. 2003;38:180-185.
Tumor Necrosis Factor (TNF) Sustains Th1 Responses in CD
↑ IL-12 mRNA expression
Location/Cell Type Mononuclear cells in actively inflamed tissue Ileal lamina propria and gastric mucosa Lamina/muscularis propria
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
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
Clinical Evidence Location/Cell Type Correlation
↑ TNF- levels
Stool (children)
Disease activity
↑ TNF- secretion
Lamina propria
Mucosal
mononuclear cells involvement
Disease Mechanisms: Chronic Immune Activation
Natural History of Crohn’s Disease: Chronic Progression
Monoclonal Antibodies for the Treatment of CD
Etiology of CD: Chronic Activation of the Mucosal Immune Response
• 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.
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.
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
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
stricturing
10
0
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months
• 增加CD的发病率 • 饮用热水成为习惯：OR 5.0 (95%CI1.4-17.3) • 不再使用公共浴室：OR 3.3 (95%CI1.3–8.3) • 儿童期胃肠道感染可能是 CD的保护因素?
Gent Lancet 1994
克罗恩病
• 病因、发病机制迄今未明。
• 主要集中在环境、遗传和免疫异常 等方面。
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
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
IL-12 TNF- IFN-
Th1 cell
Inflammation
Genetic factors
Th1 cell
Normal controlled inflammation via apoptosis of Th1 cells (programmed cell death)
Normal state
↑ 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.
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
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
The Likelihood for Disease Complications in CD Increases Over Time
• Occurrence of a stricturing and/or penetrating complication was assessed retrospectively in 2,002 consecutive CD patients (1974–2000)
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.
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
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
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
• 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
• 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)
会上升
亚洲国家克罗恩病发病率在上升
国家
报告时间
CD
1965
0.01
1979
0.78
日本
1986
0.60
1991
0.51
1998
1.2
新加坡
Hale Waihona Puke Baidu
1956 - 1970
0.04
1992
1.3
国内近15年克罗恩病病例数
年代
89-93 94-98 99-03
小计
CD
236 1041 1633
2910
提高城市化：公共卫生水平
• The estimated risks for penetrating CD at 5 and 20 years after diagnosis are 40% and 70%
100
Cumulative probability %
90
80
70
penetrating
60
50
40
30
20
inflammatory
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
Berrebi D et al. Am J Pathol. 1998;152:667-672.
Nielsen OH et al. Scand J Gastroenterol. 2003;38:180-185.
Tumor Necrosis Factor (TNF) Sustains Th1 Responses in CD
↑ IL-12 mRNA expression
Location/Cell Type Mononuclear cells in actively inflamed tissue Ileal lamina propria and gastric mucosa Lamina/muscularis propria
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
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
Clinical Evidence Location/Cell Type Correlation
↑ TNF- levels
Stool (children)
Disease activity
↑ TNF- secretion
Lamina propria
Mucosal
mononuclear cells involvement
Disease Mechanisms: Chronic Immune Activation
Natural History of Crohn’s Disease: Chronic Progression
Monoclonal Antibodies for the Treatment of CD
Etiology of CD: Chronic Activation of the Mucosal Immune Response
• 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.