臨床検査55巻11号

2011年10月発行

特集 ここまでわかった自己免疫疾患 各論 4．そのほかの自己免疫疾患

8) Crohn病・潰瘍性大腸炎

著者： 鈴木雅博¹ 永石宇司¹ 渡辺守¹

所属機関： ¹東京医科歯科大学大学院医歯学総合研究科消化器病態学分野

ページ範囲：P.1258 - P.1264

分子生物学・免疫学が飛躍的に進歩したことによって，潰瘍性大腸炎やCrohn病といった炎症性腸疾患(IBD)は何らかの遺伝的背景を有する宿主において免疫学的異常と環境因子が関与して誘導される病態であることが明らかになりつつある．そうした病態によって腸内細菌もしくは食餌抗原に対する過剰な免疫反応と腸管粘膜の防御機構の破綻が慢性的な腸管の炎症を形成しているものと理解されている．本稿では，これまでに明らかにされているIBDの病態に関与する粘膜免疫学の知見を概説する．

参考文献

1) Neutral MR, Kraehenbuhl JP : Cellular and Molecular Basis for Antigen Transport Across Epitherial Barriers. Mucosal Immunology, 3rd Edition, (Mestecky J, Lamm ME, McGhee JR), Academic Press, Waltham，pp111-130，2005

2) Wehkamp J, Salzman NH, Porter E, et al : Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natal Acad Sic USA　102：18129-18134，2005

3) Wehkamp J, Wang G, Kübler I, et al : The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4．J Immunol　179：3109-3118，2007

4) Fellermann K, Stange DE, Schaeffeler E, et al : A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am J Hun Genet　79：439-448，2006

5) Wehkamp J, Harder J, Weichenthal M, et al : NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut　53：1658-1664，2004

6) Schmitz H, Barmeyer C, Fromm M, et al : Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology　116：301-309，1999

7) Lala S, Ogura Y, Osborne C, et al : Crohn's disease and the NOD2 gene ; A role for paneth cells. Gastroenterology　125：47-57，2003

8) Ogura Y, Lala S, Xin W, et al : Expression of NOD2 in Paneth cells ; a possible link to Crohn's ileitis. Gut　52：1591-1597，2003

9) Akira S, Uematsu S, Takeuchi O : Pathogen recognition and innate immunity. Cell　124：783-801，2006

10) Ayabe T, Satchell DP, Wilson CL, et al : Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol　1：113-118，2000

11) Watanabe M, Ueno Y, Yajima T, et al : Interleukin7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes. J Clin Invest　95：2945-2953，1995

12) Oshima S, Nakamura T, Namiki S, et al : Interferon regulatory factor1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of interleukin-7 in human intestinal epithelial cells. Mol Cell Biol　24：6298-6310，2004

13) Colgan SP, Pitman RS, Nagaishi T, et al : Intestinal heat shock protein 110 regulates expression of CD1d on intestinal epithelial cells. J Clin Invest　112：745-754，2003

Edition (Mestecky J, Lamm ME, McGhee JR), Academic Press, Waltham，pp435-450，2005

15) Fuss IJ, Heller F, Boirivant M, et al : Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize and atypical Th2 response in ulcerative colitis. J Clin Invest　113：1490-1497，2004

16) Brozovic S, Nagaishi T, Yoshida M, et al : CD1d function is regulated by microsomal triglyceride transfer protein. Nat Med　10：535-539，2004

17) Mizoguchi A, Mizoguchi E, Takedatsu H, et al : Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity　16：219-230，2002

18) Kamada N, Hisamatsu T, Okamoto S, et al : Abnormally differenciated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria. J Immunol　175：6900-6908，2005

19) Watanabe M, Ueno Y, Yajima T, et al : Interleukin7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa. J Exp Med　187：389-402，1998

macrophages in intestinal lamina propria exhibit potent antigen-presenting ability. J Immunol　183：1724-1731，2009

21) Hollander D, Vadheim CM, Brettholz E, et al : Increased intestinal permeability in patients with Crohn's disease and their relatives ; A possible etiologic factor. Ann Intern Med　105：883-885，1986

22) Schmidt C, Giese T, Ludwig B, et al : Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease : elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis. Inflamm Bowel Dis　11：16-23，2005

23) Duerr RH, Taylor KD, Brant SR, et al : A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science　314：1461-1463，2006

24) Barret JC, Hansoul S, Nicolae DL, et al : Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet　40：955-962，2008

25) Annunziato F, Cosmi L, Santarlasci V, et al : Phenotypic and functional features of human Th17 cells. J Exp Med　204：1849-1861，2007

26) Kamada N, Hisamatsu T, Okamoto S, et al : Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest　118：2269-2280，2008

27) Mizoguchi A, Ogawa A, Takedatsu H, et al : Dependence of intestinal granuloma formation on unique myeloid DC-like cells. J Clin Invest　117：605-615，2007

28) Prehn JL, Mehdizadeh S, Landers CJ, et al : Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation. Clin Immunol　112：66-77，2004

29) Yamazaki K, McGovern D, Ragoussis J, et al : Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease. Hum Mol Genet　14：3499-3506，2005

30) Smythies LE, Sellers M, Clements RH, et al : Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest　115：66-75，2005

31) Stoll M, Corneliussen B, Costello CM, et al : Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet　36：476-480，2004