Henckaerts Liesbet, Pierik Marie, Joossens Marie, Ferrante Marc, Rutgeerts Paul, Vermeire Séverine
Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
Gut. 2007 Nov;56(11):1536-42. doi: 10.1136/gut.2007.125468. Epub 2007 Jun 26.
A number of antibodies against microbial epitopes or self-antigens have been associated with Crohn's disease. The development of antibodies reflects a loss of tolerance to intestinal bacteria that underlies Crohn's disease, resulting in an exaggerated adaptive immune response to these bacteria. It was hypothesised that the development of antimicrobial antibodies is influenced by the presence of genetic variants in pattern recognition receptor genes. The aim of this study was therefore to investigate the influence of mutations in these innate immune receptor genes (nucleotide oligomerisation domain (NOD) 2/caspase recruitment domain (CARD) 15, NOD1/CARD4, TUCAN/CARDINAL/CARD8, Toll-like receptor (TLR) 4, TLR2, TLR1 and TLR6) on the development of antimicrobial and antiglycan antibodies in inflammatory bowel disease (IBD).
A cohort of 1163 unrelated patients with IBD (874 Crohn's disease, 259 ulcerative colitis, 30 indeterminate colitis) and 312 controls were analysed for anti-Saccharomyces cerevisiae antibodies (gASCA) IgG, anti-laminaribioside antibodies (ALCA) IgG, anti-chitobioside antibodies (ACCA) IgA, anti-mannobioside antibodies (AMCA) IgG and outer membrane porin (Omp) IgA and were genotyped for variants in NOD2/CARD15, TUCAN/CARDINAL/CARD8, NOD1/CARD4, TLR4, TLR1, TLR2 and TLR6.
When compared with Crohn's disease patients without CARD15 mutations, the presence of at least one CARD15 variant in Crohn's disease patients more frequently led to gASCA positivity (66.1% versus 51.5%, p < 0.0001) and ALCA positivity (43.3% versus 34.9%, p = 0.018) and higher gASCA titers (85.7 versus 51.8 ELISA units, p < 0.0001), independent of ileal involvement. A gene dosage effect, with increasing gASCA and ALCA positivity for patients carrying none, one and two CARD15 variants, respectively, was seen for both markers. Similarly, Crohn's disease patients carrying NOD1/CARD4 indel had a higher prevalence of gASCA antibodies than wild-type patients (63.8% versus 55.2%, p = 0.014), also with a gene dosage effect. An opposite effect was observed for the TLR4 D299G and TLR2 P631H variants, with a lower prevalence of ACCA antibodies (23.4% versus 35%, p = 0.013) and Omp antibodies (20.5% versus 34.6%, p = 0.009), respectively.
Variants in innate immune receptor genes were found to influence antibody formation against microbial epitopes. In this respect, it is intriguing that an opposite effect of CARD15 and TLR4 variants was observed. These findings may contribute to an understanding of the aetiology of the seroreactivity observed in IBD.
多种针对微生物表位或自身抗原的抗体与克罗恩病相关。抗体的产生反映了对肠道细菌耐受性的丧失，这是克罗恩病的潜在病因，导致对这些细菌的适应性免疫反应过度。据推测，抗微生物抗体的产生受模式识别受体基因中遗传变异的影响。因此，本研究的目的是调查这些先天性免疫受体基因（核苷酸寡聚化结构域（NOD）2/胱天蛋白酶招募结构域（CARD）15、NOD1/CARD4、TUCAN/CARDINAL/CARD8、Toll样受体（TLR）4、TLR2、TLR1和TLR6）中的突变对炎症性肠病（IBD）中抗微生物和抗聚糖抗体产生的影响。
对1163例无亲缘关系的IBD患者（874例克罗恩病、259例溃疡性结肠炎、30例未定型结肠炎）和312例对照者检测抗酿酒酵母抗体（gASCA）IgG、抗层连二糖苷抗体（ALCA）IgG、抗壳二糖苷抗体（ACCA）IgA、抗甘露二糖苷抗体（AMCA）IgG和外膜孔蛋白（Omp）IgA，并对NOD2/CARD15、TUCAN/CARDINAL/CARD8、NOD1/CARD4、TLR4、TLR1、TLR2和TLR6中的变异进行基因分型。
与无CARD15突变的克罗恩病患者相比，至少携带一种CARD15变异的克罗恩病患者更易出现gASCA阳性（66.1%对5l.5%，p<0.0001）和ALCA阳性（43.3%对34.9%，p = 0.018），且gASCA滴度更高（85.7对51.8 ELISA单位，p<0.0001），与回肠受累情况无关。两种标志物均显示出基因剂量效应，分别携带无、一个和两个CARD15变异的患者，其gASCA和ALCA阳性率逐渐升高。同样，携带NOD1/CARD4插入缺失的克罗恩病患者gASCA抗体的患病率高于野生型患者（63.8%对55.2%，p = 0.014），也存在基因剂量效应。对于TLR4 D299G和TLR2 P631H变异，观察到相反的效应，ACCA抗体（23.4%对35%，p = 0.013）和Omp抗体（20.5%对34.6%，p = 0.009）的患病率较低。
发现先天性免疫受体基因中的变异会影响针对微生物表位的抗体形成。在这方面，有趣的是观察到CARD15和TLR4变异的相反效应。这些发现可能有助于理解IBD中观察到的血清反应性的病因。
