葡萄牙波尔图大学Salomé S. Pinho研究团队发现，一种独特的血清IgG糖基化特征可预测克罗恩病的发展并与甘露糖致病抗体有关。这一研究成果于2024年7月30日在线发表在国际学术期刊《自然—免疫学》上。

通过对在炎症性肠病（IBD）诊断前最多6年的临床前血清样本分析（来自PREDICTS队列），研究人员揭示了循环抗体（IgG）上的独特糖基化特征，该特征表现为IgG片段结晶域（Fc）糖基化水平的降低，并在疾病诊断前保持稳定。这一特定的IgG2 Fc糖基特征与抗微生物抗体水平增加相关，特别是抗酵母菌抗体（ASCA），指示出一个糖基组–ASCA中心，在克罗恩病（CD）发展前多年已在血清中被检测到。

机制研究表明，临床前阶段检测到的无半乳糖糖基化ASCA IgG通过FcγR依赖机制激活和重编程固有免疫细胞，如树突状细胞和自然杀伤细胞，从而引发促炎免疫通路，激活NF-κB和CARD9信号通路，进而引发炎症小体激活。ASCA的促炎作用依赖于甘露糖糖基识别和IgG Fc域的半乳糖基化水平。

这种（抗甘露糖）ASCA IgG的致病特性在体内得到了验证。将ASCA抗体转移到受体野生型小鼠中，导致了肠道炎症的易感性增加，而在受体FcγR缺失的小鼠中恢复正常。研究人员识别了循环IgG中一个糖基化特征，该特征在CD发病前出现，并指出一个特定的糖基组–ASCA途径作为炎症启动的核心因素，远在CD诊断之前。这一致病糖基组可能成为CD预测的有前景的新血清生物标志物，并作为疾病预防的潜在靶点。

据介绍，IBD的特征是肠道的慢性炎症。越来越多的证据表明，CD存在一个临床前阶段，其特征是免疫学变化在症状出现之前多年开始。这一阶段的深入了解将有助于疾病的预测和预防。

附：英文原文

Title: A unique serum IgG glycosylation signature predicts development of Crohn’s disease and is associated with pathogenic antibodies to mannose glycan

Author: Gaifem, Joana, Rodrigues, Cludia S., Petralia, Francesca, Alves, Ins, Leite-Gomes, Eduarda, Cavadas, Bruno, Dias, Ana M., Moreira-Barbosa, Catarina, Revs, Joana, Laird, Renee M., Novokmet, Mislav, tambuk, Jerko, Habazin, Sinia, Turhan, Berk, Gm, Zeynep H., Ungaro, Ryan, Torres, Joana, Lauc, Gordan, Colombel, Jean-Frederic, Porter, Chad K., Pinho, Salom S.

Issue&Volume: 2024-07-30

Abstract: Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn’s disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome–ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome–ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention.

DOI: 10.1038/s41590-024-01916-8

Source: https://www.nature.com/articles/s41590-024-01916-8