Portal de Periódicos da CAPES

Becalming Type 17 Inflammation in Ulcerative Colitis

2019; Cell Press; Volume: 50; Issue: 4 Linguagem: Inglês

10.1016/j.immuni.2019.03.019

1097-4180

Hannah H. Chen, Alison Simmons,

Eosinophilic Esophagitis

Genome-wide association studies in ulcerative colitis point to a role for FcγRIIA, a receptor for IgG. Castro-Dopico et al., 2019Castro-Dopico T. Dennison T.W. Ferdinand J.R. Mathews R.J. Fleming A. Clift D. Stewart B.J. Jing C. Strongili K. Labzin L.I. et al.Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.Immunity. 2019; 50 (this issue): 1099-1114Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar find a profound induction of anti-commensal IgG in the colonic mucosa of UC patients and outline a pathway whereby FcγR activation by IgG triggers IL-1β production, type 17 immunity, and the exacerbation of inflammation. Genome-wide association studies in ulcerative colitis point to a role for FcγRIIA, a receptor for IgG. Castro-Dopico et al., 2019Castro-Dopico T. Dennison T.W. Ferdinand J.R. Mathews R.J. Fleming A. Clift D. Stewart B.J. Jing C. Strongili K. Labzin L.I. et al.Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.Immunity. 2019; 50 (this issue): 1099-1114Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar find a profound induction of anti-commensal IgG in the colonic mucosa of UC patients and outline a pathway whereby FcγR activation by IgG triggers IL-1β production, type 17 immunity, and the exacerbation of inflammation. Inflammatory bowel disease (IBD) consisting of Crohn's and ulcerative colitis (UC) results from failure of the host immune system to tolerate commensal microflora. Both innate and adaptive limbs of the immune system contribute to IBD pathology, but, although there is strong evidence that activated T cells perpetuate inflammation, tissue destruction, and impaired mucosal healing, the role of B cells has been less clear. Because a significant proportion of IBD patients fail to respond to currently available treatments, there is intense interest in defining molecular pathways promoting mucosal inflammation that may present improved therapeutic targets. B cells are an important component of mucosal immune responses in health and disease. It is so far unclear whether B cells predominantly drive or protect against tissue destruction in IBD. The increased numbers of B cells within tissue immune infiltrates and the frequent presence of circulating antibodies to self- and microbial antigens suggested a pathogenic role (Lodes et al., 2004Lodes M.J. Cong Y. Elson C.O. Mohamath R. Landers C.J. Targan S.R. Fort M. Hershberg R.M. Bacterial flagellin is a dominant antigen in Crohn disease.J. Clin. Invest. 2004; 113: 1296-1306Crossref PubMed Scopus (655) Google Scholar). Studies in experimental colitis models provide evidence for both pro-inflammatory (Olson et al., 2004Olson T.S. Bamias G. Naganuma M. Rivera-Nieves J. Burcin T.L. Ross W. Morris M.A. Pizarro T.T. Ernst P.B. Cominelli F. Ley K. Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn disease.J. Clin. Invest. 2004; 114: 389-398Crossref PubMed Scopus (94) Google Scholar) and suppressive roles (Mizoguchi et al., 2002Mizoguchi A. Mizoguchi E. Takedatsu H. Blumberg R.S. Bhan A.K. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation.Immunity. 2002; 16: 219-230Abstract Full Text Full Text PDF PubMed Scopus (756) Google Scholar). Intestinal B cells produce Immunoglobulin A (IgA), the major secretory immunoglobulin isotype that protects the luminal surface. Intestinal epithelial cell (IEC) endoplasmic reticulum (ER) stress induces activation of peritoneal B1b cells, leading to a protective polyreactive IgA response that is enhanced in patients with defective IEC autophagy and ER stress (Grootjans et al., 2019Grootjans J. Krupka N. Hosomi S. Matute J.D. Hanley T. Saveljeva S. Gensollen T. Heijmans J. Li H. Limenitakis J.P. et al.Epithelial endoplasmic reticulum stress orchestrates a protective IgA response.Science. 2019; 363: 993-998Crossref PubMed Scopus (41) Google Scholar), thus linking an important genetic susceptibility pathway with a protective IgA response. In this issue of Immunity, Castro-Dopico et al., 2019Castro-Dopico T. Dennison T.W. Ferdinand J.R. Mathews R.J. Fleming A. Clift D. Stewart B.J. Jing C. Strongili K. Labzin L.I. et al.Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.Immunity. 2019; 50 (this issue): 1099-1114Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar examine the contribution of the IBD-susceptibility gene FCGR2A (Fc fragment of IgG receptor II-a), a single nucleotide polymorphism (SNP), which alters the binding affinity of the antibody receptor it encodes, FcγRIIA. An SNP in FCGR2A results in an amino-acid substitution (histidine to arginine at position 131) that decreases receptor affinity for IgG and leads to reduced activation of target cells. FcγRIIA-R131 is protective in UC, suggesting that IgG may play a pathogenic role in intestinal inflammation (Jostins et al., 2012Jostins L. Ripke S. Weersma R.K. Duerr R.H. McGovern D.P. Hui K.Y. Lee J.C. Schumm L.P. Sharma Y. Anderson C.A. et al.International IBD Genetics Consortium (IIBDGC)Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3230) Google Scholar). Their findings reveal an important contribution of IgG-mediated inflammation in an IgA-dominated organ. Castro-Dopico et al., 2019Castro-Dopico T. Dennison T.W. Ferdinand J.R. Mathews R.J. Fleming A. Clift D. Stewart B.J. Jing C. Strongili K. Labzin L.I. et al.Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.Immunity. 2019; 50 (this issue): 1099-1114Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar examined intestinal antibody profiles in UC patients and found a marked increase in IgG-bound commensals that correlated with disease severity. These observations were mirrored in a murine model of DSS-induced colitis. Consistent with an increase in commensal-specific IgG, stool samples from UC patients exhibited a significantly higher proportion of luminal commensals bound by IgG compared with those from healthy members from the same household. The authors then asked whether commensal-bound IgG contributes to UC tissue pathology via signaling through Fc gamma receptors (FcγRs). FcγRs with activating (A) or inhibitory (I) functions are expressed on the surface of cells such as macrophages, and their combined signaling, fine-tuned by the A:I ratio, dictates the level of macrophage activation. Commensal IgG bound to FcγRIIA, activating NLR family pyrin domain containing 3 (NLRP3) and reactive oxygen species-dependent production of interleukin (IL)-1β and chemokines associated with the recruitment of neutrophils—C-X-C motif chemokine ligand 1 (Cxcl1) and Cxcl2. These effects were influenced by the FCGR2A genotype expressed: FcγRIIA-R131, compared to the FcγRIIA-H131 variant, led to reduced IL-1β induction after IgG stimulation of human macrophages. Thus, the authors' findings provide mechanistic insight into the protective effect of the FcγRIIA-R131 variant in UC. To address the role of FcγR signaling in intestinal inflammation, the authors surveyed FcγR mRNA expression in mucosal biopsies. Activating FcγR gene transcripts, including FCGR2A and FCGR3A and B, were among the most differentially expressed genes in inflamed UC biopsies compared to those of healthy controls. In contrast, a more modest induction of the inhibitory receptor FCGR2B was observed. The authors moved to mouse models to examine the impact of commensal-IgG FcγRIIA signaling to colitis in vivo. Both human and murine intestinal macrophages predominantly express a single inhibitory receptor, FcγRIIB, and one low-affinity functionally homologous activating FcγR. Because mice do not express FcγRIIA, the authors utilized mouse models with intact activating FcγR signaling and either absent, wild type, or high (Brownlie et al., 2008Brownlie R.J. Lawlor K.E. Niederer H.A. Cutler A.J. Xiang Z. Clatworthy M.R. Floto R.A. Greaves D.R. Lyons P.A. Smith K.G. Distinct cell-specific control of autoimmunity and infection by FcgammaRIIb.J. Exp. Med. 2008; 205: 883-895Crossref PubMed Scopus (139) Google Scholar) inhibitory-receptor expression to mimic the effect of varying magnitudes of activating FcγR signaling strength observed in the presence of IBD-associated FCGR2A polymorphisms. Upon DSS challenge, Fcgr2b−/− mice demonstrated a more-severe disease course, with increased mucosal IL1b transcripts and pro-ILβ-expressing colonic CX3CR1+ mononuclear phagocytes (MNPs) compared to wild-type (WT) mice, whereas FcrgR+/− exhibited an intermediate phenotype. Mice in which macrophages expressed high amounts of FcγRIIB had a less-severe disease course; reduced IL1b, Cxcl1, Cxcl2I, and Ccl2 transcripts; and reduced colonic neutrophil infiltration (Figure 1). No differences in titers of anti-commensal IgG were found between mice with differing levels of FcγRIIB expression, adding weight to a role for enhanced macrophage IL-1β in driving disease severity. Finally, Castro-Dopico et al., 2019Castro-Dopico T. Dennison T.W. Ferdinand J.R. Mathews R.J. Fleming A. Clift D. Stewart B.J. Jing C. Strongili K. Labzin L.I. et al.Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.Immunity. 2019; 50 (this issue): 1099-1114Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar examined the consequences of enhanced macrophage-expressed IL-1β in their system. IL-1β contributes to the differentiation and maintenance of Th17 cells, which play a role in intestinal inflammation. They found IgG immune-complex stimulation of inflamed colonic lamina propria mononuclear cells (LPMCs) led to induction of Type-17 associated cytokines, including IL-17, GM-CSF, and IL-22. The levels of these factors correlated with levels of expression of Fcrg2b and were abrogated by treatment with an anti-IL-1R1 blocking antibody. In contrast, in FcgRIIB-over-expressing mice, reduced mucosal IL-17A-producing T cells were observed after DSS challenge. The findings by Castro-Dopico et al., 2019Castro-Dopico T. Dennison T.W. Ferdinand J.R. Mathews R.J. Fleming A. Clift D. Stewart B.J. Jing C. Strongili K. Labzin L.I. et al.Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.Immunity. 2019; 50 (this issue): 1099-1114Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar define a role for IgG in UC and provide a mechanistic explanation for the protection associated with polymorphisms in FCGR2A. Although many susceptibility genes have been mapped, there is much work to do in understanding how these operate, either in isolation or in combination. IBD-susceptibility genes such as ATG16L1 (autophagy-related protein 16-1), LRRK2 (leucine-rich repeat kinase 2), IRGM (immunity-related GTPase M), RIPK2 (receptor-interacting serine/threonine-protein kinase 2), XIAP (X-linked inhibitor of apoptosis), LACC1 (laccase domain containing 1) or FAMIN (fatty acid metabolic immune nexus), and NOD2 (nucleotide-binding oligomerization domain-containing protein 2) are expressed in myeloid cells (Verstockt et al., 2018Verstockt B. Smith K.G. Lee J.C. Genome-wide association studies in Crohn's disease: Past, present and future.Clin. Transl. Immunology. 2018; 7: e1001Crossref PubMed Scopus (48) Google Scholar). How simultaneous expression of multiple macrophage-expressed IBD-associated polymorphisms in these genes affect processes such as microbe internalization and degradation, inflammasome activation, and tissue remodeling in the context of differing thresholds of FcγR triggering in intestinal myeloid cells will be a future challenge. For example, impaired-myeloid-cell autophagic killing or antigen presentation of internalized antigen might compound any pro-inflammatory state mediated via FcγRIIA signaling. FcγR polymorphisms may also influence patients' response to treatment with intravenous immunoglobulin and therapeutic monoclonal antibodies (mAbs). Often, mAbs used in therapy are based on human IgG antibodies and are either chimeric mouse and human or fully human, allowing their interaction with all human FcγRs (Bruhns et al., 2009Bruhns P. Iannascoli B. England P. Mancardi D.A. Fernandez N. Jorieux S. Daëron M. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses.Blood. 2009; 113: 3716-3725Crossref PubMed Scopus (981) Google Scholar). Fc-receptor-mediated effects may contribute to the therapeutic response of anti-TNF antibodies in IBD (McRae et al., 2016McRae B.L. Levin A.D. Wildenberg M.E. Koelink P.J. Bousquet P. Mikaelian I. Sterman A.S. Bryant S. D'Haens G. Kamath R. et al.Fc Receptor-mediated Effector Function Contributes to the Therapeutic Response of Anti-TNF Monoclonal Antibodies in a Mouse Model of Inflammatory Bowel Disease.J. Crohn's Colitis. 2016; 10: 69-76Crossref PubMed Scopus (23) Google Scholar). Whether therapeutic mAbs block commensal-IgG FcγRIIA signaling and how IBD-associated polymorphisms influence this process will be interesting to explore. Chronic inflammation characterized by IgG-producing-plasma-cell infiltration of colonic mucosa is a histological hallmark of ulcerative colitis (UC), and whether its function is pathogenic or protective has remained unclear. This work adds considerable weight to a role for commensal bound IgG in driving inflammation in UC. How different immunoglobulin subtypes contribute to different disease phenotypes or stages of disease or in differing geographical locations of the intestine will be a subject for further study, particularly if this axis is to be targeted therapeutically. Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative ColitisCastro-Dopico et al.ImmunityMarch 12, 2019In BriefCastro-Dopico et al. find a profound induction of anti-commensal IgG in the colonic mucosa of UC patients and outline a pathway whereby FcγR receptor activation by IgG leads to IL-1β production, type 17 immunity, and the exacerbation of inflammation. Their findings reveal an important contribution of IgG-mediated inflammation in an IgA-dominated organ. Full-Text PDF Open Access