Related IgA1 and IgG producing cells in blood and diseased mucosa in ulcerative colitis

Abstract

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease in which the colonic mucosa is infiltrated with plasma cells producing IgG autoantibodies. It is not known whether this represents a local mucosal response which has switched to IgG or a peripheral response which may have been initiated by peripheral antigen which homed to the colonic mucosa. The clonal distribution of IgG secreting cells and isotype switched variants in UC is not known. Aims: To investigate the clonal distribution of mucosal IgG in UC and to search for related IgG and IgA secreting cells in normal and diseased mucosa and blood in UC. To investigate characteristics which may discriminate between the mucosal and peripheral repertoire in the normal mucosa and in UC.Patients: Blood and normal and diseased mucosa from two patients with UC were studied. Methods: Immunoglobulin gene analysis and clone specific polymerase chain reaction were used to study the clonal distribution and characteristics of IgG and related IgA in the mucosa and blood of patients with UC. Results: The IgG response in the mucosa of UC patients included widespread clones of cells that were present in both the diseased mucosa and blood but that were scarce in normal mucosa. Clonally related IgA class switch variants, all IgA1, were detected but also only in the diseased mucosa and blood. This suggests that these clones home preferentially to the diseased mucosa. We showed that J H 1 usage was characteristic of the peripheral repertoire, and that examples of J H 1 usage were observed in mucosal IgG in UC. Conclusions: Overall, these data are consistent with a model of UC in which a peripheral response is expressed and expanded in the colonic mucosa.

B‐cell clonal diversification and gut‐lymph node trafficking in ulcerative colitis revealed using lineage tree analysis

“…Lineage tree characteristics (described below) were analyzed using our MTree r program [60,61], and compared with samples taken from healthy intestinal tissue of intestinal carcinoma cases. The results of our analysis confirm that diversification processes do occur in B-cell clones found in the inflamed and healthy intestinal tissues [59]. Most importantly, our finding of clonal relationships between …”

CCR5-Δ32 mutation is strongly associated with primary sclerosing cholangitis

“…3 In UC, the inflammatory cell infiltrate is characterized by a large number of plasma cells secreting IgG, which by binding complement contributes to tissue damage and ongoing disease. 4 Within IBD, there is a subgroup of patients who develop primary sclerosing cholangitis (PSC), a chronic fibrosing liver disease characterized by progressive destruction of both intrahepatic and extrahepatic bile ducts by a combination of inflammation and fibrosis. 5 A majority of PSC patients have UC (60-100%), whereas a much smaller number of UC patients develop the liver disease (2.4-7.5%) in Caucasian populations.…”

Molecular characterization of the cervical and systemic B-cell repertoire

“…The identification of highly related and even identical V H sequences between the cervical mucosa and the peripheral blood compartments is of particular interest because, to the authors' knowledge, this is the first time this has been seen. While highly specific CDR3 clone specific primers have been used to identify related IgG clones in different compartments, 60 they do not permit an evaluation of the frequency of the observed clones. Our use of V H family specific primers in the present study, while biased to germline encoded V gene families, is relatively non-biased to combinatorial assemblages; indeed, it is of much lower bias than targeting a somatically combined CDR region as in Thoree et al 60 and this allows us to make conclusions about the regularity of observed clones.…”

“…While highly specific CDR3 clone specific primers have been used to identify related IgG clones in different compartments, 60 they do not permit an evaluation of the frequency of the observed clones. Our use of V H family specific primers in the present study, while biased to germline encoded V gene families, is relatively non-biased to combinatorial assemblages; indeed, it is of much lower bias than targeting a somatically combined CDR region as in Thoree et al 60 and this allows us to make conclusions about the regularity of observed clones. The identification of related CMC and PBMC clones does not necessarily imply that the observed mucosal response is of peripheral origin, as B cells migrate to other mucosal tissues via the blood.…”

“…We recognize that a larger and more robust study involving samples from multiple subjects collected at different time points can now be done using cuttingedge technology; however, this study remains as a comparator for the current technology. These data show a complex pattern of B-cell sharing and compartmentalization and further repertoire characterization by ultra-deep pyrosequencing 39 and assembly of monoclonal antibodies from the V-genes 73,74 of locally present IgM B cells in the intestinal mucosa, spleen, salivary gland and the duodenum, relative to isotype controls, 21,53,60 Dunn-Walters et al 53 identified related IgM and IgA sequences in the salivary gland in which the IgM clone had accumulated more mutations than the class switched clone. IgM plasma cells in the intestine have also been shown to have similar frequencies of mutation as IgA plasma cells.…”