Ansu Noronha

Hyperactivated B cells in human inflammatory bowel disease

IBD is characterized by a chronic, dysregulated immune response to intestinal bacteria. Past work has focused on the role of T cells and myeloid cells in mediating chronic gastrointestinal and systemic inflammation. Here, we show that circulating and tissue B cells from CD patients demonstrate elevated basal levels of activation. CD patient B cells express surface TLR2, spontaneously secrete high levels of IL‐8, and contain increased ex vivo levels of phosphorylated signaling proteins. CD clinical activity correlates directly with B cell expression of IL‐8 and TLR2, suggesting a positive relationship between these B cell inflammatory mediators and disease pathogenesis. In contrast, B cells from UC patients express TLR2 but generally do not demonstrate spontaneous IL‐8 secretion; however, significant IL‐8 production is inducible via TLR2 stimulation. Furthermore, UC clinical activity correlates inversely with levels of circulating TLR2+ B cells, which is opposite to the association observed in CD. In conclusion, TLR2+ B cells are associated with clinical measures of disease activity and differentially associated with CD‐ and UC‐specific patterns of inflammatory mediators, suggesting a formerly unappreciated role of B cells in the pathogenesis of IBD

Systemic toll-like receptor ligands modify B-cell responses in human inflammatory bowel disease

Background: Bacteria have a central, although poorly understood, role in inflammatory bowel disease (IBD). Host–bacteria interactions primarily take place in the gastrointestinal tract, but cells may also encounter translocated bacteria in the bloodstream. IBD is associated with activated, circulating Toll‐like receptor (TLR)2 and TLR4‐expressing B cells suggesting that blood‐borne microbial TLR ligands modulate B cell responses. Methods: Serum levels of lipopolysaccharide (LPS)/endotoxin and high mobility group box 1 (HMGB1), an endogenous TLR ligand, were quantified in Crohns disease (CD) and ulcerative colitis (UC). Responses of purified B cells to LPS and HMGB1 were correlated with levels of systemic TLR ligands and clinical parameters of disease. Results: While IBD patients have increased levels of blood LPS, the net effect of endotoxemia has unexpected characteristics illustrating that LPS has both pro‐ and antiinflammatory roles through TLR4+ B cells. Experimental treatment of B cells demonstrates that the antiinflammatory effect of LPS is due to its hypo‐acylation of lipid A suggesting an increased prevalence of systemic, hypo‐acylated LPS in CD. In contrast, high levels of LPS are associated with disease activity in UC. HMGB1 activates B cells through TLR2 and CD36. Serum levels of HMGB1 correlate with spontaneous IL‐8 production by B cells suggesting that blood‐borne TLR2 ligands increase B‐cell activation in vivo. Conclusions: Systemic TLR ligands modulate B cells towards either proinflammatory or antiinflammatory activity depending on the predominant ligand(s). Further, the circulating B cell may represent an important proxy for quantifying the LPS lipid A acylation burden in patients with IBD. (Inflamm Bowel Dis 2011;)

Toll-like receptor 2 induces mucosal homing receptor expression and IgA production by human B cells

There is a need for developing vaccines that elicit mucosal immunity. Although oral or nasal vaccination methods would be ideal, current strategies have yielded mixed success. Toll-like receptor 2 (TLR2) ligands are effective adjuvants and are currently used in the Haemophilus influenzae type B vaccine. Induction of humoral immunity in the mucosa is critical for effective vaccination; thus, we sought to determine the effects of TLR2 ligands on human mucosal B cell differentiation. We demonstrate that TLR2 ligands induce CCR9 and CCR10 expression by circulating B cells and increased chemotaxis to cognate chemokines CCL25 and CCL28 suggesting that TLR2 induces B cell homing to the gastrointestinal tract. TLR2 stimulation of B cells also induced J chain and IgA production demonstrating the induction of mucosal-like antibody secreting cells. These observations suggest that vaccines containing TLR2-ligands as adjuvants could induce mucosal B cell immunity even when delivered in a non-mucosal manner.

B Cells Secrete Eotaxin-1 in Human Inflammatory Bowel Disease

Background:Our previous studies have demonstrated that B cells in human inflammatory bowel disease (IBD) are highly activated and produce copious amounts of chemokines. Here, we showed that B cells produce eotaxin-1, a selective chemokine for acute eosinophilia. Increased levels of activated eosinophils have been found in the intestinal mucosa in patients with IBD, but their role(s) and the regulation of their migration patterns remain poorly defined. Methods:To determine how B-cell secretion of eotaxin-1 influences eosinophil activation and migration, we performed immunoepidemiological approaches coupled with in vitro studies. B cells and eosinophils from patients with Crohn’s disease and ulcerative colitis were isolated, and responses to Toll-like receptor ligands (TLR) were measured and assessed for the relationship with clinical disease. Results:Eotaxin-1 from recirculating B cells, and TLR ligands, regulated eosinophil homing mechanisms in IBD. B cells stimulated with hypo-acylated lipopolysaccharide (LPS) produced copious amounts of eotaxin-1, which influenced eosinophil activation profiles in the bloodstream. We also found that hexa-acylated LPS, such Escherichia coli LPS, directly activated TLR2-expressing and TLR4-expressing eosinophils from patients with IBD to express a different repertoire of mucosal homing receptors, namely CCR9 and CCR10. Whereas B-cell production of eotaxin-1 was correlated with reduced disease activity, eosinophil activation by hexa-acylated LPS was associated with increased disease activity. Conclusions:These results suggest that systemic TLR ligands influence eosinophil migration patterns, both directly and indirectly, through B cells. Our report uncovers unexpected mechanisms of cross talk between certain immune cells that shed new light on IBD immunology.

New insights into the role of IL‐17 in inflammatory bowel disease

T he pathogenesis of the inflammatory bowel diseases (IBD) is thought to be due to an aberrant immune response to commensal gut bacteria. Much effort has been put into investigating the pathways that modulate this inflammatory response in order to find the best options for treatment. It has generally been accepted that Crohn’s disease (CD) is a Th1-associated disease, while Th2 cytokines are thought to be predominant in ulcerative colitis (UC). In recent years the importance of Th17 lymphocytes has been further investigated as we better elucidate the role of these cells in IBD. Rovedatti et al. used analysis of endoscopic biopsies and surgical specimens from both patients with IBD and healthy controls. The protocols involved the analysis of inflamed and uninflamed portions of colonic mucosa of patients with IBD, as well as inflamed colonic mucosa of non-IBD patients and healthy mucosa of control subjects. Also, levels of IL-17 and IFNc, two well-defined Th17 associated cytokines, were measured ex vivo in organ culture and in vitro from cell supernatants of lamina propria mononuclear cells (LPMCs) isolated from the mucosal specimens. IL-17 and IFNc levels were elevated in the inflamed mucosal tissue as well as LPMC supernatants of IBD patients versus those of controls and areas of uninflamed tissue, with no difference between CD and UC. Interestingly, IL-17 was not elevated in inflamed regions of tissue from patients who did not have IBD, but IFNc production was enhanced in these subjects with non-IBD mucosal inflammation such as radiation colitis, diverticulitis, and ischemic colitis. An increase in Th1, Th17, and Th1/Th17-producing cells was noted in subjects with CD and UC. When LPMCs were stimulated with IL-12, there was significantly increased IFNc production, whereas it resulted in decreased IL-17 levels by IBD LPMCs. IL-12 blockade also decreased IL-17 secretion by CD LPMCs.

Elective colectomy for severe ulcerative colitis may reduce mortality more than medical therapy

Commentary on: Bewtra M, Newcomb CW, Wu Q, et al. Mortality associated with medical therapy versus elective colectomy in ulcerative colitis: a cohort study. Ann Intern Med 2015;163:262–70.[OpenUrl][1][CrossRef][2][PubMed][3] The management of patients with moderate to severe ulcerative colitis (UC) is challenging, and the definition of successful treatment is unclear. Clinical practice is moving from symptomatic improvement to mucosal healing as this has shown to result in longer clinical remission, lower rates of hospitalisation and reduced need for surgery.1 Surgical management is reserved for patients refractory to medical therapy or in those that develop colorectal neoplasia. This study aims to assess whether patients with severe UC have improved survival after elective colectomy compared to those being treated with certain immunosuppressive therapies. A retrospective matched cohort study was conducted … [1]: {openurl}?query=rft.jtitle%253DAnn%2BIntern%2BMed%26rft.volume%253D163%26rft.spage%253D262%26rft_id%253Dinfo%253Adoi%252F10.7326%252FM14-0960%26rft_id%253Dinfo%253Apmid%252F26168366%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.7326/M14-0960&link_type=DOI [3]: /lookup/external-ref?access_num=26168366&link_type=MED&atom=%2Febmed%2Fearly%2F2015%2F12%2F07%2Febmed-2015-110311.atom