Our current data support previous clinical studies in suggesting a role of E. coli in human PBC. Hopf et al. [63] reported an association between PBC and the presence of rough-form mutants of E. coli in the patients’ fecal RAD001 in vitro samples. In addition, Butler et al. reported reactivity to PDC-E2 in 52% of sera from patients with chronic UTIs [7, 64]. In the first controlled epidemiological analysis for the relationship between

E. coli and PBC, Parikh-Patel et al. showed a positive association between PBC and recurrent UTI [65]. A recent epidemiological study on 1032 PBC patients followed-up in 20 tertiary referral centres in the United States and 1041 demographically matched controls confirms earlier studies indicating a connection SCH727965 molecular weight of UTI with PBC [66]. The discovery of E. coli infection-triggered autoimmunity and liver pathology warrant further consideration in the elucidation of aetiological mechanisms of autoimmune syndromes and may suggest new and simpler ways to diagnose and treat these debilitating diseases. Our data also highlight the importance of microbial

infections in autoimmunity either as primary or co-existing secondary inciting events. This work was supported in part by National Institutes of Health grants DK39588 (M. E. G.) DK067003 (M. E. G.), AI71922 (M. K.) and AI083029 (J. L. V.) The authors have no financial conflicts of interest. “
“Bidirectional signals via Eph receptors/ephrins have been recognized as major forms of contact-dependent cell communications such as cell attraction and repulsion. T cells express EphBs, and their ligands, the ephrin-Bs, have been

known as costimulatory molecules for T-cell proliferation. Recently, another remarkable feature of ephrin-As has emerged in the form of a concentration-dependent transition from promotion to inhibition in axon growth. Here we examined whether this modification plays a role in ephrin-B costimulation in murine primary T cells. Low doses of ephrin-B1 and ephrin-B2 costimulated T-cell proliferation induced by anti-CD3, but selleck inhibitor high concentrations strongly inhibited it. In contrast, ephrin-B3 showed a steadily increasing stimulatory effect. This modulation was virtually preserved in T cells from mice simultaneously lacking four genes, EphB1, EphB2, EphB3, and EphB6. High concentrations of ephrin-B1/B2, but not ephrin-B3, inhibited the anti-CD3-induced phosphorylation of Lck and its downstream signals such as Erk and Akt. Additionally, high doses of any ephrin-Bs could phosphorylate EphB4. However, only ephrin-B1/B2 but not ephrin-B3 recruited SHP1, a phosphatase to suppress the phosphorylation of Lck. These data suggest that EphB4 signaling could engage in negative feedback to TCR signals. T-cell activation may be finely adjusted by the combination and concentration of ephrin-Bs expressed in the immunological microenvironment.