Behçet's disease is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent ocular symptoms, oral and genital ulcers and skin lesions. We conducted a genome-wide association study in a Japanese cohort including 612 individuals with Behçet's disease and 740 unaffected individuals (controls). We identified two suggestive associations on chromosomes 1p31.3 (IL23R-IL12RB2, rs12119179, P = 2.7 x 10(-8)) and 1q32.1 (IL10, rs1554286, P = 8.0 x 10(-8)). A meta-analysis of these two loci with results from additional Turkish and Korean cohorts showed genome-wide significant associations (rs1495965 in IL23R-IL12RB2, P = 1.9 x 10(-11), odds ratio = 1.35; rs1800871 in IL10, P = 1.0 x 10(-14), odds ratio = 1.45).

The new proposed criteria derived from multinational data exhibits much improved sensitivity over the ISG criteria while maintaining reasonable specificity. It is proposed that the ICBD criteria to be adopted both as a guide for diagnosis and classification of BD.

Recently, we have found that the neuropeptide alpha‐melanocyte stimulating hormone (α‐MSH) not only suppresses IFN‐γ production, but also induces TGF‐β1 production by activated effector T cells. These α‐MSH‐ treated effector T cells function as regulatory T cells in that they suppress IFN‐γ production and hypersensitivity mediated by other effector T cells. Experimental autoimmune uveoretinitis (EAU) was suppressed in its severity and incidence in mice that were injected with primed T cells activated in vitro by APC and antigen in the presence of α‐MSH. Moreover, it appeared that α‐MSH had converted a population of effector T cells polarized to mediate hypersensitivity into a population of T cells that now mediated immunoregulation. To characterize these α‐MSH‐ treated T cells, primed T cells were TCR‐stimulated in the presence of α‐MSH in vitro and their lymphokine profile was examined. Such effector T cells displayed enhanced levels of TGF‐β1 production and no IFN‐γ or IL‐10, with IL‐4 levels remaining unchanged in comparison with inactivated T cells. In addition, if soluble TGF‐β receptor II was added to cocultures of α‐MSH‐treated T cells and activated Th1 cells, the α‐MSH‐treated T cells could not suppress IFN‐γ production by the Th1 cells. These results suggest that α‐MSH induces T cells with a regulatory lymphokine pattern, and that through their production of TGF‐β1 these cells suppress other effector T cells. Examination of the α‐MSH‐treated T cells showed that α‐MSH did not alter the phosphorylation of CD3 molecules following TCR engagement. Primed T cells express the melanocortin 5 receptor (MC5r), a receptor that is linked to an intracellular signalling pathway shared by other cytokine receptors. Blocking the receptor with antibody prevented α‐MSH from suppressing IFN‐γ production by the activated regulatory T cells, suggesting that α‐MSH immunoregulation is through the MC5r on primed T cells. Surface staining and cell sorting of the α‐MSH‐ treated primed T cells showed that the regulatory T cells are CD25+ CD4+ T cells. From these results we find that α‐MSH can mediate the induction of CD25+ CD4+ regulatory T cells. These regulatory T cells require specific antigen for activation, but through non‐specific TGF‐β1‐mediated mechanisms they can suppress other effector T cells.

Aims: To examine the effi cacy of tacrolimus ophthalmic suspension 0.1% in treating severe allergic conjunctivitis. Methods: This was a multicenter, randomized, double-masked, placebo-controlled clinical trial. Fifty-six patients with severe allergic conjunctivitis in whom topical antiallergic agents and corticosteroids had been ineffective were randomized to tacrolimus or placebo treatment. Patients were treated either with tacrolimus or placebo twice-daily for 4 weeks. Severity of objective signs in palpebral and bulbar conjunctiva, limbus, and corneal involvement was assessed using 4 grades. Seven subjective symptoms were evaluated by visual analog scale (VAS) assessment. The primary effi cacy endpoint was change in the total score of objective signs at the end of treatment. The secondary effi cacy endpoints included change in the score for each objective sign and change in the VAS for each subjective symptom. Safety was assessed based on the severity and the incidence of adverse events. Results: Mean change from baseline in total score for objective signs was signifi cantly greater in the tacrolimus (−5.6 ± 5.1) than in the placebo group (−0.1 ± 4.5; P < 0.001). Tacrolimus signifi cantly improved giant papillae ( P = 0.001) and corneal involvement ( P = 0.005). Five subjective symptoms (itching, discharge, hyperemia, lacrimation, and foreign body sensation) were signifi cantly better in the tacrolimus than in the placebo group. The most frequent treatment-related adverse event in the tacrolimus group was mild ocular irritation upon topical instillation, which was well-tolerated. Conclusion: Tacrolimus ophthalmic suspension 0.1% is effective in treating severe allergic conjunctivitis.

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BackgroundThe objective of this study was to investigate the efficacy of topical 0.1% tacrolimus in treating refractory allergic conjunctivitis with proliferative lesions and/or corneal involvement.MethodsThis prospective observational study included 1436 patients with refractory allergic conjunctivitis whose condition had responded poorly to conventional antiallergic drugs and/or topical steroids and/or topical cyclosporine. All patients received tacrolimus eye drops twice daily during the study period. Ten clinical signs and six clinical symptoms were rated on a four-grade scale. The primary endpoint was the change from baseline in total clinical signs and symptoms score at the last observation or following 6 months of treatment.ResultsTotal signs and symptoms score significantly decreased after 1 month of treatment (p<0.001). Giant papillae and corneal lesions were also reduced by tacrolimus eye drop use (p<0.001). The drug proved effective in patients whose condition did not respond well to topical cyclosporine therapy. About 50% of all patients using topical steroids were weaned. The most common adverse reaction was a transient burning sensation (3.20%).ConclusionsTacrolimus eye drops are highly effective in treating refractory allergic conjunctivitis with proliferative lesions and/or corneal involvement, and may reduce or replace topical steroid use.Trial registration numberUMIN 000008640.

These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD.

The immune-privileged eye has the potential to induce regulatory immunity along with local mechanisms of immunosuppression. Rodent models of human autoimmune uveoretinitis [experimental autoimmune uveoretinitis (EAU)] recover without spontaneous recurrence of uveitis, which differs from uveitis in some humans. This raises the possibility that the mechanism of immune privilege in the rodent eye can reimpose itself during autoimmune uveoretinitis and re-establish tolerance to autoantigen. To investigate this possibility, we examined the spleens of EAU-recovered mice for regulatory immunity. We detected regulatory immunity when we adoptively transferred post-EAU spleen cells into other mice immunized for EAU. We could not detect this regulatory immunity in enucleated mice nor in naive mice. Moreover, unlike the mechanisms of anterior chamber-associated immune deviation, the suppression was only mediated by post-EAU CD4 + T cells, which required activation with autoantigen presented by post-EAU spleen antigen-presenting cells (APC). Our results demonstrate that when the immune-privileged ocular microenvironment recovers from an autoimmune response, it has influenced systemic immunity to retinal autoantigen by affecting APC and mediating induction of potential regulatory CD4 + T cells laying in wait in the post-EAU spleen for restimulation.