Go Muto

Smad2 and Smad3 Are Redundantly Essential for the TGF-β–Mediated Regulation of Regulatory T Plasticity and Th1 Development

Although it has been well established that TGF-β plays a pivotal role in immune regulation, the roles of its downstream transcription factors, Smad2 and Smad3, have not been fully clarified. Specifically, the function of Smad2 in the immune system has not been investigated because of the embryonic lethality of Smad2-deficient mice. In this study, we generated T cell-specific Smad2 conditional knockout (KO) mice and unexpectedly found that Smad2 and Smad3 were redundantly essential for TGF-β–mediated induction of Foxp3-expressing regulatory T cells and suppression of IFN-γ production in CD4+ T cells. Consistent with these observations, Smad2/Smad3-double KO mice, but not single KO mice, developed fatal inflammatory diseases with higher IFN-γ production and reduced Foxp3 expression in CD4+ T cells at the periphery. Although it has been suggested that Foxp3 induction might underlie TGF-β–mediated immunosuppression, TGF-β still can suppress Th1 cell development in Foxp3-deficient T cells, suggesting that the Smad2/3 pathway inhibits Th1 cell development with Foxp3-independent mechanisms. We also found that Th17 cell development was reduced in Smad-deficient CD4+ T cells because of higher production of Th17-inhibotory cytokines from these T cells. However, TGF-β–mediated induction of RORγt, a master regulator of Th17 cell, was independent of both Smad2 and Smad3, suggesting that TGF-β regulates Th17 development through Smad2/3-dependent and -independent mechanisms.

SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

SOCS1 is required to restrict IFN-γ and IL-17 expression and maintain Foxp3 expression in and function of regulatory T cells.

TGF-β Function in Immune Suppression

Transforming growth factor-β (TGF-β) has been shown to play an essential role in establishing immunological tolerance, yet recent studies have revealed the pro-inflammatory roles of TGF-β in inflammatory responses. TGF-β induces Foxp3-positive regulatory T cells (iTregs), while in the presence of IL-6, it induces pathogenic IL-17 producing Th17 cells. TGF-β inhibits the proliferation of T cells as well as cytokine production via Foxp3-dependent and independent mechanisms. On the one hand, little is known about molecular mechanisms involved in immune suppression via TGF-β; however, recent studies suggest that Smad2 as well as Smad3 play essential roles in Foxp3 induction and cytokine suppression, whereas Th17 differentiation is promoted via the Smad-independent pathway. Mutual suppression of signaling between TGF-β and inflammatory cytokines has been shown to be necessary for the balance of immunity and tolerance.

Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance

Interleukin 10 (IL-10) and regulatory T cells (Tregs) maintain tolerance to intestinal microorganisms. However, Il10−/−Rag2−/− mice, which lack IL-10 and Tregs, remain healthy, suggesting the existence of other mechanisms of tolerance. Here, we identify suppressor of cytokine signalling 1 (SOCS1) as an essential mediator of immune tolerance in the intestine. Socs1−/−Rag2−/− mice develop severe colitis, which can be prevented by the reduction of microbiota and the transfer of IL-10-sufficient Tregs. Additionally, we find an essential role for prostaglandin E2 (PGE2) in the maintenance of tolerance within the intestine in the absence of Tregs. Socs1−/− dendritic cells are resistant to PGE2-mediated immunosuppression because of dysregulated cytokine signalling. Thus, we propose that SOCS1 and PGE2, potentially interacting together, act as an alternative intestinal tolerance mechanism distinct from IL-10 and Tregs.

Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model

Recently, T cell cytokines such as IL-17 and IFN-γ have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates γδT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than γδT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke.

TRAF6 Is Essential for Maintenance of Regulatory T Cells That Suppress Th2 Type Autoimmunity

Regulatory T cells (Tregs) maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR). T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO) mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 + Tregs into Rag2-/- mice revealed that TRAF6-deficient Tregs converted into Foxp3- cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3+ to Foxp3- (exFoxp3 cells) was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs.

A case of Sjögren's syndrome complicated by protein-losing gastroenteropathy with unprecedented pulmonary interstitial lesions.

The search for an underlying disease was conducted, revealing dry mouth and anti-SS-A and anti-SS-B antibody positivity. The gum test, salivary scintigraphy and minor salivary gland biopsy showed salivary gland disorders and marked lymphocyte populations, respectively. According to the American – European Consensus Group criteria for SS, a defi nitive diagnosis of SS was made. Thus, water-soluble prednisolone for PLGE was started at a dose of 60 mg/day. After 3 weeks, the albumin level had normalized and the edema had disappeared. Pulmonary interstitial shadows on chest computed tomography nearly disappeared. Moreover, the CA-125 and total cholesterol levels improved signifi cantly. In May 2011, the prednisolone dose was decreased to 5 mg/day. She is currently in remission. To our knowledge, there have been no reports of SS complicated by PLGE with unprecedented, antecedent pulmonary interstitial lesions. The mechanisms of protein loss from the gastrointestinal wall involve abnormality of the intestinal lymphatic system, increased papillary permeability or abnormality of the gastric mucosal epithelium. However, the exact mechanism of PLGE in association with collagen disease remains unclear. With regard to pathological observations, capillary hyperpermeability due to deposition of immunoglobulins and complement components in vascular endothelial cells of the intestinal mucosa is thought to be related to PLGE associated with autoimmune diseases [7]. In general, as in our patient, those with PLGE complicating collagen disease tend to respond favorably to steroids; steroidresistant patients are said to benefi t from immunosuppressive agents, especially cyclophosphamide [6,8]. Moreover, some patients resistant to steroid pulse and cyclophosphamide pulse treatments have reportedly achieved complete remission with rituximab based on the pathogenic mechanism described by Uraoka et al. [1]. It is generally accepted that in intestinal lymphangiectasia, loss of lymphatic fl uid causes both hypoproteinemia and hypocholesterolemia. However, increased capillary permeability has been reported in patients with collagen diseases, as mentioned previously. Most cholesterol in serum exists as large complexes. The smallest compound, high-density-lipoprotein cholesterol, Mod Rheumatol, 2013; Early Online: 1–3

Information exchange using a prescribed form and involvement of occupational health nurses promotes occupational physicians to collaborate with attending physicians for supporting workers with illness in Japan

The maintenance of a balance between work and disease treatment is an important issue in Japan. This study explored factors that affect collaboration between occupational physicians (OPs) and attending physicians (APs). A questionnaire was mailed to 1,102 OPs. The questionnaire assessed the demographic characteristics of OPs; their opinions and behaviors related to collaboration, including the exchange of medical information with APs; and the occupational health service system at their establishments. In total, 275 OPs completed the questionnaire (25.0% response rate). Over 80% of respondents believed OPs should collaborate with APs. After adjusting for company size, collaboration ≥10 times/yr (with regard to both returning to work following sick leave and annual health check-ups for employees) was significantly associated with environmental factors, such as the presence of occupational health nurses (odds ratio (OR): 5.56 and 5.01, respectively, p<0.05) and the use of prescribed forms for information exchange (OR: 4.21 and 3.63, respectively, p<0.05) but not with the demographic characteristics of the OPs (p>0.05). The majority of OPs believed that collaboration with APs is important for supporting workers with illnesses. Support systems including prescribed forms of information exchange and occupational health nurses, play pivotal roles in promoting this collaboration.

Durations of first and second periods of depression-induced sick leave among Japanese employees: the Japan sickness absence and return to work (J-SAR) study

This study aimed to clarify the difference between the durations of first and second periods of depression-induced sick leave and to identify predictors of a prolonged second period of depression-induced sick leave. Among Japanese employees who were registered in the Japan sickness absence and return to work (J-SAR) study, the subjects were those employees who returned to work after an initial period of depression-induced sick leave (F3; ICD-10, based on a psychiatrist’s certificate), and returned to work after a second period of depression-induced sick leave. The subjects’ second periods of sick leave (mean: 156.9 d) were longer than their first periods of sick leave (107.3 d) (Wilcoxon test, p=0.007). In the logistic regression analysis (Table 2), “longer duration of the first period of sick leave” (Odds ratio: 3.258, 95%CI: 1.780–5.963, p<0.001) was identified as a significant predictor of a longer recurrent period of sick leave. Individuals who experience a long initial period of depression-induced sick leave should be supported carefully by occupational health professionals after they RTW.

Toward the harmonization of work with treatment and prevention for patients with chronic respiratory failure

Home oxygen therapy (HOT), also known as long-term oxygen therapy, is prescribed to patients with chronic respiratory failure (CRF) due to advanced respiratory diseases, as it has been shown to improve the prognosis of patients with chronic obstructive pulmonary disease (COPD). However, the therapeutic impact of HOT does not fully reflect the “socialization” of patients, which is one of the final goals of “comprehensive pulmonary rehabilitation”, proposed by the Japanese Respiratory Society. Since working is one form of socialization, we evaluated a 55-yr-old worker prescribed with HOT for the management of advanced COPD to elucidate and assess the social barriers experienced by HOT users. This case demonstrates a variety of factors affecting patients, respiratory physicians, occupational physicians, and management teams, which prevents patients from working. By elucidating these factors and seeking solutions, the promotion of the “harmonization of work with treatment and prevention” will both improve working environments and encourage CRF patients to continue working, leading to better socialization. Thus, the “harmonization of working with treatment and prevention” for CRF patients is a core goal for the promotion of both “health and productivity management” and “comprehensive pulmonary rehabilitation.”