Th1 and Th17 T cells are often colocalized in pathological environments, yet Th1-derived IFN-γ inhibits Th17 cell development in vitro. We explored the physiologic basis of this paradox in humans. In this study, we demonstrate increased the number of CD4+ and CD8+ IL-17+ T cells in skin lesions of psoriasis. Furthermore, we show that myeloid APCs potently support induction of IL-17+ T cells, and that this activity is greatly increased in psoriasis. We tested stimuli that might account for this activity. Th1 cells and IFN-γ are increased in psoriatic blood and lesional skin. We show that IFN-γ programs myeloid APCs to induce human IL-17+ T cells via IL-1 and IL-23. IFN-γ also stimulates APC production of CCL20, supporting migration of IL-17+ T cells, and synergizes with IL-17 in the production of human β-defensin 2, an antimicrobial and chemotactic protein highly overexpressed by psoriatic keratinocytes. This study reveals a novel mechanistic interaction between Th1 and IL-17+ T cells, challenges the view that Th1 cells suppress Th17 development through IFN-γ, and suggests that Th1 and IL-17+ T cells may collaboratively contribute to human autoimmune diseases.

Rationale: Previously, we have found that changes in the location of intracellular heat shock protein (HSP)60 are associated with apoptosis. HSP60 has been reported to be a ligand of Toll-like receptor (TLR)-4. Objective: We hypothesized that extracellular HSP60 (exHSP60) would mediate apoptosis via TLR4. Methods and Results: Adult rat cardiac myocytes were treated with HSP60, either recombinant human or with HSP60 purified from the media of injured rat cardiac myocytes. ExHSP60 induced apoptosis in cardiac myocytes, as detected by increased caspase 3 activity and increased DNA fragmentation. Apoptosis could be reduced by blocking antibodies to TLR4 and by nuclear factor B binding decoys, but not completely inhibited, even though similar treatment blocked lipopolysaccharide-induced apoptosis. Three distinct controls showed no evidence for involvement of a ligand other than exHSP60 in the mediation of apoptosis. Conclusions: This is the first report of HSP60-induced apoptosis via the TLRs. HSP60-mediated activation of TLR4 may be a mechanism of myocyte loss in heart failure, where HSP60 has been detected in the plasma. (Circ Res. 2009;105:1186-1195.)Key Words: Toll-like receptor-4 Ⅲ apoptosis Ⅲ heat shock protein 60 Ⅲ cardiac myocytes Ⅲ tumor necrosis factor Ⅲ TLR4 Ⅲ inflammation T oll-like receptors (TLRs) have been recognized in the last 15 years as an important part of the immune system. The TLRs are a key component of innate immunity, a primitive immunity characterized by the rapid recognition of bacterial and other motifs as dangerous, followed by an inflammatory response that includes the production of cytokines, such as tumor necrosis factor (TNF)-␣. Heat shock protein (HSP)60 is thought to be a ligand of TLR4, which has been found on the surface of cardiac myocytes. 1,2 In the immune system, activation of TLR4 is characterized by activation of nuclear factor (NF)B followed by production of TNF-␣. Limited studies have addressed the function of the TLRs in nonimmune system cells. We hypothesized that extracellular (ex)HSP60 activated TLR4 and that this would induce cardiac myocyte apoptosis.Lipopolysaccharide (LPS) has also been identified as a ligand for TLR4. Some controversy persists as to whether observed effects with other proteins activating TLR4 do so directly, or are actually contaminated with LPS. 3 However, it is becoming clear that extracellular HSPs have an important role in cell signaling. 4 To address the issue of LPS contamination, in addition to careful controls, we examined the effect of LPS on apoptosis, and the effect of a TLR4 blocking antibody on the LPS and exHSP60 induced apoptosis.We report here that exHSP60 binds selectively to the cardiac myocyte and induces apoptosis. Apoptosis is decreased by anti-TLR4 blocking antibodies but not by blocking antibodies to TLR-2 or CD14. These findings imply that HSP60 released during cardiac injury can have a paracrine effect on neighboring myocytes leading to cell death. This is the first report of HSP60 having a toxic effect on cardiac myocyte...

The absence of no attachment and FDL tendon to the FHL between the two tendons in the foot may be more frequent than previously reported. Only two configurations of the anatomical relationship were found in this study. In over 96 % of the feet, a proximal to distal connection from the FHL to the FDL was found, which might contribute to the residual function of the lesser toes after FDL transfer.

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Anti-CTLA-4 + anti-PD-1/PD-L1 combination is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAE). Here we report that targeting of HIF-1 suppressed PD-L1 expression on tumor cells and tumorinfiltrated myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFNγdependent mechanism. Targeting the HIF-1-PD-L1 axis in tumor cells reactivated tumorinfiltrating lymphocytes (TILs) and caused tumor rejection. The HIF-1 inhibitor echinomycin potentiated cancer immunotherapeutic effects of anti-CTLA-4 therapy with efficacy comparable to anti-CTLA-4+anti-PD-1 antibodies. However, while anti-PD-1 exacerbated irAE triggered by Ipilimumab, echinomycin protected mice against irAE by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1fortifies the immune tolerance function of the PD-1:PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment (TME) to achieve safer and more effective immunotherapy.

To evaluate the rationality and limitations of the seventh edition of the American Joint Committee on Cancer (the 7th AJCC edition) T-staging system for locally advanced nasopharyngeal carcinoma (NPC). The prognosis of 358 patients with stage T3/T4 NPC treated with intensity-modulated radiotherapy (IMRT) was analyzed with the Kaplan–Meier method or the log-rank test. The 7th AJCC staging system of NPC has some limitations in that the T category is neither the significant factor in OS/LRFS nor the independent prognostic factor in OS/LRFS/DMFS/DFS (P > 0.05). After adjustment by anatomic structures, univariate analysis has shown that the adjusted-T category has statistical significance between T3 and T4 for OS (86.4% and 71.3%, P = 0.002), LRFS (97% and 90.9%, P = 0.048), DMFS (90.9% and 77.2%, P = 0.001), and DFS (86.2% and 67.5%, P = 0.000), and multivariate analysis has shown that the adjusted-T category is an independent prognostic factor for OS/DMFS/DFS (with the exception of LRFS). Then, GTV-P was taken into consideration. Multivariate analysis showed that these nT categories serve as suitable independent prognostic factors for OS/DMFS/DFS (P < 0.001) and LRFS (HR = 3.131; 95% CI, 1.090–8.990; P = 0.043). The 7th AJCC staging system has limitations and should be improved by including the modifications suggested, such as anatomic structures and tumor volume adjustment.

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BackgroundThis study aimed to investigate the bone morphogenetic protein-2 (BMP-2) levels in serum and synovial fluid (SF) of patients with primary knee osteoarthritis (OA) and to exam its correlation with radiographic and symptomatic severity of the disease.Material/MethodsA total of 37 knee OA patients and 20 healthy controls were enrolled in this study. Knee OA radiographic grading was performed according to the Kellgren-Lawrence (KL) grading system by evaluating X-ray changes observed in anteroposterior knee radiography. Symptomatic severity of the disease was evaluated according to the Western Ontario McMaster University Osteoarthritis Index (WOMAC) scores. BMP-2 levels in serum and SF were determined using enzyme-linked immunosorbent assay.ResultsSerum BMP-2 level in patients with knee OA was higher than that in healthy controls. Knee OA patients with KL grade 4 showed significantly elevated BMP-2 levels in the serum and SF compared with those with KL grade 2 and 3. Knee OA patients with KL grade 3 had significant higher SF levels of BMP-2 than those with KL grade 2. BMP-2 levels in the serum and SF of knee OA patients were both positively correlated with KL grades and WOMAC scores.ConclusionsBMP2 levels in serum and SF were closely related to the radiographic and symptomatic severity of knee OA and may serve as an alternative biochemical parameter to determine disease severity of primary knee OA.