Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density.

Our previous genome-wide association study (GWAS) in a Hong Kong Southern Chinese population with extreme bone mineral density (BMD) scores revealed suggestive association with MPP7, which ranked second after JAG1 as a candidate gene for BMD. To follow-up this suggestive signal, we replicated the top single-nucleotide polymorphism rs4317882 of MPP7 in three additional independent Asian-descent samples (n= 2684). The association of rs4317882 reached the genome-wide significance in the meta-analysis of all available subjects (P(meta)= 4.58 × 10(-8), n= 4204). Site heterogeneity was observed, with a larger effect on spine than hip BMD. Further functional studies in a zebrafish model revealed that vertebral bone mass was lower in an mpp7 knock-down model compared with the wide-type (P= 9.64 × 10(-4), n= 21). In addition, MPP7 was found to have constitutive expression in human bone-derived cells during osteogenesis. Immunostaining of murine MC3T3-E1 cells revealed that the Mpp7 protein is localized in the plasma membrane and intracytoplasmic compartment of osteoblasts. In an assessment of the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of transcriptional factor GATA2 to the risk allele 'A' but not the 'G' allele of rs4317882. An mRNA expression study in human peripheral blood mononuclear cells confirmed that the low BMD-related allele 'A' of rs4317882 was associated with lower MPP7 expression (P= 9.07 × 10(-3), n= 135). Our data suggest a genetic and functional association of MPP7 with BMD variation.

Phagocytosis of apoptotic cells modulates mesenchymal stem cells osteogenic differentiation to enhance IL-17 and RANKL expression on CD4+ T cells.

Osteogenic differentiation of mesenchymal stem cells (MSC) is important to homeostatic bone remodeling. Infiltration of mesenchymal progenitor cells to inflamed joints has been reported in collagen-induced arthritis murine model and in patients with rheumatoid arthritis (RA). Therapeutic application of MSC in RA has been suggested and under investigation. However, the underlying mechanisms on what triggers the migration of MSC from bone marrow (BM) to inflamed joints and how MSC acts in the joints remains elusive. As hemopoietic stem cells and MSC act reciprocally and excessive apoptotic cells (AC) are observed in the BM of patients with RA, we hypothesize that AC may alter MSC osteogenic differentiation resulting in bone erosion in RA. In this study, we demonstrated for the first time that MSC were able to phagocytose AC and this phagocytosis enhanced MSC osteogenic differentiation. AC-treated MSC under osteogenic differentiation expressed CXC-chemokine receptor (CXCR)-4 and CXCR5, which might enable them to migrate toward the inflamed joints. In addition, AC-treated MSC secreted interleukin (IL)-8, monocyte chemoattractant protein-1, and RANTES, which might induce chemotaxis of CD4+ T cells to the inflamed joints. Interestingly, by coculturing AC-treated MSC under osteogenic differentiation with CD4+ T cells, T helper (Th) 17 cells development was significantly enhanced and these Th17 cells promoted osteoclasts formation and bone resorption. Furthermore, the induction of Th17 cells was dependent on increased IL-6 production from major histocompatibility complex class II-expressing AC-treated MSC under osteogenic differentiation. This data provide a novel insight on the role of AC in modulating MSC osteogenic differentiation and function in inflammatory bone diseases.

TACI Constrains TH17 Pathogenicity and Protects against Gut Inflammation.

TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) plays critical roles in B cells by promoting immunoglobulin class switching and plasma cell survival. However, its expression and function in T cells remain controversial. We show here that TACI expression can be strongly induced in murine CD4+ T cells in vitro by cytokines responsible for TH17 but not TH1 or TH2 differentiation. Frequencies and numbers of TH17 cells were elevated in TACI-/ - compared with wild-type mice as well as among TACI-/ - versus wild-type CD4+ T cells in mixed bone marrow chimeras, arguing for a T cell-intrinsic effect in the contribution of TACI deficiency to TH17 cell accumulation. TACI-/ - mice were more susceptible to severe colitis induced by dextran sodium sulfate or adoptive T cell transfer, suggesting that TACI negatively regulates TH17 function and limits intestinal inflammation in a cell-autonomous manner. Finally, transcriptomic and biochemical analyses revealed that TACI-/ - CD4+ T cells exhibited enhanced activation of TH17-promoting transcription factors NFAT, IRF4, c-MAF, and JUNB. Taken together, these findings reveal an important role of TACI in constraining TH17 pathogenicity and protecting against gut disease.

The Elusive Anti-Candida Vaccine: Lessons From the Past and Opportunities for the Future.

Candidemia is a bloodstream fungal infection caused by Candida species and is most commonly observed in hospitalized patients. Even with proper antifungal drug treatment, mortality rates remain high at 40-50%. Therefore, prophylactic or preemptive antifungal medications are currently recommended in order to prevent infections in high-risk patients. Moreover, the majority of women experience at least one episode of vulvovaginal candidiasis (VVC) throughout their lifetime and many of them suffer from recurrent VVC (RVVC) with frequent relapses for the rest of their lives. While there currently exists no definitive cure, the only available treatment for RVVC is again represented by antifungal drug therapy. However, due to the limited number of existing antifungal drugs, their associated side effects and the increasing occurrence of drug resistance, other approaches are greatly needed. An obvious prevention measure for candidemia or RVVC relapse would be to immunize at-risk patients with a vaccine effective against Candida infections. In spite of the advanced and proven techniques successfully applied to the development of antibacterial or antiviral vaccines, however, no antifungal vaccine is still available on the market. In this review, we first summarize various efforts to date in the development of anti-Candida vaccines, highlighting advantages and disadvantages of each strategy. We next unfold and discuss general hurdles encountered along these efforts, such as the existence of large genomic variation and phenotypic plasticity across Candida strains and species, and the difficulty in mounting protective immune responses in immunocompromised or immunosuppressed patients. Lastly, we review the concept of "trained immunity" and discuss how induction of this rapid and nonspecific immune response may potentially open new and alternative preventive strategies against opportunistic infections by Candida species and potentially other pathogens.

Experimental evolution of a fungal pathogen into a gut symbiont.

Gut microbes live in symbiosis with their hosts, but how mutualistic animal-microbe interactions emerge is not understood. By adaptively evolving the opportunistic fungal pathogen Candida albicans in the mouse gastrointestinal tract, we selected strains that not only had lost their main virulence program but also protected their new hosts against a variety of systemic infections. This protection was independent of adaptive immunity, arose as early as a single day postpriming, was dependent on increased innate cytokine responses, and was thus reminiscent of "trained immunity." Because both the microbe and its new host gain some advantages from their interaction, this experimental system might allow direct study of the evolutionary forces that govern the emergence of mutualism between a mammal and a fungus.

The interferon gamma gene polymorphism +874 A/T is associated with severe acute respiratory syndrome.

BACKGROUND: Cytokines play important roles in antiviral action. We examined whether polymorphisms of IFN-gamma,TNF-alpha and IL-10 affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS). METHODS: A case-control study was carried out in 476 Chinese SARS patients and 449 healthy controls. We tested the polymorphisms of IFN-gamma,TNF-alpha and IL-10 for their associations with SARS. RESULTS: IFN-gamma +874A allele was associated with susceptibility to SARS in a dose-dependent manner (P < 0.001). Individuals with IFN-gamma +874 AA and AT genotype had a 5.19-fold (95% Confidence Interval [CI], 2.78-9.68) and 2.57-fold (95% CI, 1.35-4.88) increased risk of developing SARS respectively. The polymorphisms of IL-10 and TNF-alpha were not associated with SARS susceptibility. CONCLUSION: IFN-gamma +874A allele was shown to be a risk factor in SARS susceptibility.