These findings support the hypothesis that TH-17 are involved in the active phases of GVHD and may represent a novel cellular target for developing new strategies for GVHD treatment.

Increasing knowledge about the regulation of GnRH pulsatile release, as well as the therapeutic use of its analogues, offers interesting new perspectives in the diagnosis, treatment and outcome of female reproductive disorders, including tumoral and iatrogenic diseases.

Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self‐limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin‐releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons in vitro, and perturbed migration and extension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss‐of‐function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP.‡

International audienceIndividuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (SEMA3E) in 2 brothers with Kallmann syndrome (KS), which causes inherited GnRH deficiency. Recombinant wild-type SEMA3E protected maturing GnRH neurons from cell death by triggering a plexin D1-dependent (PLXND1-dependent) activation of PI3K-mediated survival signaling. In contrast, recombinant SEMA3E carrying the KS-associated mutation did not protect GnRH neurons from death. In murine models, lack of either SEMA3E or PLXND1 increased apoptosis of GnRH neurons in the developing brain, reducing innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. Together, these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain, and elucidate SEMA3E/PLXND1/PI3K signaling as a mechanism that prevents GnRH neuron deficiency

Myelomonocytic cells play a key role in the progression of many solid tumors. However, very little is known about their contribution to the progression of hematopoietic cancers. We investigated the role of monocytes in the progression of human B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We demonstrated that coculturing human monocytes in vitro with CD19 ؉ BCP-ALL blasts from patients "conditioned" them to an inflammatory phenotype characterized by significant up-regulation of the chemokine, CXCL10. This phenotype was also observable ex vivo in monocytes isolated from BCP-ALL patients, which show elevated CXCL10 production compared with monocytes from healthy donors. Functionally, the "conditioned" monocytes promoted migration and invasive capacity of BCP-ALL cells. Increased invasion was mediated by matrix metalloproteinase 9 expression and activity in the BCP-ALL cells induced by the monocyte-derived CXCL10. However, neither the "conditioned" monocytes nor the CXCL10 produced by these cells had any effect on the proliferation/viability of BCP-ALL cells and angiogenesis. Collectively, our results strongly suggest a protumoral role for human monocytes in BCP-ALL, orchestrated by CXCL10 and its effect on tumor cell migration and invasion. These observations highlight the importance of the CXCL10/CXCR3 chemokine circuit in BCP-ALL progression. (Blood. 2012;119(1): 227-237) IntroductionMonocytes/macrophages are versatile innate immune cells that play a key role in host defense by performing a wide variety of functions. 1,2 Depending on the microenvironmental cue, monocytes/ macrophages can display distinct phenotypes and functions. 1,3,4 For example, microbial stimuli (eg, lipopolysaccharide) and IFN-␥ induce these cells to an M1 or "classical" activation state, which is characterized by up-regulation of inflammatory cytokines (eg, IL-12, IL-23, and TNF) and potent microbicidal as well as tumoricidal properties. In contrast, IL-4 and IL-13 induce an M2 (or "alternative") activation state, which is characterized by high expression of anti-inflammatory cytokines (eg, IL-10), scavenging receptors (eg, mannose receptor, CD163), and efficient phagocytic ability. These cells facilitate the resolution of inflammation, tissue repair or remodeling, and tumor-promoting activities. 5 However, it may be pointed out that M1 and M2 phenotypes represent 2 extremes of a spectrum of macrophage functional states, 3,4 and cells with overlapping M1-M2 characteristics have been noted under certain pathophysiologic settings. 6,7 In recent years, several studies have focused on the contribution of myelomonocytic cells in cancer progression. 3,8 Monocytes/ macrophages are recruited to tumor tissues where they promote tumor growth, proliferation, angiogenesis, and metastasis through the release of factors, such as TNF, IL-6, VEGF, IL-8, and matrix metalloproteinases (MMPs). 7,9,10 In line with this fact, a proangiogenic population of monocytes (termed as Tie-2-expressing monocytes) has been recently identified as the principal ...