MyD88 modulates eosinophil and neutrophil recruitment as well as IL-17A production during allergic inflammation.

The contribution of dysregulated innate immune responses to the pathogenesis of allergic disease remains largely unknown. Herein, we addressed the role of Toll-like receptor signaling in airway inflammation by studying mice rendered deficient for the myeloid differentiation factor 88 (MyD88-/-) which results in concurrent deficiencies in TLR and IL-1R1 signaling pathways. We show that the lack of MyD88 offers a partial protection from allergic disease evidenced by reduced airway eosinophilia and production of the Th17-associated effector cytokine IL-17A. By contrast, airway hyperreactivity and Th2 cytokine production, the cardinal features of allergic disease, remained unchanged. We found that the impaired IL-17A production in MyD88-/- mice was associated with defective CD4+ T cells, which failed to respond to IL-23 stimulation. The total number of Th17-associated effectors in lymph nodes was likewise decreased. Taken together, our results demonstrate that MyD88-dependent mechanisms are critical for orchestrating lung inflammatory responses, in terms of IL-17A production, as well as eosinophil and neutrophil recruitment.

NKp30 isoforms and NKp46 transcripts in metastatic melanoma patients: Unique NKp30 pattern in rare melanoma patients with favorable evolution.

Given the NK cell-based immunosurveillance of melanoma, we investigated the prognostic value of NKp46 transcript and NKp30 isoform (NKp30A, NKp30B and NKp30C) profiling in blood of 187 melanoma patients including 13 long survivors (LS), metastatic patients that have controlled the disease. Compared to healthy volunteers (HV), patients had reduced amounts of transcripts of the three NKp30 isoforms (NKp30 A, B and C) but similar ratios between NKp30 isoforms (ΔAB, ΔAC, ΔBC). Stratification of patients according to disease stage showed higher NKp30C and lower NKp46 transcripts in stage IV patients. Furthermore, patients with previous history of conventional chemotherapy displayed reduced NKp30A transcripts. The expression levels of NKp30 isoforms failed to predict survival from sampling of patients, while NKp46 expression predicted melanoma outcome. LS patients displayed elevated NKp30A levels, accordingly high ΔAB and ΔBC ratios, and a unique pattern of rare allelic variants of NKp30 SNPs. Moreover, NK cells from LS displayed correlated NKp30/NKp46 membrane expression, high spontaneous and NKp30- or NKp46-triggered degranulation. These data outline the impact of NKp30 and NKp46 transcripts on melanoma evolution and identify unique genetic features of NKp30 associated with higher NK activation in rare LS melanoma patients that control a metastatic disease.