IL-17A enhances IL-13 activity by enhancing IL-13-induced signal transducer and activator of transcription 6 activation.

BACKGROUND: Increased IL-17A production has been associated with more severe asthma; however, the mechanisms whereby IL-17A can contribute to IL-13-driven pathology in asthmatic patients remain unclear. OBJECTIVE: We sought to gain mechanistic insight into how IL-17A can influence IL-13-driven responses. METHODS: The effect of IL-17A on IL-13-induced airway hyperresponsiveness, gene expression, mucus hypersecretion, and airway inflammation was assessed by using in vivo models of IL-13-induced lung pathology and in vitro culture of murine fibroblast cell lines and primary fibroblasts and human epithelial cell lines or primary human epithelial cells exposed to IL-13, IL-17A, or both. RESULTS: Compared with mice given intratracheal IL-13 alone, those exposed to IL-13 and IL-17A had augmented airway hyperresponsiveness, mucus production, airway inflammation, and IL-13-induced gene expression. In vitro, IL-17A enhanced IL-13-induced gene expression in asthma-relevant murine and human cells. In contrast to the exacerbating influence of IL-17A on IL-13-induced responses, coexposure to IL-13 inhibited IL-17A-driven antimicrobial gene expression in vivo and in vitro. Mechanistically, in both primary human and murine cells, the IL-17A-driven increase in IL-13-induced gene expression was associated with enhanced IL-13-driven signal transducer and activator of transcription 6 activation. CONCLUSIONS: Our data suggest that IL-17A contributes to asthma pathophysiology by increasing the capacity of IL-13 to activate intracellular signaling pathways, such as signal transducer and activator of transcription 6. These data represent the first mechanistic explanation of how IL-17A can directly contribute to the pathogenesis of IL-13-driven pathology.

Megakaryocytic hyperplasia in myeloproliferative neoplasms is driven by disordered proliferative, apoptotic and epigenetic mechanisms.

AIMS: Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal proliferative bone marrow diseases characterised by extensive megakaryocytic hyperplasia and morphological atypia. Despite knowledge of genomic defects, the pathobiological processes driving these megakaryocytic abnormalities in MPN remain poorly explained. We have explored the proliferative, apoptotic and epigenetic profiles of megakaryocytes in human MPN. METHODS: Immunohistochemical staining was performed on bone marrow trephine biopsies of 81 MPN (with and without JAK2(V617F) and CALR mutations) and 15 normal controls to assess the megakaryocytic expression of biomarkers associated with proliferation (Ki67), apoptosis (Bcl-XL, BNIP-3) and epigenetic regulation (EZH2, SUZ12). RESULTS: Myeloproliferative megakaryocytes showed significantly greater expression of proliferative Ki67 and anti-apoptotic Bcl-XL, reduced pro-apoptotic BNIP-3 and increased SUZ12 compared with controls. In essential thrombocythaemia, large-giant megakaryocytes with hyperlobated nuclei showed a trend towards a proliferative signature. In contrast, myelofibrotic megakaryocytes with condensed nuclear chromatin, and cases with CALR mutations, had significant reductions in pro-apoptotic BNIP-3. CONCLUSIONS: Uncontrolled megakaryocytic expansion in MPN results from a combination of increased proliferation, attenuated apoptosis and defective epigenetic regulation with CALR mutations favouring apoptotic failure. The higher platelet counts reported to be seen in MPN with CALR mutations may be due to greater dysregulation of megakaryocyte apoptosis.

Significance of abnormal protein bands in patients with multiple myeloma following autologous stem cell transplantation.

AIM: We studied the characteristics of small abnormal protein bands (APB) (including oligoclonal bands and new apparent monoclonal bands) that are frequently detected by serum protein electrophoresis (SPEP) and isoelectric focusing (IEF) in the post-autologous stem cell transplant setting. METHODS: In a retrospective analysis of patients with multiple myeloma undergoing transplantation, paraprotein identity and quantification were performed using standard immunofixation electrophoresis. The nature of any new bands was determined by IEF which distinguished between oligoclonal bands and apparent monoclonal bands. RESULTS: Of 49 myeloma cases, the median follow-up was 33.7 months (range, 5.6-97.5 months) and 24 patients had relapsed. Thirty six (73%) developed APB. 22 patients had more than one episode of APB and 6 patients had more than 2 episodes resulting in a total of 69 episodes of APB observed post-transplant. IEF demonstrated 54 of these APB were oligoclonal bands and 15 appeared to be monoclonal. Of the 15 episodes of apparent monoclonal bands, 10 had differing heavy or light chain restriction compared to the original myeloma paraprotein and 5 had the same heavy and light chain restriction but different band location in the SPEP lane. Ten of these apparent monoclonal bands resolved, 5 persisted, and only one represented true disease progression. The presence of APB impacted favourably on event-free survival (p=0.05). CONCLUSION: Small APB are very frequent post-transplant for myeloma, and IEF can identify these APB as oligoclonal or monoclonal. Apparent monoclonal bands may represent relapsed disease, but in the vast majority of cases it does not, and most likely represents a transient phenomenon representing regeneration of a limited immune response.