Background Studies with c- kit mutant mast cell (MC)–deficient mice and antibody-mediated depletion of basophils suggest that both MCs and basophils can contribute to peanut-induced anaphylaxis ...(PIA). However, interpretation of data obtained by using such approaches is complicated because c- kit mutant mice have several phenotypic abnormalities in addition to MC deficiency and because basophil-depleting antibodies can also react with MCs. Objective We analyzed (1) the changes in the features of PIA in mice after the selective and inducible ablation of MCs or basophils and (2) the possible importance of effector cells other than MCs and basophils in the PIA response. Methods Wild-type and various mutant mice were orally sensitized with peanut extract and cholera toxin weekly for 4 weeks and challenged intraperitoneally with peanut extract 2 weeks later. Results Peanut-challenged, MC-deficient Kit W-sh/W-sh mice had reduced immediate hypothermia, as well as a late-phase decrease in body temperature that was abrogated by antibody-mediated depletion of neutrophils. Diphtheria toxin–mediated selective depletion of MCs or basophils in Mcpt5-Cre ; iDTR and Mcpt8 DTR mice, respectively, and treatment of wild-type mice with the basophil-depleting antibody Ba103 significantly reduced peanut-induced hypothermia. Non–c- kit mutant MC- and basophil-deficient Cpa3-Cre;Mcl-1 fl/fl mice had reduced but still significant responses to peanut. Conclusion Inducible and selective ablation of MCs or basophils in non–c- kit mutant mice can significantly reduce PIA, but partial responses to peanut can still be observed in the virtual absence of both cell types. The neutrophilia in Kit W-sh/W-sh mice might influence the responses of these mice in this PIA model.
Background Mastocytosis, characterized by pathologic accumulation of mast cells, can manifest itself in adulthood or childhood. Pediatric patients usually have cutaneous mastocytosis (CM) with mast ...cell infiltrates limited to the skin and spontaneous improvement of skin lesions after several years. However, there are some patients with persistent disease resembling adulthood-onset mastocytosis. Objective The current classification of CM differentiates between 3 subforms. In clinical practice we noticed that different variants of these subforms might exist, particularly in patients with childhood-onset mastocytosis. Therefore, in the present study, we aimed to investigate whether specific cutaneous lesions in patients with childhood-onset mastocytosis are associated with other disease parameters. Methods We analyzed 144 patients with a disease onset of less than age 17 years using a systematic dermatologic approach. Results One hundred twenty-two patients presented with maculopapular cutaneous mastocytosis (MPCM), 12 patients presented with diffuse CM, and 10 patients presented with solitary mastocytoma of the skin. Patients with MPCM showed particularly heterogeneous cutaneous lesions and were therefore grouped into 3 variants presenting either with small lesions (MPCM-small, skin lesions <1 cm in diameter; n = 19), large lesions (MPCM-large, skin lesions ≥1 cm in diameter; n = 89), or atypical lesions (MPCM-other, n = 14). Patients with MPCM-large lesions, compared with those with MPCM-small lesions, were characterized by significantly lower tryptase levels, shorter disease duration, and earlier disease onset. In addition, more patients with MPCM-large lesions exhibited spontaneous regression of cutaneous lesions. Conclusion Our data show that patients with MPCM-large lesions compared with those with MPCM-small lesions have a more favorable disease course and suggest exploring the size of cutaneous lesions as a prognostic parameter in childhood-onset MPCM.
In recent years, it has become evident that the novel cytokine IL-31 plays an important role in the induction of chronic skin inflammation.5,6 Patients with atopic dermatitis, chronic spontaneous ...urticaria, allergic contact dermatitis, prurigo nodularis, and primary cutaneous lymphomas express increased serum IL-31 and IL31 mRNA levels in the skin.6,7 IL-31 serum levels in patients with atopic dermatitis also correlate with disease activity7 and levels of TH2 cytokines, such as IL-4 and IL-13. ...gene variants of IL31 are associated with the development of atopic dermatitis. Surprisingly, when we compared the group of 12 pediatric patients, who all had CM, with the group of 28 adult patients with CM or ISM, we observed significantly increased IL-31 levels in pediatric patients (P = .0279; Fig 1, A). Because pediatric patients typically show lower tryptase levels than adult patients, which was also confirmed in our study (see Fig E1, A), this finding was unexpected.
Bone mineral density (BMD) data of lumbar spine and femoral neck were collected in 56 patients with different categories of SM, classified according to established World Health Organization criteria ...(patient group 1; n = 56; see Table E1 in this article's Online Repository at www.jacionline.org).1 Absolute BMD values were converted into T scores, defining a T score below -2.5 SD as osteoporosis and below -1.0 SD and equal or above -2.5 SD as osteopenia. Interestingly, serum levels of RANKL (Fig 1, E) and OPG (Fig 1, F) were significantly increased in patients with ISM than in controls, suggesting the involvement of the RANKL/RANK/OPG pathway in mastocytosis-related osteoporosis. ...levels of SOST were significantly enhanced (Fig 1, H), indicating that the Wnt pathway may additionally be affected.
According to phenotype and extent of MC infiltration, mastocytosis is classified into cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), systemic mastocytosis with associated ...hematological non-MC lineage disease (SM-AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL). In accordance, treatment of these tumors, such as advanced melanoma, lung carcinoma, renal cell carcinoma, and Hodgkin's lymphoma, with antibodies against PD-1 (nivolumab and lambrolizumab) or PD-L1 (BMS-936559) has been demonstrated to be highly effective.5,7-9 Immune checkpoint blockade by these antibodies promotes antitumor activity by enhancing immune responses, such as the cytotoxic function of tumor-specific T cells.
Background Microphthalmia transcription factor, an MiT transcription family member closely related to transcription factor E3 (TFE3), is essential for mast cell development and survival. TFE3 was ...previously reported to play a role in the functions of B and T cells; however, its role in mast cells has not yet been explored. Objective We sought to explore the role played by TFE3 in mast cell function. Methods Mast cell numbers were evaluated by using toluidine blue staining. FACS analysis was used to determine percentages of Kit and FcϵRI double-positive cells in the peritoneum of wild-type (WT) and TFE3 knockout (TFE3−/− ) mice. Cytokine and inflammatory mediator secretion were measured in immunologically activated cultured mast cells derived from either knockout or WT mice. In vivo plasma histamine levels were measured after immunologic triggering of these mice. Results No significant differences in mast cell numbers between WT and TFE3−/− mice were observed in the peritoneum, lung, and skin. However, TFE3−/− mice showed a marked decrease in the number of Kit+ and FcϵRI+ peritoneal and cultured mast cells. Surface expression levels of FcϵRI in TFE3−/− peritoneal mast cells was significantly lower than in control cells. Cultured mast cells derived from TFE3−/− mice showed a marked decrease in degranulation and mediator secretion. In vivo experiments showed that the level of plasma histamine in TFE3−/− mice after an allergic trigger was substantially less than that seen in WT mice. Conclusion TFE3 is a novel regulator of mast cell functions and as such could emerge as a new target for the manipulation of allergic diseases.
...to these alterations in CTMCs, MMC numbers were comparable between Mcpt5Cre/Dicerfl/fl mice and Dicerfl/fl control animals, as indicated by unchanged serum levels of mMCP-1 (Fig 1, H) and ...comparable expression of Mcpt1 and Mcpt2 mRNA in the small intestine in both groups (Fig 1, I and J). Because MCs are major effector cells of anaphylaxis, we next sought to investigate the response of Mcpt5Cre/Dicerfl/fl mice in IgE-mediated passive systemic anaphylaxis (Fig 1, K). In line with our findings, Dicer ablation in vivo has been shown to also affect maturation of granulocyte/macrophage progenitors toward neutrophils, macrophages, and dendritic cells, as well as T-cell differentiation, B-cell development, and germinal center formation.2,8 Expression of Mcpt5Cre has previously been demonstrated to be highly specific for CTMCs,4 with the exception of TH2 cell-mediated expansion of MMCs.9 To further assess the specificity of Mcpt5Cre-mediated deletion of Dicer, we next analyzed the number of different myeloid and lymphoid cells in peripheral blood, the spleen, and the peritoneal cavity (Fig 2).
Abstract Background Endothelial dysfunction plays a major role in cardiovascular diseases, including acute myocardial infarction (AMI). However, its quantification has not been available as a ...clinical tool. Methods In a prospective international multicentre study, we analyzed the diagnostic and prognostic utility of endothelial dysfunction as quantified by C-terminal proendothelin-1 (CT-proET-1) in 658 consecutive patients presenting with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long-term for mortality. Results The adjudicated final diagnosis was AMI in 145 patients (22%). The diagnostic performance of CT-proET-1 for AMI was moderate; its area under the receiver operating characteristic (ROC) curve amounted to 0.66 (95% confidence interval CI, 0.61-0.72; P < 0.001). There was no significant increase in the AUC when CT-proET-1 was added to either cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT). Seventy four percent of patients who died during the first 24 months (n = 50) were in the fourth quartile of the CT-proET-1 presentation value (>82 pmol/L). The prognostic accuracy of CT-proET-1 regarding mortality was tantamount to that of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and outperformed cTnT and hs-cTnT both in patients with AMI and in patients without acute coronary syndrome. CT-proET-1 at presentation yielded high prognostic accuracy that was similar to that of the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores. The TIMI risk score could be significantly improved by adding CT-proET-1 (integrated discriminatory improvement IDI of 0.074 P = 0.004). Conclusions Use of CT-proET-1 improves risk stratification of unselected patients with suspected AMI. CT-proET-1 did not provide additional diagnostic value.
Background Inherited deficiencies of IL-10 or IL-10 receptor (IL-10R) lead to immune dysregulation with life-threatening early-onset enterocolitis. Objectives We sought to gather clinical data of ...IL-10/IL-10R–deficient patients and devise guidelines for diagnosis and management, including hematopoietic stem cell transplantation (HSCT). Methods We enrolled 40 patients with early-onset enterocolitis and screened for mutations in IL10 / IL10R using genetic studies, functional studies, or both of the IL-10 signaling pathway. Medical records of IL-10/IL-10R–deficient patients were reviewed and compiled. Results Of 40 patients, we identified 7 with novel mutations, predominantly in consanguineous families with more than 1 affected member. IL-10/IL-10R–deficient patients had intractable enterocolitis, perianal disease, and fistula formation. HSCT was carried out in 2 patients with IL-10 deficiency and 1 patient with IL-10R α chain deficiency and proved to be an effective therapy, leading to rapid improvement of clinical symptoms and quality of life. Conclusion Because the defect in patients with IL-10/IL-10R deficiency resides in hematopoietic lineage cells and their colitis is resistant to standard immunosuppressive therapy, HSCT should be considered early as a potentially curative therapeutic option.
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