Summary
Mast cells and basophils play a pathogenetic role in allergic, inflammatory, and autoimmune disorders. These cells have different development, anatomical location and life span but share many ...similarities in mechanisms of activation and type of mediators. Mediators secreted by mast cells and basophils correlate with clinical severity in asthma, chronic urticaria, anaphylaxis, and other diseases. Therefore, effective biomarkers to measure mast cell and basophil activation in vivo could potentially have high diagnostic and prognostic values. An ideal biomarker should be specific for mast cells or basophils, easily and reproducibly detectable in blood or biological fluids and should be metabolically stable. Markers of mast cell and basophil include molecules secreted by stimulated cells and surface molecules expressed upon activation. Some markers, such as histamine and lipid mediators are common to mast cells and basophils whereas others, such as tryptase and other proteases, are relatively specific for mast cells. The best surface markers of activation expressed on mast cells and basophils are CD63 and CD203. While these mediators and surface molecules have been associated to a variety of diseases, none of them fulfills requirements for an optimal biomarker and search for better indicators of mast cell/basophil activation in vivo is ongoing.
Mast cells and basophils are associated with T helper 2 (Th2) immune responses. Newly developed mast cell-deficient mice have provided evidence that mast cells initiate contact hypersensitivity via ...activating dendritic cells. Studies using basophil-deficient mice have also revealed that basophils are responsible for cutaneous Th2 skewing to haptens and peptide antigens but not to protein antigens. Recently, several studies reported the existence of innate lymphoid cells (ILCs), which differ from classic T cells in that they lack the T cell receptor. Mast cells and basophils can interact with ILCs and play some roles in the pathogenesis of Th2 responses. Basophil-derived interleukin (IL)-4 enhances the expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in ILC2s, leading to the accumulation of eosinophils in allergic reactions. IL-33-stimulated mast cells can play a regulatory role in the development of ILC2-mediated non-antigen-specific protease-induced acute inflammation. In this review, we discuss the recent advances in our understanding of mast cells and basophils in immunity and inflammation.
Atopic dermatitis (AD) is a common and chronic inflammatory skin disease of type 2 immunity. Keratinocyte-derived cytokines, including thymic stromal lymphopoietin (TSLP) and IL-33, are considered to ...induce the development of AD. Production of prostanoids, a family of lipid mediators, is increased in AD lesions. However, their physiologic functions remain to be clarified.
We sought to elucidate the functions of prostanoids in the development of AD.
The roles of prostanoids were investigated in a mouse model of AD induced by repeated application of hapten and PAM212, a keratinocyte cell line.
Application of indomethacin, which blocks prostanoid synthesis, leads to enhanced TSLP and IL-33 production in the skin, increased serum IgE levels, and exacerbation of skin inflammation in this AD model. The skin inflammation was attenuated in TSLP receptor–deficient mice but not in IL-33–deficient mice, and the indomethacin-enhanced type 2 immune responses were abolished in TSLP receptor–deficient mice. Indomethacin increased protease-activated receptor 2–mediated TSLP production in keratinocytes in vitro, and prostaglandin E2 reversed the increase in TSLP levels through its receptor, the prostaglandin E2 receptor (EP2), by downregulating surface expression of protease-activated receptor 2. Administration of an EP2 agonist canceled indomethacin-enhanced TSLP production and type 2 immune responses in the skin, whereas an EP2 antagonist caused an enhancement of TSLP production and type 2 immune responses in the skin.
Prostaglandin E2–EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.
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•Immune-related AEs (irAEs) correlate with changes in routine blood count parameter.•WBC count and relative lymphocyte count correlate with severe irAEs.•Similarly, those parameters also correlate ...with lung or gastrointestinal irAEs.•Routine blood test may be easy and cost-effective method to detect irAEs.
Although nivolumab significantly prolongs survival of metastatic melanoma, about 10% of patients experience severe, even fatal immune-related adverse events (irAEs). Biomarkers to predict irAEs are, therefore, of great interest.
We aimed to correlate changes in routine blood count parameters to the occurrence of serious irAEs (grade 3/4 G3/4 or lung/gastrointestinal lung/GI irAEs) in patients with melanoma who were treated with nivolumab.
We retrospectively analyzed data from 101 patient with melanoma treated with nivolumab from 8 institutes in Japan. We used logistic regression analyses to investigate associations between severe irAEs and fluctuations in routine blood count parameters (total white blood cell WBC count, relative neutrophil, monocyte, lymphocyte, and eosinophil count) during the treatment. Receiver-operating characteristic curve was used to determine a cutoff value for the blood count parameters and area under the curve (AUC).
Univariate analysis revealed that G3/4 irAEs were associated with increased total WBC count (P=0.034, cutoff value=+27%, AUC=0.68, odds ratio OR=1.58) and decreased relative lymphocyte count (RLC, P=0.042, cutoff value=−23%, AUC=0.65, OR=1.65). However, multivariate analysis showed that the same factors, increased WBC count (P=0.014, cutoff value=+59.1%, AUC=0.79, OR=6.04) and decreased RLC (P=0.012, cutoff value=−32.3%, AUC=0.81, OR=5.01) were independent factors associated with lung/GI irAEs.
Our results suggest that increased WBC count and decreased RLC are associated with G3/4 and lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence was noticed and, therefore, these factors are not predictive, however, they could be a “signal” of severe irAE occurrence in patients with melanoma treated with nivolumab.
Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence ...cutaneous acquired immune responses remain to be clarified.
This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses.
We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS.
CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP in vitro.
These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.
Background
The objective of this study was to identify predictive markers, including inflammatory and nutritional status measures, of early progressive disease (EPD) in unresectable melanoma patients ...treated with nivolumab.
Methods
A retrospective review was performed on 39 consecutive patients with unresectable melanoma treated with nivolumab. EPD was defined as progressive disease within 60 days after starting nivolumab according to Response Evaluation Criteria in Solid Tumors version 1.1. The predictive index model melanoma inflammation index (MII) was determined by the number of predictive factors.
Results
Seventeen patients had cutaneous melanoma and 22 patients had mucosal melanoma. The overall response rate was 18.4%, and the response rates for cutaneous and mucosal melanoma were 29.4% and 9.5%, respectively. EPD was observed in 13 patients (34.2%). By multivariate analysis, body mass index (BMI) and C-reactive protein to albumin ratio (CAR) were independently and significantly associated with EPD, disease control rate, progression-free survival, and overall survival. Low BMI (cutoff 20) and high CAR (cutoff 0.0055) were predictive factors of EPD and were determined to be prognostic factors. MII, from 0 to 2, was determined by the number of these factors. The incidence of EPD was 0% in the low-risk group (MII = 0), 50% in the intermediate-risk group (MII = 1), and 83% in the high-risk group (MII = 2).
Conclusions
An MII status of low BMI and high CAR may be used to predict EPD in unresectable melanoma patients treated with nivolumab.
Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great ...interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4
+
T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8
+
T cells, and serum cytokine levels (IFNγ, IL-4, IL-9, IL-10, TGF-β) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-β compared to non-responders. Th9 induction by IL-4 and TGF-β was enhanced by PD-1/PD-L1 blockade in vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8
+
T cells was enhanced in the presence of IL-9 in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.
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