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CRH is a stimulator for mucosal-type mast cell degranulation and proliferation
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Abstracts / Journal of Dermatological Science 84 (2016) e89–e180
neutralizing antibodies or by crossing IL-1␣ and IL-1 double knockout mice. IL-1s are major inflammatory mediators in AD and psoriasis. Here, we propose a concept of IL-1 mediated inflammatory skin march modified from the diagram of psoriasis march by Boehncke. In psoriasis march, higher levels of IL-1s are connected to the presence of atherosclerosis. Interestingly, the sclerotic changes of the arteries in this mouse lack the atheroma plaques. The concept of IL-1 mediated inflammatory skin march warns presence of the risk of cardio and cerebrovascular events in severe inflammatory skin diseases as well as psoriasis, and proposes the potential of anti-IL-1s therapies to various skin and systemic inflammatory diseases. http://dx.doi.org/10.1016/j.jdermsci.2016.08.289 P01-21[C04-04] Decreased levels of regulatory B cells in patients with systemic sclerosis: Association with autoantibody production and disease activity Takashi Matsushita 1,∗ , Yasuhito Hamaguchi 1 , Minoru Hasegawa 2 , Manabu Fujimoto 3 , Kazuhiko Takehara 1 1 Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan 2 Department of Dermatology, University of Fukui, Japan 3 Department of Dermatology, Faculty of Medicine, University of Tsukuba, Japan
Objective: B cell abnormalities characterized by autoantibody production and polyclonal B cell activation play an important role in the pathogenesis of systemic sclerosis (SSc). IL-10 producing regulatory B (Breg) cells play an important role in the negative immune response. Recently, we identified a human Breg cell subset and it was predominantly found within the CD24hi CD27+ B cell subpopulation. However, the role of Breg cells in SSc remains unknown. In this study, we investigated the clinical association of Breg cells in SSc patients. Methods: Blood IL-10 producing Breg cell levels were determined by FACS in 35 SSc patients and 30 healthy subjects. In a follow-up study, we analyzed 6 individual dcSSc patients before and after treatment. Results: The frequency of blood Breg cells was significantly lower in SSc patients than in healthy controls (p < 0.0001). Similarly, the frequency of CD24hi CD27+ B cells was significantly lower in SSc patients with than in healthy controls (p < 0.0001). SSc patients with decreased Breg cell levels more frequently had interstitial lung disease (p < 0.05). Furthermore, Breg cell levels correlated negatively with the titer of anti-topoisomerase I Ab and anticentromere Ab in SSc patients. For a follow-up study, Breg cell levels in dcSSc patients after treatment were found to be significantly increased comparing with that before treatment (p < 0.05), accompanied with decreased disease activity. Thus, Breg cell levels inversely correlated with disease activity of SSc. Conclusion: These results suggest that decreased Breg cell levels may contribute to the development of SSc. http://dx.doi.org/10.1016/j.jdermsci.2016.08.290
P01-22[C04-05] CRH is a stimulator for mucosal-type mast cell degranulation and proliferation Yukari Mizukami 1,∗ , Koji Sugawara 1 , Ralf Paus 2 , Daisuke Tsuruta 1 1
Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan 2 Centre for Dermatology, Institute of Inflammation and Repair, University of Manchester, Manchester, UK Corticotropin releasing hormone (CRH) plays a crucial role as a central stress mediator in the hypothalamic-pituitary-adrenal axis. CRH receptors (CRHR) have recently been identified in peripheral tissues including the skin and hair follicle (HF), and reported as important regulators in the peripheral tissue response to perceived stress. Mast cells (MCs) are crucial cells in the development of various types of skin diseases, allergy and can also control the hair cycle. MCs also play central roles in CRH mediated stress responses. We have previously shown that connective tissue type (CT)-MC of human HFs expressed CRHR, and CRH treatment with organ cultured human HFs stimulated CT-MC degranulation and promoted maturation but not proliferation. Activated CT-MC maturation was partially mediated by the increased expression of stem cell factor (SCF) within the HF epithelium. Here we investigated whether CRH can affect mucosal type (M)-MC biology by using human nasal polyp organ culture. As a result, we found that Kit or typtase positive human M-MCs express CRHR. CRH treatment (10−7 M, 24 h) significantly increased tryptase + M-MC number and induced degranulation. This was partially abrogated by the coadministration of SCF neutralizing antibody. CRH also increased SCF expression within the epithelium of nasal polyps. In contrast to CT-MC, CRH significantly increased typtase + M-MC proliferarion. Furthermore, the effect of CRH on M-MCs degranulation and number were partially abrogated by CRHR gene knockdown. These results indicate that CRH induces both cutaneous and mucosal type neuroinflammation by promoting MC activity and increasing the number. Our results indicate that the control of SCF or CRHR signaling might be a novel future target for stress-related disorders. http://dx.doi.org/10.1016/j.jdermsci.2016.08.291 P01-23[C04-02] Characterization of the population like follicular helper T cells in the peripheral blood in patients with pemphigus Jun Yamagami ∗ , Aki Kamata, Masayuki Amagai Department of Dermatology, Keio University School of Medicine, Tokyo, Japan Pemphigus is an autoimmune disease characterized by mucous and cutaneous blisters caused by IgG autoantibodies against desmogleins (Dsgs). The mechanism of production of anti-Dsg autoantibodies in pemphigus has not been elucidated. Recent studies have shown that T cell help to B cells is fundamental in antibody production and the interrelated and multifaceted processes of B cell affinity maturation, class switch recombination, plasma cell differentiation, and memory B cell differentiation predominantly occur within germinal centers (GCs) through T–B interactions. Follicular helper CD4T cells (Tfhs) are necessary to maintain GCs and considered as specialized providers of B cell help. Tfhs are basically located near GCs, and we aimed to establish Tfh-like population in the peripheral blood that is supposed to have an important role
Abstracts / Journal of Dermatological Science 84 (2016) e89–e180
neutralizing antibodies or by crossing IL-1␣ and IL-1 double knockout mice. IL-1s are major inflammatory mediators in AD and psoriasis. Here, we propose a concept of IL-1 mediated inflammatory skin march modified from the diagram of psoriasis march by Boehncke. In psoriasis march, higher levels of IL-1s are connected to the presence of atherosclerosis. Interestingly, the sclerotic changes of the arteries in this mouse lack the atheroma plaques. The concept of IL-1 mediated inflammatory skin march warns presence of the risk of cardio and cerebrovascular events in severe inflammatory skin diseases as well as psoriasis, and proposes the potential of anti-IL-1s therapies to various skin and systemic inflammatory diseases. http://dx.doi.org/10.1016/j.jdermsci.2016.08.289 P01-21[C04-04] Decreased levels of regulatory B cells in patients with systemic sclerosis: Association with autoantibody production and disease activity Takashi Matsushita 1,∗ , Yasuhito Hamaguchi 1 , Minoru Hasegawa 2 , Manabu Fujimoto 3 , Kazuhiko Takehara 1 1 Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan 2 Department of Dermatology, University of Fukui, Japan 3 Department of Dermatology, Faculty of Medicine, University of Tsukuba, Japan
Objective: B cell abnormalities characterized by autoantibody production and polyclonal B cell activation play an important role in the pathogenesis of systemic sclerosis (SSc). IL-10 producing regulatory B (Breg) cells play an important role in the negative immune response. Recently, we identified a human Breg cell subset and it was predominantly found within the CD24hi CD27+ B cell subpopulation. However, the role of Breg cells in SSc remains unknown. In this study, we investigated the clinical association of Breg cells in SSc patients. Methods: Blood IL-10 producing Breg cell levels were determined by FACS in 35 SSc patients and 30 healthy subjects. In a follow-up study, we analyzed 6 individual dcSSc patients before and after treatment. Results: The frequency of blood Breg cells was significantly lower in SSc patients than in healthy controls (p < 0.0001). Similarly, the frequency of CD24hi CD27+ B cells was significantly lower in SSc patients with than in healthy controls (p < 0.0001). SSc patients with decreased Breg cell levels more frequently had interstitial lung disease (p < 0.05). Furthermore, Breg cell levels correlated negatively with the titer of anti-topoisomerase I Ab and anticentromere Ab in SSc patients. For a follow-up study, Breg cell levels in dcSSc patients after treatment were found to be significantly increased comparing with that before treatment (p < 0.05), accompanied with decreased disease activity. Thus, Breg cell levels inversely correlated with disease activity of SSc. Conclusion: These results suggest that decreased Breg cell levels may contribute to the development of SSc. http://dx.doi.org/10.1016/j.jdermsci.2016.08.290
P01-22[C04-05] CRH is a stimulator for mucosal-type mast cell degranulation and proliferation Yukari Mizukami 1,∗ , Koji Sugawara 1 , Ralf Paus 2 , Daisuke Tsuruta 1 1
Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan 2 Centre for Dermatology, Institute of Inflammation and Repair, University of Manchester, Manchester, UK Corticotropin releasing hormone (CRH) plays a crucial role as a central stress mediator in the hypothalamic-pituitary-adrenal axis. CRH receptors (CRHR) have recently been identified in peripheral tissues including the skin and hair follicle (HF), and reported as important regulators in the peripheral tissue response to perceived stress. Mast cells (MCs) are crucial cells in the development of various types of skin diseases, allergy and can also control the hair cycle. MCs also play central roles in CRH mediated stress responses. We have previously shown that connective tissue type (CT)-MC of human HFs expressed CRHR, and CRH treatment with organ cultured human HFs stimulated CT-MC degranulation and promoted maturation but not proliferation. Activated CT-MC maturation was partially mediated by the increased expression of stem cell factor (SCF) within the HF epithelium. Here we investigated whether CRH can affect mucosal type (M)-MC biology by using human nasal polyp organ culture. As a result, we found that Kit or typtase positive human M-MCs express CRHR. CRH treatment (10−7 M, 24 h) significantly increased tryptase + M-MC number and induced degranulation. This was partially abrogated by the coadministration of SCF neutralizing antibody. CRH also increased SCF expression within the epithelium of nasal polyps. In contrast to CT-MC, CRH significantly increased typtase + M-MC proliferarion. Furthermore, the effect of CRH on M-MCs degranulation and number were partially abrogated by CRHR gene knockdown. These results indicate that CRH induces both cutaneous and mucosal type neuroinflammation by promoting MC activity and increasing the number. Our results indicate that the control of SCF or CRHR signaling might be a novel future target for stress-related disorders. http://dx.doi.org/10.1016/j.jdermsci.2016.08.291 P01-23[C04-02] Characterization of the population like follicular helper T cells in the peripheral blood in patients with pemphigus Jun Yamagami ∗ , Aki Kamata, Masayuki Amagai Department of Dermatology, Keio University School of Medicine, Tokyo, Japan Pemphigus is an autoimmune disease characterized by mucous and cutaneous blisters caused by IgG autoantibodies against desmogleins (Dsgs). The mechanism of production of anti-Dsg autoantibodies in pemphigus has not been elucidated. Recent studies have shown that T cell help to B cells is fundamental in antibody production and the interrelated and multifaceted processes of B cell affinity maturation, class switch recombination, plasma cell differentiation, and memory B cell differentiation predominantly occur within germinal centers (GCs) through T–B interactions. Follicular helper CD4T cells (Tfhs) are necessary to maintain GCs and considered as specialized providers of B cell help. Tfhs are basically located near GCs, and we aimed to establish Tfh-like population in the peripheral blood that is supposed to have an important role