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Impact of Histone H1 on the Progression of Allergic Rhinitis and Its Suppression by Neutralizing Antibody in Mice.

Nakano T, Kamei R, Fujimura T, Takaoka Y, Hori A, Lai CY, Chiang KC, Shimada Y, Ohmori N, Goto T, Ono K, Chen CL, Goto S, Kawamoto S - PLoS ONE (2016)

Bottom Line: In the course of a bona-fide experimental allergen sensitization model upon co-injection with alum adjuvant, ovalbumin (OVA), but not PBS, induced elevated levels of circulating histone H1.A monoclonal antibody against histone H1 not only suppressed mast cell degranulation, but also ameliorated OVA-induced nasal hyperreactivity and IgE-mediated passive cutaneous anaphylaxis.Our present data suggest that nuclear histone H1 represents an alarmin-like endogenous mediator acting on mast cells, and that its blockage has a therapeutic potential for mast cell-mediated type I hyperreactivity.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

ABSTRACT
Nuclear antigens are known to trigger off innate and adaptive immune responses. Recent studies have found that the complex of nucleic acids and core histones that are derived from damaged cells may regulate allergic responses. However, no fundamental study has been performed concerning the role of linker histone H1 in mast cell-mediated type I hyperreactivity. In this study, we explored the impact of histone H1 on mast cell-mediated allergic responses both in vitro and in vivo. In the course of a bona-fide experimental allergen sensitization model upon co-injection with alum adjuvant, ovalbumin (OVA), but not PBS, induced elevated levels of circulating histone H1. Intranasal challenge with histone H1 to OVA/alum- (but not PBS/alum)-sensitized mice induced significantly severer symptoms of allergic rhinitis than those in mice sensitized and challenged with OVA. A monoclonal antibody against histone H1 not only suppressed mast cell degranulation, but also ameliorated OVA-induced nasal hyperreactivity and IgE-mediated passive cutaneous anaphylaxis. Our present data suggest that nuclear histone H1 represents an alarmin-like endogenous mediator acting on mast cells, and that its blockage has a therapeutic potential for mast cell-mediated type I hyperreactivity.

No MeSH data available.


Related in: MedlinePlus

Histone H1-mediated mast cell degranulation.(A) Exogenous histone H1 dose-dependently induced degranulation of IgE-sensitized rat basophilic leukemia cell line RBL-2H3 without cross-linking between anti-DNP-IgE and antigen (Ag: DNP-BSA). Degranulation was evaluated by β-hexosaminidase release rate. Values are presented as the mean ± S.D. from three independent experiments. A23187 (10 μM) was used as a positive control for degranulation. **, P < 0.01 versus IgE only (0 μg/ml of histone H1). (B) Exogenous histone H1 enhanced DNP-BSA-induced degranulation of RBL-2H3 cells in a dose-dependent manner. **, P < 0.01 versus (IgE + Ag: 0 μg/ml of histone H1). (C) Histone H1-targeted SSV mAb ameliorated DNP-BSA-induced degranulation of RBL-2H3 cells in a dose-dependent manner. **, P < 0.01 versus (IgE + Ag: 0 μg/ml of SSV mAb) or (IgE + Ag: 100 μg/ml of isotype IgG1). (D) The extracellular secretion of endogenous histone H1 by DNP-BSA (0.1 and 0.5 μg/ml) in BMMCs. Western blot data are representative of three independent experiments. Calf thymus histone H1 was loaded as a positive control.
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pone.0153630.g003: Histone H1-mediated mast cell degranulation.(A) Exogenous histone H1 dose-dependently induced degranulation of IgE-sensitized rat basophilic leukemia cell line RBL-2H3 without cross-linking between anti-DNP-IgE and antigen (Ag: DNP-BSA). Degranulation was evaluated by β-hexosaminidase release rate. Values are presented as the mean ± S.D. from three independent experiments. A23187 (10 μM) was used as a positive control for degranulation. **, P < 0.01 versus IgE only (0 μg/ml of histone H1). (B) Exogenous histone H1 enhanced DNP-BSA-induced degranulation of RBL-2H3 cells in a dose-dependent manner. **, P < 0.01 versus (IgE + Ag: 0 μg/ml of histone H1). (C) Histone H1-targeted SSV mAb ameliorated DNP-BSA-induced degranulation of RBL-2H3 cells in a dose-dependent manner. **, P < 0.01 versus (IgE + Ag: 0 μg/ml of SSV mAb) or (IgE + Ag: 100 μg/ml of isotype IgG1). (D) The extracellular secretion of endogenous histone H1 by DNP-BSA (0.1 and 0.5 μg/ml) in BMMCs. Western blot data are representative of three independent experiments. Calf thymus histone H1 was loaded as a positive control.

Mentions: To demonstrate the pathophysiological roles of histone H1 on mast cell-mediated allergic responses in vitro, rat basophilic leukemia cell line RBL-2H3 were sensitized with anti-DNP IgE and then stimulated with calf thymus histone H1 (25, 50 and 100 μg/ml) in the absence of DNP-BSA. As shown in Fig 3A, exogenous histone H1 significantly induced the degranulation without cross-linking in a dose-dependent manner. Furthermore, histone H1 enhanced DNP-BSA-induced degranulation in a dose-dependent manner (Fig 3B). To further explore the role of histone H1 and therapeutic potential of histone H1-targeted SSV mAb on degranulation, rat RBL-2H3 were sensitized with anti-DNP IgE and then treated with SSV mAb (25, 50 and 100 μg/ml) or isotype IgG1 (100 μg/ml) under stimulation with DNP-BSA. Similar data were also obtained by using BMMCs (data not shown). As shown in Fig 3C, DNP-BSA-induced degranulation was significantly suppressed by SSV mAb. The extracellular secretion of endogenous histone H1 by DNP-BSA in BMMCs suggested the autocrine/paracrine effects of histone H1 in the course of degranulation (Fig 3D).


Impact of Histone H1 on the Progression of Allergic Rhinitis and Its Suppression by Neutralizing Antibody in Mice.

Nakano T, Kamei R, Fujimura T, Takaoka Y, Hori A, Lai CY, Chiang KC, Shimada Y, Ohmori N, Goto T, Ono K, Chen CL, Goto S, Kawamoto S - PLoS ONE (2016)

Histone H1-mediated mast cell degranulation.(A) Exogenous histone H1 dose-dependently induced degranulation of IgE-sensitized rat basophilic leukemia cell line RBL-2H3 without cross-linking between anti-DNP-IgE and antigen (Ag: DNP-BSA). Degranulation was evaluated by β-hexosaminidase release rate. Values are presented as the mean ± S.D. from three independent experiments. A23187 (10 μM) was used as a positive control for degranulation. **, P < 0.01 versus IgE only (0 μg/ml of histone H1). (B) Exogenous histone H1 enhanced DNP-BSA-induced degranulation of RBL-2H3 cells in a dose-dependent manner. **, P < 0.01 versus (IgE + Ag: 0 μg/ml of histone H1). (C) Histone H1-targeted SSV mAb ameliorated DNP-BSA-induced degranulation of RBL-2H3 cells in a dose-dependent manner. **, P < 0.01 versus (IgE + Ag: 0 μg/ml of SSV mAb) or (IgE + Ag: 100 μg/ml of isotype IgG1). (D) The extracellular secretion of endogenous histone H1 by DNP-BSA (0.1 and 0.5 μg/ml) in BMMCs. Western blot data are representative of three independent experiments. Calf thymus histone H1 was loaded as a positive control.
© Copyright Policy
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4835108&req=5

pone.0153630.g003: Histone H1-mediated mast cell degranulation.(A) Exogenous histone H1 dose-dependently induced degranulation of IgE-sensitized rat basophilic leukemia cell line RBL-2H3 without cross-linking between anti-DNP-IgE and antigen (Ag: DNP-BSA). Degranulation was evaluated by β-hexosaminidase release rate. Values are presented as the mean ± S.D. from three independent experiments. A23187 (10 μM) was used as a positive control for degranulation. **, P < 0.01 versus IgE only (0 μg/ml of histone H1). (B) Exogenous histone H1 enhanced DNP-BSA-induced degranulation of RBL-2H3 cells in a dose-dependent manner. **, P < 0.01 versus (IgE + Ag: 0 μg/ml of histone H1). (C) Histone H1-targeted SSV mAb ameliorated DNP-BSA-induced degranulation of RBL-2H3 cells in a dose-dependent manner. **, P < 0.01 versus (IgE + Ag: 0 μg/ml of SSV mAb) or (IgE + Ag: 100 μg/ml of isotype IgG1). (D) The extracellular secretion of endogenous histone H1 by DNP-BSA (0.1 and 0.5 μg/ml) in BMMCs. Western blot data are representative of three independent experiments. Calf thymus histone H1 was loaded as a positive control.
Mentions: To demonstrate the pathophysiological roles of histone H1 on mast cell-mediated allergic responses in vitro, rat basophilic leukemia cell line RBL-2H3 were sensitized with anti-DNP IgE and then stimulated with calf thymus histone H1 (25, 50 and 100 μg/ml) in the absence of DNP-BSA. As shown in Fig 3A, exogenous histone H1 significantly induced the degranulation without cross-linking in a dose-dependent manner. Furthermore, histone H1 enhanced DNP-BSA-induced degranulation in a dose-dependent manner (Fig 3B). To further explore the role of histone H1 and therapeutic potential of histone H1-targeted SSV mAb on degranulation, rat RBL-2H3 were sensitized with anti-DNP IgE and then treated with SSV mAb (25, 50 and 100 μg/ml) or isotype IgG1 (100 μg/ml) under stimulation with DNP-BSA. Similar data were also obtained by using BMMCs (data not shown). As shown in Fig 3C, DNP-BSA-induced degranulation was significantly suppressed by SSV mAb. The extracellular secretion of endogenous histone H1 by DNP-BSA in BMMCs suggested the autocrine/paracrine effects of histone H1 in the course of degranulation (Fig 3D).

Bottom Line: In the course of a bona-fide experimental allergen sensitization model upon co-injection with alum adjuvant, ovalbumin (OVA), but not PBS, induced elevated levels of circulating histone H1.A monoclonal antibody against histone H1 not only suppressed mast cell degranulation, but also ameliorated OVA-induced nasal hyperreactivity and IgE-mediated passive cutaneous anaphylaxis.Our present data suggest that nuclear histone H1 represents an alarmin-like endogenous mediator acting on mast cells, and that its blockage has a therapeutic potential for mast cell-mediated type I hyperreactivity.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

ABSTRACT
Nuclear antigens are known to trigger off innate and adaptive immune responses. Recent studies have found that the complex of nucleic acids and core histones that are derived from damaged cells may regulate allergic responses. However, no fundamental study has been performed concerning the role of linker histone H1 in mast cell-mediated type I hyperreactivity. In this study, we explored the impact of histone H1 on mast cell-mediated allergic responses both in vitro and in vivo. In the course of a bona-fide experimental allergen sensitization model upon co-injection with alum adjuvant, ovalbumin (OVA), but not PBS, induced elevated levels of circulating histone H1. Intranasal challenge with histone H1 to OVA/alum- (but not PBS/alum)-sensitized mice induced significantly severer symptoms of allergic rhinitis than those in mice sensitized and challenged with OVA. A monoclonal antibody against histone H1 not only suppressed mast cell degranulation, but also ameliorated OVA-induced nasal hyperreactivity and IgE-mediated passive cutaneous anaphylaxis. Our present data suggest that nuclear histone H1 represents an alarmin-like endogenous mediator acting on mast cells, and that its blockage has a therapeutic potential for mast cell-mediated type I hyperreactivity.

No MeSH data available.


Related in: MedlinePlus