SHIP-1 Is Critical in Regulation of Severe Anaphylaxis

Abstract

RationaleSHIP-1 regulates signaling pathways triggered by antigens and cytokines. SHIP-1 deficient mice develop a spontaneous allergic pulmonary inflammation but have impaired adaptive immune response to allergen stimulation. To determine the roles of SHIP-1 in regulation of anaphylaxis, we examined IgE-dependent passive (PSA) and OVA-induced active systemic anaphylactic (ASA) responses in mice lacking SHIP-1.MethodsSHIP-1-/- mice were compared with BALB/c wild type (WT) mice. For PSA, 24 h after passive immunization with 10 μg anti-DNP IgE, mice were challenged i.v. with 1 mg of DNP-HSA. For ASA, mice were immunized i.p. with 50 μg of OVA/Alum and challenged i.v. with 1 mg of OVA 1 week (ASA-1W) or 2 weeks (ASA-2W) later. The core body temperature and clinical symptoms were monitored and blood was collected for serum immunoglobulins.ResultsCompared to WT mice, SHIP-1-/- mice developed significantly enhanced IgE-dependent PSA as expected. In ASA-1W, however, SHIP-1-/- mice showed diminished ASA, possibly due to lower serum levels of OVA-specific IgE and IgG1. Strikingly, SHIP-1-/- mice in ASA-2W showed a high mortality rate (8 out of 9) compared to WT mice (0 out of 9). In SHIP-1-/- mice serum OVA-specific IgE was significantly lower, IgG1 was comparable, but IgG2a was significantly higher.ConclusionsThese studies demonstrate that SHIP-1 deficiency leads to enhanced PSA but diminished ASA due to decreased production of IgE and IgG1. However, SHIP-1 deficiency leads to fatal anaphylaxis even with low IgE and comparable IgG1, suggesting that SHIP-1 plays a critical role in regulating fatal anaphylaxis in IgE-dependent and IgE-independent pathways. RationaleSHIP-1 regulates signaling pathways triggered by antigens and cytokines. SHIP-1 deficient mice develop a spontaneous allergic pulmonary inflammation but have impaired adaptive immune response to allergen stimulation. To determine the roles of SHIP-1 in regulation of anaphylaxis, we examined IgE-dependent passive (PSA) and OVA-induced active systemic anaphylactic (ASA) responses in mice lacking SHIP-1. SHIP-1 regulates signaling pathways triggered by antigens and cytokines. SHIP-1 deficient mice develop a spontaneous allergic pulmonary inflammation but have impaired adaptive immune response to allergen stimulation. To determine the roles of SHIP-1 in regulation of anaphylaxis, we examined IgE-dependent passive (PSA) and OVA-induced active systemic anaphylactic (ASA) responses in mice lacking SHIP-1. MethodsSHIP-1-/- mice were compared with BALB/c wild type (WT) mice. For PSA, 24 h after passive immunization with 10 μg anti-DNP IgE, mice were challenged i.v. with 1 mg of DNP-HSA. For ASA, mice were immunized i.p. with 50 μg of OVA/Alum and challenged i.v. with 1 mg of OVA 1 week (ASA-1W) or 2 weeks (ASA-2W) later. The core body temperature and clinical symptoms were monitored and blood was collected for serum immunoglobulins. SHIP-1-/- mice were compared with BALB/c wild type (WT) mice. For PSA, 24 h after passive immunization with 10 μg anti-DNP IgE, mice were challenged i.v. with 1 mg of DNP-HSA. For ASA, mice were immunized i.p. with 50 μg of OVA/Alum and challenged i.v. with 1 mg of OVA 1 week (ASA-1W) or 2 weeks (ASA-2W) later. The core body temperature and clinical symptoms were monitored and blood was collected for serum immunoglobulins. ResultsCompared to WT mice, SHIP-1-/- mice developed significantly enhanced IgE-dependent PSA as expected. In ASA-1W, however, SHIP-1-/- mice showed diminished ASA, possibly due to lower serum levels of OVA-specific IgE and IgG1. Strikingly, SHIP-1-/- mice in ASA-2W showed a high mortality rate (8 out of 9) compared to WT mice (0 out of 9). In SHIP-1-/- mice serum OVA-specific IgE was significantly lower, IgG1 was comparable, but IgG2a was significantly higher. Compared to WT mice, SHIP-1-/- mice developed significantly enhanced IgE-dependent PSA as expected. In ASA-1W, however, SHIP-1-/- mice showed diminished ASA, possibly due to lower serum levels of OVA-specific IgE and IgG1. Strikingly, SHIP-1-/- mice in ASA-2W showed a high mortality rate (8 out of 9) compared to WT mice (0 out of 9). In SHIP-1-/- mice serum OVA-specific IgE was significantly lower, IgG1 was comparable, but IgG2a was significantly higher. ConclusionsThese studies demonstrate that SHIP-1 deficiency leads to enhanced PSA but diminished ASA due to decreased production of IgE and IgG1. However, SHIP-1 deficiency leads to fatal anaphylaxis even with low IgE and comparable IgG1, suggesting that SHIP-1 plays a critical role in regulating fatal anaphylaxis in IgE-dependent and IgE-independent pathways. These studies demonstrate that SHIP-1 deficiency leads to enhanced PSA but diminished ASA due to decreased production of IgE and IgG1. However, SHIP-1 deficiency leads to fatal anaphylaxis even with low IgE and comparable IgG1, suggesting that SHIP-1 plays a critical role in regulating fatal anaphylaxis in IgE-dependent and IgE-independent pathways.