IgE antibodies, FcεRIα, and IgE-mediated local anaphylaxis can limit snake venom toxicity

Abstract

Background: Type 2 cytokine-related immune responses associated with development of antigen-specific IgE antibodies can contribute to pathology in patients with allergic diseases and to fatal anaphylaxis. However, recent findings in mice indicate that IgE also can enhance defense against honeybee venom.

Objective: We tested whether IgE antibodies, IgE-dependent effector mechanisms, and a local anaphylactic reaction to an unrelated antigen can enhance defense against Russell viper venom (RVV) and determined whether such responses can be influenced by immunization protocol or mouse strain.

Methods: We compared the resistance of RVV-immunized wild-type, IgE-deficient, and Fcer1a-deficient mice after injection of a potentially lethal dose of RVV.

Results: A single prior exposure to RVV enhanced the ability of wild-type mice, but not mice lacking IgE or functional FcεRI, to survive challenge with a potentially lethal amount of RVV. Moreover, IgE-dependent local passive cutaneous anaphylaxis in response to challenge with an antigen not naturally present in RVV significantly enhanced resistance to the venom. Finally, we observed different effects on resistance to RVV or honeybee venom in BALB/c versus C57BL/6 mice that had received a second exposure to that venom before challenge with a high dose of that venom.

Conclusion: These observations illustrate the potential benefit of IgE-dependent effector mechanisms in acquired host defense against venoms. The extent to which type 2 immune responses against venoms can decrease pathology associated with envenomation seems to be influenced by the type of venom, the frequency of venom exposure, and the genetic background of the host.

Keywords: Acquired resistance; Daboia russelii; FcεRIα; IgE; Russell viper; allergy; honeybee; mast cells; toxin hypothesis; type 2 immunity; venom.

Fig 1

RVV can induce local MC degranulation, recruitment of innate inflammatory cells, and hypothermia. A,B, Toluidine Blue- (A) and Hematoxylin & Eosin- (B) stained back skin sections; A, Extent of MC degranulation (mean+SD). C,D, flow cytometry plots (C) and quantification (D) (mean+SD, from 3 mice, representative of 2 experiments) of CD45⁺ skin cells. E,F, temperature (E) and survival (F) after RVV injection. G,H, temperature (right panel magnifies the area in the dashed box) (G) and survival (H) of RVV-treated mice pretreated with anti-histamine and/or PAF-receptor antagonist. P values: Chi-Square test (A); Student's t test (D,E,G); Mantel-Cox test (H). Symbols in (E): comparison of group in that color with vehicle-treated mice for that time point. E-H, data pooled from 2-3 experiments.

Fig 2

MCs can contribute to innate resistance and behavioral responses to RVV. A, Experimental outline. B and E, body temperature; C and F, survival; D and G, scratching attempts, of MC-deficient Cpa3-Cre⁺; Mcl-1^fl/fl (B-D) and Kit^W-sh/W-sh (E-G) mice and corresponding control mice after RVV injection. P values: (B,D,E,G) Student's t test; (C,F) Mantel-Cox test. Data pooled from 2-4 experiments (n=5-21/group).

Fig 3

IgE can contribute to acquired resistance to RVV. A Outline of experiments with IgE-deficient (Igh-7^−/−) and control (Igh-7^+/+) C57BL/6 mice (B-E). B,C, Serum RVV-specific IgG₁ (B) and total IgE (C). D,E, Body temperature (D) and survival (E). F, Outline of serum transfer experiments in C57BL/6 mice (G-J). G,H, Serum RVV-specific IgG₁ (G) and total IgE (H). I,J, Body temperature (I) and survival (J). Data pooled from 3-4 experiments (n= 9-25/group). P values: Mann-Whitney test (B,C,G,H), Student's t test (D,I) and Mantel-Cox test (E,J).

Fig 4

FcεRIα and FcεRIα–bearing cells can contribute to acquired resistance to RVV. A, Outline of experiments with Fcer1a^−/− and control (Fcer1a^+/+) C57BL/6 mice (panels B-E). B,C, Serum RVV-specific IgG₁ (B) and total IgE (C). D,E, Body temperature (D) and survival (E). F, Outline of serum transfer experiments involving MC-deficient C57BL/6 mice (G,H). G,H, Body temperature (G) and survival (H). Data pooled from 3 experiments (n=9-17/group). P values: Mann-Whitney test (B,C); Student's t test (D,G); Mantel-Cox test (E,H).

Fig 5

IgE-dependent passive cutaneous anaphylaxis to an irrelevant antigen can increase resistance to a potentially lethal challenge with RVV. A, Experimental outline. B,C, Body temperature (B) and survival (C) of C57BL/6 mice treated with 3 s.c. injections of saline alone or containing 50 ng anti-DNP IgE, IgG₁ or IgG_2b antibody and challenged 18 h later with 2 s.c. injections, each containing 37.5 μg RVV and 0.5 μg DNP-HSA. Data pooled from 2-5 independent experiments (n=10-25/group). P values: Student's t test (B); Mantel-Cox test (C).

Fig 6

Influence of genetic background and immunization regimen on acquired resistance to RVV. A, Experimental outline. B-G, Serum RVV-specific IgG₁ (B,C); total IgE (D,E); and RVV-specific IgE (F,G). H,I, Body temperature. J,K, Survival. Data pooled from 3-4 experiments (n=11-16/group). P values: Mann-Whitney test (B-G), Student's t test (H,I) or Mantel-Cox test (J,K).

Fig 7

Influence of genetic background and immunization regimen on acquired resistance to BV. A, Experimental outline. B-G, Serum BV-specific IgG₁ (B,C); total IgE (D,E); and bvPLA₂-specific IgE (F,G). H-I, Body temperature. J-K, Survival. Data pooled from 3 experiments (n=9-11/group). P values: Mann-Whitney test (B-G); Student's t test (H,I); Mantel-Cox test (J,K).