The role of sex and the microbiome in production of 'natural antibodies: impact on ABO antibodies in a mouse model

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Background: ABO histo-blood group incompatibility is a barrier in solid organ transplant due to ‘natural’ preformed ABO antibodies (West et al., 2001). The ABH glycan microarray, a novel technique developed in the West lab (Jeyakanthan et al., 2016), was used to determine the isotype (IgM/IgG) and ABH subtype specificity (subtypes I-VI) of natural ABO antibodies in a mouse model (Motyka et al., 2016). We previously found that BALB/c (BALB) mice produce anti-A antibodies that are specific to subtypes III/IV A-antigens whereas antibodies specific to subtype II A-antigens were low/absent (Anjum et al., 2020). Females had significantly higher levels of anti-A antibodies compared to males; moreover, females, but not males, showed a distinct shift in anti-A antibody production from IgM to IgG isotype at about the age of sexual maturity (6-9 weeks). It has been hypothesized that natural ABO antibodies develop due to cross-reactivity with components of the gut microbiome (Springer & Horton, 1969). To test this hypothesis, we examined serum ABO antibody levels in germ-free and conventionally-housed male and female mice of different ages. Methods: Germ-free mice and conventionally-housed mice included the inbred strains C57BL/6 (B6) (females/males, n=10 /10) and BALB (females/males, n=10/10), and the outbred strain Swiss Webster (SW) (females/males, n=4/6). Plasma obtained from tail bleeds at different ages was assessed by ABH glycan microarray for ABO antibodies, including subtype specificity and antibody isotype. Results: Anti-A and anti-B antibodies were present in germ-free B6, BALB and SW mice at levels similar to that of conventional mice. At 4-weeks of age, IgG (but not IgM) anti-A antibodies were detected in male and female mice at levels similar to that of older (12 weeks) female mice. Anti-A antibodies were present in male mice >8-weeks of age, however these were at low levels vs female mice and remained mostly IgM. In female mice, anti-A antibodies were mostly IgG isotype at 4-weeks of age, predominately IgM isotype at 8-weeks of age, and then shifted to mostly IgG isotype by 12-weeks of age. Anti-B antibodies were detected in both sexes by 8-weeks of age, remained mostly IgM, and were present at lower levels vs anti-A antibodies. Most natural anti-A antibodies, in germ-free or conventionally-housed mice, were specific to subtypes III/IV whereas antibodies specific to subtype II antigens were low/absent. Conclusion: The distinct IgM to IgG anti-A antibody class-switching in female mice at about the time of sexual maturity (8 weeks) may provide early immunity to pups through passive transfer of IgG anti-A antibody during pregnancy. Detection of natural anti-A antibodies in germ-free mice combined with higher levels of natural anti-A antibody in females vs males suggests a unique sex-dependent, alternative mechanism of natural ABO antibody production than cross-reactivity with gut microbiome antigens.

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