Maternal schistosomiasis impairs offspring Interleukin-4 production and B cell expansion

Abstract

Epidemiological studies have identified a correlation between maternal helminth infections and reduced immunity to some early childhood vaccinations, but the cellular basis for this is poorly understood. Here, we investigated the effects of maternal Schistosoma mansoni infection on steady-state offspring immunity, as well as immunity induced by a commercial tetanus/diphtheria vaccine using a dual IL-4 reporter mouse model of maternal schistosomiasis. We demonstrate that offspring born to S. mansoni infected mothers have reduced circulating plasma cells and peripheral lymph node follicular dendritic cells at steady state. These reductions correlate with reduced production of IL-4 by iNKT cells, the cellular source of IL-4 in the peripheral lymph node during early life. These defects in follicular dendritic cells and IL-4 production were maintained long-term with reduced secretion of IL-4 in the germinal center and reduced generation of TFH, memory B, and memory T cells in response to immunization with tetanus/diphtheria. Using single-cell RNASeq following tetanus/diphtheria immunization of offspring, we identified a defect in cell-cycle and cell-proliferation pathways in addition to a reduction in Ebf-1, a key B-cell transcription factor, in the majority of follicular B cells. These reductions are dependent on the presence of egg antigens in the mother, as offspring born to single-sex infected mothers do not have these transcriptional defects. These data indicate that maternal schistosomiasis leads to long-term defects in antigen-induced cellular immunity, and for the first time provide key mechanistic insight into the factors regulating reduced immunity in offspring born to S. mansoni infected mothers.

The Road to Elimination: Current State of Schistosomiasis Research and Progress Towards the End Game

“…Using a dual IL-4 reporter mouse model, the group by Cortés-Selva et al., demonstrated that babies born to schistosome infected mothers had reduced circulating plasma cells and peripheral lymph node follicular dendritic cells that correlated with long term reduction in production of IL-4 by iNKT cells. Using single-cell RNAseq after vaccination with tetanus and diphtheria, they identified defects in cell cycle, cell proliferation pathways and reduction of Ebf-1 (a key B-cell transcription factor) in majority of follicular B cells that signify long-term defects in antigen-induced cellular immunity ( 301 ). Presence of helminth infections further contribute to low prevalence of allergic diseases in endemic areas.…”

Altered Offspring Immunity in Maternal Parasitic Infections

“…Although a specific mechanism has not been attributed to these changes, a recent study has found that there is a decrease in H4 acetylation at the IL-4 loci in murine pups born to schistosome-infected dams (73), implying that at least in the mouse model, there are long-lived epigenetic changes that can alter offspring immunity. It has also been shown that murine pups from chronically infected mothers have an impaired humoral immune response, including lower frequency and impaired proliferation of B cells linked to transcriptional changes in key cell cycle and B cell identity genes such as EBF1 and the JUN/JUNB pathways, leading to lower vaccine-induced humoral immunity (74). Taken together, these data suggest that similar to maternal filariasis, offspring immunomodulation induced by maternal schistosomiasis may last long into childhood, a possibility bolstered by recent work that demonstrated that anti-measles Abs remain suppressed at 2 y of age in children born to Schistosoma mansoniinfected mothers (18).…”

Praziquantel Reduces Maternal Mortality and Offspring Morbidity by Enhancing Anti-Helminthic Immune Responses

“…One potential driver of this phenomenon is in utero exposure to circulating schistosome antigens during maternal infection, which could influence the developing immune system of children, and modify anti-schistosome immunity. Immunomodulatory effects of schistosome infection are well-described in the context of bystander immune responses ( 1 , 2 ), as are modulated immune responses following exposure to maternal infection ( 3 – 5 ), increased levels of schistosome adult-worm specific IgE and IgG in newborns cord blood whose mothers were infected during pregnancy (and not treated) ( 6 ). Schistosome antigens can drive immunomodulatory changes via presence in breastmilk ( 7 ), and have been detected as persisting in human children and murine offspring following exposure to maternal infection ( 8 , 9 ).…”

“…Schistosome antigens can drive immunomodulatory changes via presence in breastmilk ( 7 ), and have been detected as persisting in human children and murine offspring following exposure to maternal infection ( 8 , 9 ). Murine models demonstrate that exposure to maternal infection with schistosomes consistently modifies immune development, with recent findings included impact upon B cell priming and DC-T cell interactions ( 5 ), as well as NKT cells ( 3 ).…”