Maternal Filarial Infection Influences the Development of Regulatory T Cells in Children from Infancy to Early Childhood

Abstract

BackgroundChildren born from filarial infected mothers are comparatively more susceptible to filarial infection than the children born to uninfected mothers. But the mechanism of such increased susceptibility to infection in early childhood is not exactly known. Several studies have shown the association of active filarial infection with T cell hypo-responsiveness which is mediated by regulatory T cells (Tregs). Since the Tregs develop in the thymus from CD4+ CD25hi thymocytes at an early stage of the human fetus, it can be hypothesized that the maternal infection during pregnancy affects the development of Tregs in children at birth as well as early childhood. Hence the present study was designed to test the hypothesis by selecting a cohort of pregnant mothers and children born to them subsequently in a filarial endemic area of Odisha, India.Methodology and Principal findingA total number of 49 pregnant mothers and children born to them subsequently have been followed up (mean duration 4.4 years) in an area where the microfilariae (Mf) rate has come down to <1% after institution of 10 rounds of annual mass drug administration (MDA). The infection status of mother, cord and children were assessed through detection of microfilariae (Mf) and circulating filarial antigen (CFA). Expression of Tregs cells were measured by flow cytometry. The levels of IL-10 were evaluated by using commercially available ELISA kit. A significantly high level of IL-10 and Tregs have been observed in children born to infected mother compared to children of uninfected mother at the time of birth as well as during early childhood. Moreover a positive correlation between Tregs and IL-10 has been observed among the children born to infected mother.SignificanceFrom these observations we predict that early priming of the fetal immune system by filarial antigens modulate the development of Tregs, which ultimately scale up the production of IL-10 in neonates and creates a milieu for high rate of acquisition of infection in children born to infected mothers. The mechanism of susceptibility and implication of the results in global elimination programme of filariasis has been discussed.

Filarial infection during pregnancy has profound consequences on immune response and disease outcome in children: A birth cohort study

“…During the present study the high level of filaria-specific IgG4 in children born from infected mothers as well as cord blood as shown in our previous study exhibits that in utero priming to filarial antigens can induce non-complement-fixing immunoglobulin (IgG4) which unable to activate any of the protective immune mechanisms that involve complement as well as antibody dependent cell-mediated cytotoxicity [ 8 , 12 ]. Further role of regulatory T cells in modulation of human immune response and induction of IgG4 production in helminthic infection that promotes parasite tolerance highlights its importance in immunity to infectious agents [ 13 ].High expression of T-reg cells in children and cord blood of infected mother as evident in our earlier study[ 7 ] and elevated level of IgG4 in infected children born to infected mother in the present study reveals that increasing susceptibility to infection might be due to in utero modification of foetal immune responses towards the production immunoregulatory antibody (IgG4) that helps for survival of the parasite. In addition absence of clinical symptoms in infected children during follow up might be because of high plasma concentration of IgG4 as evident by others in asymptomatic filarial infection.…”

“…bancrofti ). Detailed information on the methodology and design of the cohort for enrollment of the participants is provided elsewhere [ 7 ]. The study subjects were children born to pregnant mothers who were admitted in O&G Department of Khurda District Headquarter Hospital for delivery from July 2009–July 2011.The enrolled children were born full-term, healthy with all baseline information and whose mothers had agreed to continue participation during follow up were included in the study.…”

“…It appears that trans-placental trafficking of filarial antigens from mother to foetus occurs on a frequent basis [ 6 ].Studies have shown that high level of T-regulatory (T-reg) cells at the time of birth and early childhood in children born to infected mother emphasizes that maternal filarial infection influences the development of T-reg cells from infancy to early childhood [ 7 ]. Since T- reg cells can induce immunomodulatory cytokine IL-10 that often implicated in induction of immunoregulatory antibody IgG4 and we have observed an increased level of IL-10 / IgG4 and decreased levels of IFN- γ/ IgG3 in cord blood of infected mother [ 7 , 8 ] indicating an initiation of modulation of immune responses in the placenta due to in utero priming. Further results of an earlier study has shown that children sensitized to parasite antigens in utero produce Th2-dependent specific IgG4 and IgE antibodies at a young age [ 9 ].…”

Expression and quantity dynamics of CK5+-immunopositive thymic epithelial cells of the subcapsular zone in rats of the early postnatal period after prenatal introduction of staphylococcal anatoxin.

“…В основі порушення формування і дозрівання імунної системи плода лежить її пригнічення внаслідок надмірної антигенної стимуляції та іншими чужорідними агентами, які надходять від матері, що супроводжується надходженням великої кількості імунологічно незрілих лімфоцитів на периферію і викликає зміни в органогенезі різної тривалості та може бути основою для розвитку патології в дорослому віці [3,9]. Існує думка, що неонатальна захворюваність є продовженням внутрішньоутробного запального процесу, який отримав назву синдром запальної відповіді плода (СЗВП).…”

Local and global asymptotic behavior of malaria-filariasis coinfections in compliant and noncompliant susceptible pregnant women to antenatal medical program in the tropics

“…In 2014, Nigeria launches Africa's first nationwide malaria and lymphatic filariasis elimination coimplementation plan to protect the citizens from this dreaded disease [5,7]. In this paper, our focus is on analyzing the dynamics of the spread of coinfectious malaria -filariasis disease among susceptible pregnant women in Nigeria, who are compliant or noncompliant to antenatal medical program to access treatment and care to reduce cases of maternal and foetal mortality [4,6,9]. The works of [10 − 12, 14 − 22, 24] have proved very useful in the understanding of coinfection dynamics of the spread of diseases.…”