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Red Cell Biology & its Disorders
Exposure to non-inherited maternal antigens by breastfeeding affects antibody responsiveness
Ferrata Storti Foundation
Haematologica 2018 Volume 104(2):263-268
Henk Schonewille,1,2 Jon J. van Rood,3† Esther P. Verduin,1,2,3
Leo M.G. van de Watering,1,2 Geert W. Haasnoot,3 Frans H.J. Claas,3 Dick Oepkes,4 Enrico Lopriore5 and Anneke Brand1,3
1Center for Clinical Transfusion Research, Sanquin Research, Leiden; 2Jon J van Rood Center for Clinical Transfusion Research, Sanquin-Leiden University Medical Center, Amsterdam; 3Department of Immunohematology and Blood Transfusion, Leiden University Medical Center; 4Division of Fetal Medicine, Department of Obstetrics, Leiden University Medical Center; 5Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, the Netherlands
ABSTRACT
The observation, by Ray Owen and colleagues in 1954, that D-neg- ative women were less likely to form anti-D antibodies against their D-positive fetus if their mother possessed the D-antigen, was not found in all later studies. We hypothesized that breastfeeding, received by the mother, may affect her immunity against non-inherited maternal red blood cell antigens. We studied a cohort of 125 grandmoth- er-mother-child combinations, from a follow-up study of mothers after intrauterine transfusion of the fetus for alloimmune hemolytic disease. For mismatched red blood cell antigens the mother was exposed to, whether or not antibodies were formed, we determined whether her mother, the grandmother, carried these antigens. The duration for which the mothers were breastfed was estimated by way of a questionnaire. Using multivariate logistic regression analyses, the interaction term (non- inherited maternal antigen exposure by categorized breastfeeding peri- od) showed that a longer breastfeeding period was associated with decreased alloimmunization against non-inherited maternal antigens (adjusted odds ratio 0.66; 95% confidence interval 0.48-0.93). Sensitivity analysis with dichotomized (shorter versus longer) breastfeeding periods showed that this lower risk was reached after two months (aOR 0.22; 95% CI 0.07-0.71) and longer duration of breastfeeding did not seem to provide additional protection. These data suggest that oral neonatal exposure to non-inherited maternal red blood cell antigens through breastfeeding for at least two months diminishes the risk of alloimmu- nization against these antigens when encountered later in life.
Introduction
In utero, all humans are exposed to non-inherited maternal antigens (NIMAs), however only pregnant women encounter inherited paternal antigens (IPAs). NIMAs and IPAs can involve the same antigens (Figure 1). Maternal antibodies against IPAs expressed on red blood cells (RBC) such as Rh and K antigens, can cause severe hemolytic disease of the fetus and newborn (HDFN).
In 1954, Owen and colleagues found that D-negative mothers were less likely to form anti-D against a D-positive fetus if they had previously been exposed to the D blood group as a NIMA, a phenomenon referred to as the “grandmother effect”.1 These findings seemed in accordance with the concept of neonatal tolerance in mice, published a year earlier by Billingham and collegues.2 However, subsequent investigations did not confirm the grandmother theory.3-5 Some studies even report- ed that a D-negative child may develop anti-D against the D NIMA.6,7 As a result, the grandmother concept was almost forgotten.
Decades later, in 1988, Claas and colleagues observed that hyper-immunized dial- ysis patients awaiting renal allograft, formed antibodies against non-inherited
Correspondence:
h.schonewille@sanquin.nl
Received: June 14, 2018.
Accepted: September 11, 2018. Pre-published: September 27, 2018.
doi:10.3324/haematol.2018.199406
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/2/263
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