Placental Malaria is Associated with Higher LILRB2 Expression in Monocyte Subsets and Lower Anti-Malarial IgG Antibodies During Infancy

Abstract

BackgroundPlacental malaria (PM) is associated with a higher susceptibility of infants to Plasmodium falciparum (Pf) malaria. A hypothesis of immune tolerance has been suggested but no clear explanation has been provided so far. Our goal was to investigate the involvement of inhibitory receptors LILRB1 and LILRB2, known to drive immune evasion upon ligation with pathogen and/or host ligands, in PM-induced immune tolerance.MethodInfants of women with or without PM were enrolled in Allada, southern Benin, and followed-up for 24 months. Antibodies with specificity for five blood stage parasite antigens were quantified by ELISA, and the frequency of immune cell subsets was quantified by flow cytometry. LILRB1 or LILRB2 expression was assessed on cells collected at 18 and 24 months of age.FindingsInfants born to women with PM had a higher risk of developing symptomatic malaria than those born to women without PM (IRR=1.53, p=0.040), and such infants displayed a lower frequency of non-classical monocytes (OR=0.74, p=0.01) that overexpressed LILRB2 (OR=1.36, p=0.002). Moreover, infants born to women with PM had lower levels of cytophilic IgG and higher levels of IL-10 during active infection.InterpretationModulation of IgG and IL-10 levels could impair monocyte functions (opsonisation/phagocytosis) in infants born to women with PM, possibly contributing to their higher susceptibility to malaria. The long-lasting effect of PM on infants’ monocytes was notable, raising questions about the capacity of ligands such as Rifins or HLA-I molecules to bind to LILRB1 and LILRB2 and to modulate immune responses, and about the reprogramming of neonatal monocytes/macrophages.

Extensive flow cytometric immunophenotyping of human PBMC incorporating detection of chemokine receptors, cytokines and tetramers

“…CX3CR1 confirmed the classification of these subsets and differential expression of LILRB receptors CD85d and CD85j could be visualized [22,23,[29][30][31]. Within the lymphocyte population, B cells with CD19 and CD20 expression profiles were detected and divided into classswitched, naive or memory B cells based on CD27 and IgD (Figure 3F).…”

“…While the number of monocytes is reduced as a result of overnight stimulation, this panel could distinguish the different monocyte subsets, classical, non‐classical and intermediate monocytes based on CD14 and CD16 expression (Figure 3E). Subsequent assessment of the expression of chemokine receptors CCR2 and CX3CR1 confirmed the classification of these subsets and differential expression of LILRB receptors CD85d and CD85j could be visualized [22, 23, 29–31]. Within the lymphocyte population, B cells with CD19 and CD20 expression profiles were detected and divided into class‐switched, naive or memory B cells based on CD27 and IgD (Figure 3F).…”

“…NKG2A is an inhibitory receptor expressed on NK cells, while NKG2C is an activation receptor within this lineage [18]. CD85d and CD85j are inhibitory receptors for HLA-molecules which can be expressed by both monocytes and B cells [28][29][30][31]. To address antigen-specific responses HLA-E/Mycobacterium tuberculosis-peptide tetramer was incorporated, while antigen-induced cytokine production was assessed by intracellular detection of IFN-γ and TNF-α.…”

A Non-Coding Fc Gamma Receptor Cis-Regulatory Variant within the 1q23 Gene Cluster Is Associated with Plasmodium falciparum Infection in Children Residing in Burkina Faso

“…While genome-wide association [3,4] and prospective transcriptomics studies [5,6] have explored host genetic susceptibility to control parasitemia and fever following Pf infection, research on the functional association is still needed. Monocytes and neutrophils play a crucial role in controlling parasite burden and protecting the host from malaria [7][8][9][10][11][12][13][14], and a low monocyte to neutrophil ratio has been associated with an increased risk of developing complicated malaria [15]. As demonstrated via passive transfer experiments with immunoglobulin G (IgG) in humans, antibodies drive immune responses that enable the control of the parasite via direct agglutination of the parasite or interaction with a wide variety of Fc-gamma receptors (FcγRs) expressed on immune cells [16].…”