5 research outputs found
Chronic Exposure to Malaria Is Associated with Inhibitory and Activation Markers on Atypical Memory B Cells and Marginal Zone-Like B Cells
In persistent infections that are accompanied by chronic immune activation, such as human immunodeficiency virus, hepatitis C virus, and malaria, there is an increased frequency of a phenotypically distinct subset of memory B cells lacking the classic memory marker CD27 and showing a reduced capacity to produce antibodies. However, critical knowledge gaps remain on specific B cell changes and immune adaptation in chronic infections. We hypothesized that expansion of atypical memory B cells (aMBCs) and reduction of activated peripheral marginal zone (MZ)-like B cells in constantly exposed individuals might be accompanied by phenotypic changes that would confer a tolerogenic profile, helping to establish tolerance to infections. To better understand malaria-associated phenotypic abnormalities on B cells, we analyzed peripheral blood mononuclear cells from 55 pregnant women living in a malaria-endemic area of Papua Nueva Guinea and 9 Spanish malaria-naïve individuals using four 11-color flow cytometry panels. We assessed the expression of markers of B cell specificity (IgG and IgM), activation (CD40, CD80, CD86, b220, TACI, and CD150), inhibition (PD1, CD95, and CD71), and migration (CCR3, CXCR3, and CD62l). We found higher frequencies of active and resting aMBC and marked reduction of MZ-like B cells, although changes in absolute cell counts could not be assessed. Highly exposed women had higher PD1+-, CD95+-, CD40+-, CD71+-, and CD80+-activated aMBC frequencies than non-exposed subjects. Malaria exposure increased frequencies of b220 and proapoptotic markers PD1 and CD95, and decreased expression of the activation marker TACI on MZ-like B cells. The increased frequencies of inhibitory and apoptotic markers on activated aMBCs and MZ-like B cells in malaria-exposed adults suggest an immune-homeostatic mechanism for maintaining B cell development and function while simultaneously downregulating hyperreactive B cells. This mechanism would keep the B cell activation threshold high enough to control infection but impaired enough to tolerate it, preventing systemic inflammation
Naturally Acquired Binding-Inhibitory Antibodies to Plasmodium vivax Duffy Binding Protein in Pregnant Women Are Associated with Higher Birth Weight in a Multicenter Study
A vaccine to eliminate malaria would need a multi-stage and
multi-species composition to achieve robust protection, but the
lack of knowledge about antigen targets and mechanisms of
protection precludes the development of fully efficacious
malaria vaccines, especially for Plasmodium vivax (Pv). Pregnant
women constitute a risk population who would greatly benefit
from a vaccine preventing the adverse events of Plasmodium
infection during gestation. We hypothesized that functional
immune responses against putative targets of naturally acquired
immunity to malaria and vaccine candidates will be associated
with protection against malaria infection and/or poor outcomes
during pregnancy. We measured (i) IgG responses to a large panel
of Pv and Plasmodium falciparum (Pf) antigens, (ii) the capacity
of anti-Pv ligand Duffy binding protein (PvDBP) antibodies to
inhibit binding to Duffy antigen, and (iii) cellular immune
responses to two Pv antigens, in a subset of 1,056 pregnant
women from Brazil, Colombia, Guatemala, India, and Papua New
Guinea (PNG). There were significant intraspecies and
interspecies correlations for most antibody responses (e.g.,
PfMSP119 versus PfAMA1, Spearman's rho = 0.81). Women from PNG
and Colombia had the highest levels of IgG overall.
Submicroscopic infections seemed sufficient to boost antibody
responses in Guatemala but not antigen-specific cellular
responses in PNG. Brazil had the highest percentage of Duffy
binding inhibition (p-values versus Colombia: 0.040; Guatemala:
0.047; India: 0.003, and PNG: 0.153) despite having low
anti-PvDBP IgG levels. Almost all antibodies had a positive
association with present infection, and coinfection with the
other species increased this association. Anti-PvDBP,
anti-PfMSP1, and anti-PfAMA1 IgG levels at recruitment were
positively associated with infection at delivery (p-values:
0.010, 0.003, and 0.023, respectively), suggesting that they are
markers of malaria exposure. Peripheral blood mononuclear cells
from Pv-infected women presented fewer CD8+IFN-gamma+ T cells
and secreted more G-CSF and IL-4 independently of the stimulus
used in vitro. Functional anti-PvDBP levels at recruitment had a
positive association with birth weight (difference per doubling
antibody levels: 45 g, p-value: 0.046). Thus, naturally acquired
binding-inhibitory antibodies to PvDBP might confer protection
against poor outcomes of Pv malaria in pregnancy
Chronic Exposure to Malaria Is Associated with Inhibitory and Activation Markers on Atypical Memory B Cells and Marginal Zone-Like B Cells
In persistent infections that are accompanied by chronic immune activation, such as human immunodeficiency virus, hepatitis C virus, and malaria, there is an increased frequency of a phenotypically distinct subset of memory B cells lacking the classic memory marker CD27 and showing a reduced capacity to produce antibodies. However, critical knowledge gaps remain on specific B cell changes and immune adaptation in chronic infections. We hypothesized that expansion of atypical memory B cells (aMBCs) and reduction of activated peripheral marginal zone (MZ)-like B cells in constantly exposed individuals might be accompanied by phenotypic changes that would confer a tolerogenic profile, helping to establish tolerance to infections. To better understand malaria-associated phenotypic abnormalities on B cells, we analyzed peripheral blood mononuclear cells from 55 pregnant women living in a malaria-endemic area of Papua Nueva Guinea and 9 Spanish malaria-naïve individuals using four 11-color flow cytometry panels. We assessed the expression of markers of B cell specificity (IgG and IgM), activation (CD40, CD80, CD86, b220, TACI, and CD150), inhibition (PD1, CD95, and CD71), and migration (CCR3, CXCR3, and CD62l). We found higher frequencies of active and resting aMBC and marked reduction of MZ-like B cells, although changes in absolute cell counts could not be assessed. Highly exposed women had higher PD1+-, CD95+-, CD40+-, CD71+-, and CD80+-activated aMBC frequencies than non-exposed subjects. Malaria exposure increased frequencies of b220 and proapoptotic markers PD1 and CD95, and decreased expression of the activation marker TACI on MZ-like B cells. The increased frequencies of inhibitory and apoptotic markers on activated aMBCs and MZ-like B cells in malaria-exposed adults suggest an immune-homeostatic mechanism for maintaining B cell development and function while simultaneously downregulating hyperreactive B cells. This mechanism would keep the B cell activation threshold high enough to control infection but impaired enough to tolerate it, preventing systemic inflammation
Pregnancy and Malaria Exposure Are Associated with Changes in the B Cell Pool and in Plasma Eotaxin Levels
Naturally Acquired Binding-Inhibitory Antibodies to Plasmodium vivax Duffy Binding Protein in Pregnant Women Are Associated with Higher Birth Weight in a Multicenter Study
A vaccine to eliminate malaria would need a multi-stage and
multi-species composition to achieve robust protection, but the
lack of knowledge about antigen targets and mechanisms of
protection precludes the development of fully efficacious
malaria vaccines, especially for Plasmodium vivax (Pv). Pregnant
women constitute a risk population who would greatly benefit
from a vaccine preventing the adverse events of Plasmodium
infection during gestation. We hypothesized that functional
immune responses against putative targets of naturally acquired
immunity to malaria and vaccine candidates will be associated
with protection against malaria infection and/or poor outcomes
during pregnancy. We measured (i) IgG responses to a large panel
of Pv and Plasmodium falciparum (Pf) antigens, (ii) the capacity
of anti-Pv ligand Duffy binding protein (PvDBP) antibodies to
inhibit binding to Duffy antigen, and (iii) cellular immune
responses to two Pv antigens, in a subset of 1,056 pregnant
women from Brazil, Colombia, Guatemala, India, and Papua New
Guinea (PNG). There were significant intraspecies and
interspecies correlations for most antibody responses (e.g.,
PfMSP119 versus PfAMA1, Spearman's rho = 0.81). Women from PNG
and Colombia had the highest levels of IgG overall.
Submicroscopic infections seemed sufficient to boost antibody
responses in Guatemala but not antigen-specific cellular
responses in PNG. Brazil had the highest percentage of Duffy
binding inhibition (p-values versus Colombia: 0.040; Guatemala:
0.047; India: 0.003, and PNG: 0.153) despite having low
anti-PvDBP IgG levels. Almost all antibodies had a positive
association with present infection, and coinfection with the
other species increased this association. Anti-PvDBP,
anti-PfMSP1, and anti-PfAMA1 IgG levels at recruitment were
positively associated with infection at delivery (p-values:
0.010, 0.003, and 0.023, respectively), suggesting that they are
markers of malaria exposure. Peripheral blood mononuclear cells
from Pv-infected women presented fewer CD8+IFN-gamma+ T cells
and secreted more G-CSF and IL-4 independently of the stimulus
used in vitro. Functional anti-PvDBP levels at recruitment had a
positive association with birth weight (difference per doubling
antibody levels: 45 g, p-value: 0.046). Thus, naturally acquired
binding-inhibitory antibodies to PvDBP might confer protection
against poor outcomes of Pv malaria in pregnancy