Abstract
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.
Highlights
In persistent infections that are accompanied by chronic immune activation, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), and malaria, there is constant polyclonal proliferation of antigen-specific B cells
We analyzed the proportions of the following cells: atypical MBC (aaMBC) (CD3−CD14−CD16 −CD19+CD10−IgD−CD21−CD27−); resting atypical MBC (raMBC) (CD3−CD14−CD16 −CD19+CD10−IgD−CD21+CD27−); active classical MBC (acMBC) (CD3−CD14−CD1 6−CD19+CD10−IgD−CD21−CD27+); resting classical MBC (rcMBC) (CD3−CD14−CD 16−CD19+CD10−IgD−CD21+CD27+); PCGC (CD3−CD14−CD 16−CD19+CD10−IgD−CD38high); naïve (CD3−CD14−CD16−CD 19+CD10−IgD+CD21+CD27−); active naïve (CD3−CD14−CD16 −CD19+CD10−IgD+CD21−CD27−); marginal zone (MZ)-like B cells (CD3−CD1 4−CD16−CD19+CD10−IgD+CD21+CD27+IgM+); and immature B cells (CD3−CD14−CD16−CD19+CD10+)
Malaria exposure is associated with an increase of aaMBC and a decrease of MZ-like B cell frequencies in peripheral blood, as reported in HIV [51, 58] and previous malaria [20, 26] studies
Summary
In persistent infections that are accompanied by chronic immune activation, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), and malaria, there is constant polyclonal proliferation of antigen-specific B cells. Studies of HIV- and HCV-infected individuals suggested that this CD27− MBC subset may be prone to anergy and/or apoptosis, because they expressed PD1, FcRL4, FcRL5, and CD95 and had a reduced capacity to proliferate [17, 19, 22] This phenotype gave rise to the denomination of these cells as “exhausted.” A phenotypically similar subset called “atypical MBC” (aMBC) has been associated with malaria exposure [3, 18, 23,24,25,26,27,28]. Chronic immune activation affects circulating IgM+CD19+CD27+ MBC, which frequency is greatly reduced in HIV [22] and malaria [18, 26, 29] This B cell subset is similar to marginal zone (MZ)-like B cells, found mainly in secondary lymphoid organs [30] and to a lesser extent in peripheral blood. We hypothesized that expansion of aMBC with a tolerogenic-like phenotype and reduction of activated peripheral MZ-like B cells in constantly exposed individuals may be a complementary mechanism to downregulate continuously activated B cells while simultaneously maintaining B cell functions, helping to establish tolerance to the infection [15, 17]
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