CD28 deficiency leads to accumulation of germinal-center independent IgM+ experienced B cells and to production of protective IgM during experimental malaria

Abstract

Protective immunity to blood-stage malaria is attributed to Plasmodium-specific IgG and effector-memory T helper 1 (Th1) cells. However, mice lacking the costimulatory receptor CD28 (CD28KO) maintain chronic parasitemia at low levels and do not succumb to infection, suggesting that other immune responses contribute to parasite control. We report here that CD28KO mice develop long-lasting non-sterile immunity and survive lethal parasite challenge. This protection correlated with a progressive increase of anti-parasite IgM serum levels during chronic infection. Serum IgM from chronically infected CD28KO mice recognize erythrocytes infected with mature parasites, and effectively control Plasmodium infection by promoting parasite lysis and uptake. These antibodies also recognize autoantigens and antigens from other pathogens. Chronically infected CD28KO mice have high numbers of IgM+ plasmocytes and experienced B cells, exhibiting a germinal-center independent Fas+GL7-CD38+CD73- phenotype. These cells are also present in chronically infected C57BL/6 mice although in lower numbers. Finally, IgM+ experienced B cells from cured C57BL/6 and CD28KO mice proliferate and produce anti-parasite IgM in response to infected erythrocytes. This study demonstrates that CD28 deficiency results in the generation of germinal-center independent IgM+ experienced B cells and the production of protective IgM during experimental malaria, providing evidence for an additional mechanism by which the immune system controls Plasmodium infection.

Dynamics of IgM and IgG responses to the next generation of engineered Duffy binding protein II immunogen: Strain-specific and strain-transcending immune responses over a nine-year period

“…Although the majority of high IgM responses (RI> 3) were no longer detected in the low transmission period, the results suggest that individuals in P. vivax-endemic Amazonian communities were able to sustain their DBPII-specific IgM antibody responses. These results may explain recent findings showing that IgM-expressing memory B cells are expanded in malaria patients living in endemic areas [27], and confirm data from other studies, which suggest that IgM antibodies may play an underappreciated role in immune response against malaria infections [29][30][31]. Although scant longitudinal data are available about secondary IgM responses in P. vivax-exposed populations, a recent prospective study undertaken in a low transmission area of Western India demonstrated that P. vivax alters peripheral B-cell profiles and induces https://doi.org/10.1371/journal.pone.0232786.g003…”

“…Here, we demonstrated that long-term P. vivax exposure to low and unstable levels of malaria transmission can lead to a sustained DBPII-specific IgM response. At this time, it is not possible to define if this persistent DBPII-related IgM response could indicate that IgM-experienced B cells needs to be constantly activated or if this response is rather associated with a bona-fide memory [29,46]. Of relevance, P. falciparum-specific IgM antibodies were detected for more than 6 months in Australians returning from malaria endemic areas [31].…”

“…A recent study in a murine model of malaria demonstrated that Plasmodiumspecific IgM memory B cells are somatically hypermutated, high-affinity, and dominate the early memory response to recurring malaria infections [27]. Likewise, the production of protective IgM antibodies during experimental malaria provides evidence of additional mechanisms by which the immune system controls Plasmodium infection [28,29]. These results might explain recent data associating the depth and breadth of Plasmodium-specific IgM antibodies with genetic resistance to malaria infection [30], and with the reduced risk of clinical malaria in a cohort of children [31].…”

B cell intrinsic expression of IFNλ receptor suppresses the acute humoral immune response to experimental blood-stage malaria

“…To test this hypothesis, we measured antibody titers against a truncated carboxy terminus of the blood-stage antigen merozoite surface protein (MSP1) shown to be critical for infection by ELISA [ 24 ]. We decided to measure specifically the IgG 2 c because the IgG2 c antibody appears early in plasma and can confer protection in murine models of blood-stage malaria [ 58 – 60 ]. Furthermore, we decided to measure acute antibody titers immediately prior to divergence of parasite burden between Ifnlr1 −/- mice and littermate controls, given that variations in inoculum and ongoing inflammation can have dramatic effects on antibody titers during infection with malaria [ 24 ] and other pathogens [ 61 – 63 ].…”

PIK3IP1 Promotes Extrafollicular Class Switching in T-Dependent Immune Responses

“…These lower affinity memory cells likely allow for a secondary response to a broad range of pathogen variants, whereas germinal center-derived high affinity memory cells are more tailored toward responding to reinfection with the original challenge (4,6,7,78). Early IgM memory cells are known to be important in several mouse models of infectious disease, including infection with Ehrlichia muris, a tick-borne intracellular bacteria (79,80), and malaria (81,82). Mice with specific defects in extrafollicular responses, such as those lacking PIK3IP1 in B cells described in this study, may serve as a useful model to study these diseases.…”