Secretion of parasite‐specific immunoglobulin G by purified blood B lymphocytes from immune individuals after in vitro stimulation with recombinant Plasmodium falciparum merozoite surface protein‐119 antigen

Garraud, Olivier; Diouf, Ababacar; Holm, Inge; Nguer, Cheikh Momar; Spiegel, André; Perraut, Ronald; Longacre, Shirley

doi:10.1046/j.1365-2567.1999.00763.x

Cited by 15 publications

(26 citation statements)

References 31 publications

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“…Production of anti-P. falciparum Ab in vitro required T-cell-derived signals, such as IL-2 plus IL-10 (or IL-4), in agreement with studies of other systems (17,19,20,22). We have shown that B cells from donors exposed to malaria, but not B cells from donors who are not exposed to malaria, can be reactivated in vitro to secrete malaria-specific Abs and that for many individuals the pattern of in vitro Ab production mirrors the pattern of circulating Ab in the plasma.…”

Section: Discussionsupporting

confidence: 82%

“…Culture supernatants were recovered and tested for polyclonal or Ag-specific IgGs by ELISA as described previously (17,19,39). Polyclonal peroxidaseconjugated goat anti-human IgGs were obtained from Cappel-Organon Technika, (Turnhout, Belgium) and used at the following dilutions: total IgG, 1:6,000; IgG1, 1:2,000; IgG2, 1:10,000; IgG3, 1:10,000; and IgG4, 1:30,000.…”

Section: Methodsmentioning

confidence: 99%

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Regulation of Antigen-Specific Immunoglobulin G Subclasses in Response to Conserved and PolymorphicPlasmodium falciparumAntigens in an In Vitro Model

Garraud¹,

Perraut²,

Diouf³

et al. 2002

Infect Immun

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Cytophilic antibodies (Abs) play a critical role in protection against Plasmodium falciparum blood stages, yet little is known about the parameters regulating production of these Abs. We used an in vitro culture system to study the subclass distribution of antigen (Ag)-specific immunoglobulin G (IgG) produced by peripheral blood mononuclear cells (PBMCs) from individuals exposed to P. falciparum or unexposed individuals. PBMCs, cultivated with or without cytokines and exogenous CD40/CD40L signals, were stimulated with a crude parasite extract, recombinant vaccine candidates derived from conserved Ags (19-kDa C terminus of merozoite surface protein 1 [MSP1 19 ], R23, and PfEB200), or recombinant Ags derived from the polymorphic Ags MSP1 block 2 and MSP2. No P. falciparum-specific Ab production was detected in PBMCs from unexposed individuals. PBMCs from donors exposed frequently to P. falciparum infections produced multiple IgG subclasses when they were stimulated with the parasite extract but usually only one IgG subclass when they were stimulated with a recombinant Ag. Optimal Ab production required addition of interleukin-2 (IL-2) and IL-10 for all antigenic preparations. The IgG subclass distribution was both donor and Ag dependent and was only minimally influenced by the exogenous cytokine environment. In vitro IgG production and subclass distribution correlated with plasma Abs to some Ags (MSP1 19 , R23, and MSP2) but not others (PfEB200 and the three MSP1 block 2-derived Ags). Data presented here suggest that intrinsic properties of the protein Ag itself play a major role in determining the subclass of the Ab response, which has important implications for rational design of vaccine delivery.1 Passive transfer of hyperimmune immunoglobulin G (IgG) to malaria patients has shown that antibodies (Abs) play a key role in protection against Plasmodium falciparum blood stages (12,25,30). In vitro studies have indicated that efficient parasite destruction is achieved through interaction of Abs with monocytes. Binding of Abs to an infected red blood cell results in opsonization of the infected cell (24), and Ab-dependent cellular inhibition of parasite growth is triggered by the binding of an IgG-merozoite complex to monocytes (5, 6, 40). Both mechanisms have been reported to involve IgG1 and IgG3 but not IgG2, which is normally noncytophilic (4, 8, 23). The efficiency of Ab-dependent cellular inhibition of parasite growth depends on the relative proportion of parasite-specific IgG1 and IgG3 compared to IgG2 (4). The data indicate that the subclass distribution of IgG Abs reacting with merozoite surface antigens (Ags) is an important parameter for protection against P. falciparum blood stages. In order to develop efficient blood stage vaccines, we need to better understand anti-P. falciparum IgG subclass production and/or switching.Identification of the parasite and host factors affecting Ab production by B cells might indicate ways in which vaccineinduced immune responses can be directed to ensure terminal differe...

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Section: Discussionsupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Regulation of Antigen-Specific Immunoglobulin G Subclasses in Response to Conserved and PolymorphicPlasmodium falciparumAntigens in an In Vitro Model

Garraud¹,

Perraut²,

Diouf³

et al. 2002

Infect Immun

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“…The identification of P. falciparum-derived products and of the mechanisms responsible for B-cell activation has remained elu- sive though direct and indirect mechanisms mediated by T cells and accessory cells have been proposed to explain this phenomenon (9,12,16,19). Here we show that CIDR1␣ directly activates in vitro purified B cells from nonimmune donors and binds to various Ig fragments and to Igs from different species and, therefore, could be defined as a superantigen.…”

Section: Discussionmentioning

confidence: 76%

Identification of a Polyclonal B-Cell Activator inPlasmodium falciparum

et al. 2004

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Polyclonal B-cell activation and hypergammaglobulinemia are prominent features of human malaria. We report here that Plasmodium falciparum-infected erythrocytes directly adhere to and activate peripheral blood B cells from nonimmune donors. The infected erythrocytes employ the cysteine-rich interdomain region 1␣ (CIDR1␣) of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to interact with the B cells. Stimulation with recombinant CIDR1␣ induces proliferation, an increase in B-cell size, expression of activation molecules, and secretion of immunoglobulins (immunoglobulin M) and cytokines (tumor necrosis factor alpha and interleukin-6). Furthermore, CIDR1␣ binds to Fab and Fc fragments of human immunoglobulins and to immunoglobulins purified from the sera of different animal species. This binding pattern is similar to that of the polyclonal B-cell activator Staphylococcus aureus protein A. Our findings shed light on the understanding of the molecular basis of polyclonal B-cell activation during malaria infections. The results suggest that the var gene family encoding PfEMP1 has evolved not only to mediate the sequestration of infected erythrocytes but also to manipulate the immune system to enhance the survival of the parasite.Parasites that proliferate in restricted ecological niches such as Plasmodium spp. control the contact with their hosts in order to colonize, divide, and transmit themselves. Chronic infections with Plasmodium falciparum lead to a severely dysregulated immune system, and B cells are overactivated with the subsequent secretion of an array of different autoantibodies (2, 8), the presence of hyperglobulinemia (1), and the frequent occurrence of B-cell tumors (Burkitt's lymphoma) (17). B-cell activation has been reported in studies involving the stimulation of total peripheral lymphocytes with P. falciparum-derived products, and it has been suggested to be the result of direct and indirect mechanisms mediated by T lymphocytes and accessory cells (18,19). However, the identity of the antigens and mechanisms that lead to polyclonal activation in the course of malaria infection are currently unknown.It has previously been shown that a large proportion (83%) of fresh isolates of P. falciparum-infected erythrocytes (IE) bind nonimmune immunoglobulins (Igs) though to various degrees (25, 26). One of the domains of the P. falciparum erythrocyte membrane protein 1 (PfEMP1), the cysteine-rich interdomain region 1␣ (CIDR1␣) of FCR3S1.2 (amino acids 395 to 700), binds to CD36, PECAM-1/CD31, and nonimmune Igs (4, 5, 26). Microbial Ig binding proteins (IBPs) are produced by protozoa, viruses, parasites and both gram-positive and gramnegative bacteria (31) and play important physiological roles (20). It has been suggested that during an infectious process these IBPs may act as an evasion mechanism to divert specific antibody (Ab) responses (7, 21). The binding of CIDR1␣ to nonimmune Igs led us to investigate the interaction between human B cells and P. falciparum-IE and the involvement of CIDR1␣. The pre...

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“…mAbs to MSP-1 have been found to inhibit in vitro growth of parasites (33,34). Ab levels to MSP-1 19 correlate with age-related changes in the level of asexual parasitemia in some, but not all malaria endemic areas (35)(36)(37)(38)(39)(40)(41). Primate vaccine trials (42,43) and studies of mouse malaria models indicate that immunization with MSP-1 19 (44,45) protects against blood-stage infection.…”

Section: Discussionmentioning

confidence: 99%

Acquired Immune Responses to Plasmodium falciparum Merozoite Surface Protein-1 in the Human Fetus

King

Malhotra

Wamachi

et al. 2002

The Journal of Immunology

104

108

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Infants born in areas of stable malaria transmission are relatively protected against severe morbidity and high density Plasmodium falciparum blood-stage infection. This protection may involve prenatal sensitization and immunologic reactivity to malaria surface ligands that participate in invasion of red cells. We examined cord blood T and B cell immunity to P. falciparum merozoite surface protein-1 (MSP-1) in infants born in an area of stable malaria transmission in Kenya. T cell cytokine responses to the C-terminal 19-kDa fragment of MSP-1 (MSP-119) were detected in 24 of 92 (26%) newborns (4–192 IFN-γ and 3–88 IL-4-secreting cells per 106/cord blood lymphocytes). Peptide epitopes in the N-terminal block 3 region of MSP-1 also drove IFN-γ and/or IL-13 production. There was no evidence of prenatal T cell sensitization to liver-stage Ag-1. A total of 5 of 86 (6%) newborns had cord blood anti-MSP-119 IgM Abs, an Ig isotype that does not cross the placenta and is therefore of fetal origin. The frequency of neonatal B cell sensitization was higher than that indicated by serology alone, as 5 of 27 (18%) cord blood samples contained B cells that produced IgG when stimulated with MSP-119 in vitro. Neonatal B cell IgG responses were restricted to the Q-KNG allele of MSP-119, the major variant in this endemic area, whereas T cells responded to all four MSP-119 alleles evaluated. In utero sensitization to MSP-1 correlated with the presence of malaria parasites in cord blood (χ2 = 20, p < 0.0001). These data indicate that prenatal sensitization to blood-stage Ags occurs in infants born in malaria endemic areas.

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Secretion of parasite‐specific immunoglobulin G by purified blood B lymphocytes from immune individuals after in vitro stimulation with recombinant Plasmodium falciparum merozoite surface protein‐1₁₉ antigen

Cited by 15 publications

References 31 publications

Regulation of Antigen-Specific Immunoglobulin G Subclasses in Response to Conserved and PolymorphicPlasmodium falciparumAntigens in an In Vitro Model

Regulation of Antigen-Specific Immunoglobulin G Subclasses in Response to Conserved and PolymorphicPlasmodium falciparumAntigens in an In Vitro Model

Identification of a Polyclonal B-Cell Activator inPlasmodium falciparum

Acquired Immune Responses to Plasmodium falciparum Merozoite Surface Protein-1 in the Human Fetus

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