title: TLRs innate immunereceptors and Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) CIDR1α-driven human polyclonal B-cell activation.
abstract: Chronic malaria severely affects the immune system and causes polyclonal B-cell activation, as evidenced by the presence of hypergammaglobulinemia, elevated levels of autoantibodies, loss of B-cell memory and the frequent occurrence of Burkitt's lymphomas (BL) in children living in malaria endemic areas. Previous studies have shown that the cysteine-rich interdomain region 1α (CIDR1α) of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) of the FCR3S1.2 strain, subsequently named CIDR1α, interacts with B cells partially through the binding to the B-cell receptor (BCR). This interaction leads to an activated phenotype, increased survival, and a low degree of proliferation. CIDR1α preferentially activates the memory B-cell compartment, therefore PfEMP1 is considered to act as a polyclonal B-cell activator and its role in memory maintenance has been suggested. In this report, we extend the analysis of the PfEMP1-CIDR1α B-cell interaction and demonstrate that PfEMP1-CIDR1α increases the expression of TLR7 and TLR10 mRNA transcripts and sensitizes B cells to TLR9 signalling via the MyD88 adaptor molecule. Furthermore, despite its ability to bind to surface Igs, PfEMP1-CIDR1α-induced B-cell activation does not seem to proceed through the BCR, since it does not induce Lyn and/or phospho-tyrosine mediated signalling pathways. Rather PfEMP1-CIDR1α induces the phosphorylation of downstream kinases, such as ERK1/2, p38 and IKBα, in human B cells. These findings indicate that PfEMP1-CIDR1α induces a persistent activation of B cells, which in turn can contribute to the exhaustion and impairment of B-cell functions during chronic malaria infection.
authors.affiliation: Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari Medical School, Policlinico of Bari, Italy. olivia.simone@intmed.uniba.it
authors.forename: Olivia
authors.initials: O
authors.lastname: Simone
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bejarano
authors.forename: Susan K
authors.initials: SK
authors.lastname: Pierce
authors.forename: Salvatore
authors.initials: S
authors.lastname: Antonaci
authors.forename: Mats
authors.initials: M
authors.lastname: Wahlgren
authors.forename: Marita
authors.initials: M
authors.lastname: Troye-Blomberg
authors.forename: Daria
authors.initials: D
authors.lastname: Donati
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology* / Q000469:parasitology; D006801:Humans; D008213:Lymphocyte Activation; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010963:Plasmodium falciparum / Q000276:immunology / Q000472:pathogenicity*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000276:immunology / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D051201:Toll-Like Receptor 10 / Q000096:biosynthesis; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D053594:Myeloid Differentiation Factor 88; D015800:Protozoan Proteins; D011947:Receptors, Antigen, B-Cell; D051201:Toll-Like Receptor 10; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C085731:erythrocyte membrane protein 1, Plasmodium falciparum