RESUMO
Antibodies can protect from Plasmodium falciparum (Pf) infection and clinical malaria disease. However, in the absence of constant reexposure, serum immunoglobulin (Ig) levels rapidly decline and full protection from clinical symptoms is lost, suggesting that B cell memory is functionally impaired. We show at the single cell level that natural Pf infection induces the development of classical memory B cells (CM) and atypical memory B cells (AtM) that produce broadly neutralizing antibodies against blood stage Pf parasites. CM and AtM contribute to anti-Pf serum IgG production, but only AtM show signs of active antibody secretion. AtM and CM were also different in their IgG gene repertoire, suggesting that they develop from different precursors. The findings provide direct evidence that natural Pf infection leads to the development of protective memory B cell antibody responses and suggest that constant immune activation rather than impaired memory function leads to the accumulation of AtM in malaria. Understanding the memory B cell response to natural Pf infection may be key to the development of a malaria vaccine that induces long-lived protection.
Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antiprotozoários/biossíntese , Subpopulações de Linfócitos B/imunologia , Plasmodium falciparum/imunologia , Adulto , Sequência de Aminoácidos , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/genética , Anticorpos Neutralizantes/genética , Anticorpos Antiprotozoários/genética , Antígenos de Protozoários/imunologia , Eritrócitos/imunologia , Eritrócitos/parasitologia , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/genética , Região Variável de Imunoglobulina , Memória Imunológica , Vacinas Antimaláricas/imunologia , Malária Falciparum/sangue , Malária Falciparum/genética , Malária Falciparum/imunologia , Pessoa de Meia-Idade , Dados de Sequência Molecular , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/imunologia , Adulto JovemRESUMO
DNA double-strand breaks (DSBs) are byproducts of normal cellular metabolism and obligate intermediates in antigen receptor diversification reactions. These lesions are potentially dangerous because they can lead to deletion of genetic material or chromosome translocation. The chromatin-binding protein 53BP1 and the histone variant H2AX are required for efficient class switch (CSR) and V(D)J recombination in part because they protect DNA ends from resection and thereby favor nonhomologous end joining (NHEJ). Here, we examine the mechanism of DNA end resection in primary B cells. We find that resection depends on both CtBP-interacting protein (CtIP, Rbbp8) and exonuclease 1 (Exo1). Inhibition of CtIP partially rescues the CSR defect in 53BP1- and H2AX-deficient lymphocytes, as does interference with the RecQ helicases Bloom (Blm) and Werner (Wrn). We conclude that CtIP, Exo1, and RecQ helicases contribute to the metabolism of DNA ends during DSB repair in B lymphocytes and that minimizing resection favors efficient CSR.
