CD28 Deficiency Leads to Accumulation of Germinal-center Independent IgM+ Experienced B Cells and to Production of Protective IgM During Experimental Malaria

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2018 Aug 28

PMID 30148845

Citations 5

Authors

Henrique Borges da Silva

Erika Machado de Salles

Eliana Faquim Lima-Mauro

Luiz Roberto Sardinha

Jose Maria Alvarez

Maria Regina DImperio Lima

Affiliations

Soon will be listed here.

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.

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

Borges da Silva H, de Salles E, Faquim-Mauro E, Sardinha L, Alvarez J, DImperio Lima M PLoS One. 2019; 14(3):e0211506.

PMID: 30908488 PMC: 6433221. DOI: 10.1371/journal.pone.0211506.

References

Bendelac A, Bonneville M, Kearney J . Autoreactivity by design: innate B and T lymphocytes. Nat Rev Immunol. 2002; 1(3):177-86. DOI: 10.1038/35105052. View

Kubagawa H, Oka S, Kubagawa Y, Torii I, Takayama E, Kang D . Identity of the elusive IgM Fc receptor (FcmuR) in humans. J Exp Med. 2009; 206(12):2779-93. PMC: 2806608. DOI: 10.1084/jem.20091107. View

Harding F, McArthur J, Gross J, Raulet D, Allison J . CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992; 356(6370):607-9. DOI: 10.1038/356607a0. View

Muellenbeck M, Ueberheide B, Amulic B, Epp A, Fenyo D, Busse C . Atypical and classical memory B cells produce Plasmodium falciparum neutralizing antibodies. J Exp Med. 2013; 210(2):389-99. PMC: 3570107. DOI: 10.1084/jem.20121970. View

Krishnamurty A, Thouvenel C, Portugal S, Keitany G, Kim K, Holder A . Somatically Hypermutated Plasmodium-Specific IgM(+) Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria Rechallenge. Immunity. 2016; 45(2):402-14. PMC: 5118370. DOI: 10.1016/j.immuni.2016.06.014. View

Pleass R, Moore S, Stevenson L, Hviid L . Immunoglobulin M: Restrainer of Inflammation and Mediator of Immune Evasion by Plasmodium falciparum Malaria. Trends Parasitol. 2015; 32(2):108-119. DOI: 10.1016/j.pt.2015.09.007. View

Capolunghi F, Rosado M, Sinibaldi M, Aranburu A, Carsetti R . Why do we need IgM memory B cells?. Immunol Lett. 2013; 152(2):114-20. DOI: 10.1016/j.imlet.2013.04.007. View

Taylor J, Pape K, Jenkins M . A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J Exp Med. 2012; 209(3):597-606. PMC: 3302224. DOI: 10.1084/jem.20111696. View

Atkinson J, Frank M . Studies on the in vivo effects of antibody. Interaction of IgM antibody and complement in the immune clearance and destruction of erythrocytes in man. J Clin Invest. 1974; 54(2):339-48. PMC: 301561. DOI: 10.1172/JCI107769. View

10.

Andersson J, Sjoberg O, Moller G . Induction of immunoglobulin and antibody synthesis in vitro by lipopolysaccharides. Eur J Immunol. 1972; 2(4):349-53. DOI: 10.1002/eji.1830020410. View

11.

Muxel S, Freitas do Rosario A, Zago C, Castillo-Mendez S, Sardinha L, Rodriguez-Malaga S . The spleen CD4+ T cell response to blood-stage Plasmodium chabaudi malaria develops in two phases characterized by different properties. PLoS One. 2011; 6(7):e22434. PMC: 3141041. DOI: 10.1371/journal.pone.0022434. View

12.

Lima M, Bandeira A, Falanga P, Freitas A, Kipnis T, da Silva L . Clonal analysis of B lymphocyte responses to Plasmodium chabaudi infection of normal and immunoprotected mice. Int Immunol. 1991; 3(12):1207-16. DOI: 10.1093/intimm/3.12.1207. View

13.

Arama C, Skinner J, Doumtabe D, Portugal S, Tran T, Jain A . Genetic Resistance to Malaria Is Associated With Greater Enhancement of Immunoglobulin (Ig)M Than IgG Responses to a Broad Array of Plasmodium falciparum Antigens. Open Forum Infect Dis. 2015; 2(3):ofv118. PMC: 4564391. DOI: 10.1093/ofid/ofv118. View

14.

Semblat J, Raza A, Kyes S, Rowe J . Identification of Plasmodium falciparum var1CSA and var2CSA domains that bind IgM natural antibodies. Mol Biochem Parasitol. 2006; 146(2):192-7. PMC: 2869447. DOI: 10.1016/j.molbiopara.2005.12.007. View

15.

Stevenson M, Tam M . Differential induction of helper T cell subsets during blood-stage Plasmodium chabaudi AS infection in resistant and susceptible mice. Clin Exp Immunol. 1993; 92(1):77-83. PMC: 1554870. DOI: 10.1111/j.1365-2249.1993.tb05951.x. View

16.

Portugal S, Tipton C, Sohn H, Kone Y, Wang J, Li S . Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function. Elife. 2015; 4. PMC: 4444601. DOI: 10.7554/eLife.07218. View

17.

Bruyn G, Zegers B, Van Furth R . Mechanisms of host defense against infection with Streptococcus pneumoniae. Clin Infect Dis. 1992; 14(1):251-62. DOI: 10.1093/clinids/14.1.251. View

18.

Chan J, Howell K, Reiling L, Ataide R, Mackintosh C, Fowkes F . Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity. J Clin Invest. 2012; 122(9):3227-38. PMC: 3428085. DOI: 10.1172/JCI62182. View

19.

Stephens R, Culleton R, Lamb T . The contribution of Plasmodium chabaudi to our understanding of malaria. Trends Parasitol. 2011; 28(2):73-82. PMC: 4040349. DOI: 10.1016/j.pt.2011.10.006. View

20.

Barfod L, Dalgaard M, Pleman S, Ofori M, Pleass R, Hviid L . Evasion of immunity to Plasmodium falciparum malaria by IgM masking of protective IgG epitopes in infected erythrocyte surface-exposed PfEMP1. Proc Natl Acad Sci U S A. 2011; 108(30):12485-90. PMC: 3145728. DOI: 10.1073/pnas.1103708108. View