Emerging insights into atypical B cells in pediatric chronic infectious diseases and immune system disorders: T(o)-bet on control of B-cell immune activation

Abstract

Repetitive or persistent cellular stimulation in vivo has been associated with the development of a heterogeneous B-cell population that exhibits a distinctive phenotype and, in addition to classical B-cell markers, often expresses the transcription factor T-bet and myeloid marker CD11c. Research suggests that this atypical population consists of B cells with distinct B-cell receptor specificities capable of binding the antigens responsible for their development. The expansion of this population occurs in the presence of chronic inflammatory conditions and autoimmune diseases where different nomenclatures have been used to describe them. However, as a result of the diverse contexts in which they have been investigated, these cells have remained largely enigmatic, with much ambiguity remaining regarding their phenotype and function in humoral immune response as well as their role in autoimmunity. Atypical B cells have garnered considerable interest because of their ability to produce specific antibodies and/or autoantibodies and because of their association with key disease manifestations. Although they have been widely described in the context of adults, little information is present for children. Therefore, the aim of this narrative review is to describe the characteristics of this population, suggest their function in pediatric immune-related diseases and chronic infections, and explore their potential therapeutic avenues. Repetitive or persistent cellular stimulation in vivo has been associated with the development of a heterogeneous B-cell population that exhibits a distinctive phenotype and, in addition to classical B-cell markers, often expresses the transcription factor T-bet and myeloid marker CD11c. Research suggests that this atypical population consists of B cells with distinct B-cell receptor specificities capable of binding the antigens responsible for their development. The expansion of this population occurs in the presence of chronic inflammatory conditions and autoimmune diseases where different nomenclatures have been used to describe them. However, as a result of the diverse contexts in which they have been investigated, these cells have remained largely enigmatic, with much ambiguity remaining regarding their phenotype and function in humoral immune response as well as their role in autoimmunity. Atypical B cells have garnered considerable interest because of their ability to produce specific antibodies and/or autoantibodies and because of their association with key disease manifestations. Although they have been widely described in the context of adults, little information is present for children. Therefore, the aim of this narrative review is to describe the characteristics of this population, suggest their function in pediatric immune-related diseases and chronic infections, and explore their potential therapeutic avenues. B cells constitute a critical arm of the immune system and are responsible for short- and long-term generation of humoral antibody responses. B cells also perform antibody-independent functions including antigen presentation, modulation of T-cell differentiation and survival, and production of both regulatory and proinflammatory cytokines.1Wang Y. Liu J. Burrows P.D. Wang J.Y. B cell development and maturation.Adv Exp Med Biol. 2020; 1254: 1-22Crossref PubMed Scopus (96) Google Scholar, 2Lund F.E. Garvy B.A. Randall T.D. Harris D.P. Regulatory roles for cytokine-producing B cells in infection and autoimmune disease.Curr Dir Autoimmun. 2005; 8: 25-54Crossref PubMed Google Scholar, 3Shen P. Fillatreau S. Antibody-independent functions of B cells: a focus on cytokines.Nat Rev Immunol. 2015; 15: 441-451Crossref PubMed Scopus (331) Google Scholar The B-cell lineage undergoes a maturation process resulting in considerable plasticity of the antibody response. The differentiation process results in the generation of 2 types of affinity-matured B cells: memory B cells (MBCs) and antibody-secreting plasma cells (PCs).4LeBien T.W. Tedder T.F. B lymphocytes: how they develop and function.Blood. 2008; 112: 1570-1580Crossref PubMed Scopus (839) Google Scholar, 5Mesin L. Ersching J. Victora G.D. Germinal center B cell dynamics.Immunity. 2016; 45: 471-482Abstract Full Text Full Text PDF PubMed Scopus (620) Google Scholar, 6Shlomchik M.J. Weisel F. Germinal center selection and the development of memory B and plasma cells.Immunol Rev. 2012; 247: 52-63Crossref PubMed Scopus (326) Google Scholar Although the steps that underlie the activation and differentiation of antigen-engaged B cells have been extensively characterized, studies have revealed additional complexities to these responses, especially in the context of chronic immune stimulation. Indeed, over the past decade, it has become increasingly evident that many chronic human infectious diseases as well as immune system disorders are associated with alterations in the composition of MBCs’ compartment. A common feature of these diseases appears to be a large expansion of a unique B-cell subset, often denoted as age-associated B cells (ABCs), atypical B cells, or proinflammatory B cells.7Cancro M.P. Age-associated B cells.Annu Rev Immunol. 2020; 38: 315-340Crossref PubMed Scopus (161) Google Scholar, 8Courey-Ghaouzi A.D. Kleberg L. Sundling C. Alternative B cell differentiation during infection and inflammation.Front Immunol. 2022; 13908034Crossref PubMed Scopus (5) Google Scholar, 9Knox J.J. Myles A. Cancro M.P. T-bet+ memory B cells: generation, function, and fate.Immunol Rev. 2019; 288: 149-160Crossref PubMed Scopus (77) Google Scholar, 10Cooper L. Good-Jacobson K.L. Dysregulation of humoral immunity in chronic infection.Immunol Cell Biol. 2020; 98: 456-466Crossref PubMed Scopus (9) Google Scholar Since their initial discovery, downregulation of both CD21 and CD27 and expression of the TH1 master transcription factor T-bet and the integrin CD11c have become a well-known feature of this population, so these cells are also now known as T-bet+CD11c+ B cells.7Cancro M.P. Age-associated B cells.Annu Rev Immunol. 2020; 38: 315-340Crossref PubMed Scopus (161) Google Scholar,11Myles A. Sanz I. Cancro M.P. T-bet+ B cells: a common denominator in protective and autoreactive antibody responses?.Curr Opin Immunol. 2019; 57: 40-45Crossref PubMed Scopus (26) Google Scholar,12Phalke S. Rivera-Correa J. Jenkins D. Flores Castro D. Giannopoulou E. Pernis A.B. Molecular mechanisms controlling age-associated B cells in autoimmunity.Immunol Rev. 2022; 307: 79-100Crossref PubMed Scopus (10) Google Scholar This novel population was classified as a memory cell because of the negligible expression of BCL6 and BLIMP1, which are hallmark transcription factors of germinal center (GC) B cells and PC, respectively.13Ehrhardt G.R.A. Hsu J.T. Gartland L. Leu C.M. Zhang S. Davis R.S. of the a distinctive population of memory B Exp 2005; PubMed Scopus Google Scholar these cells as on the of the presence of additional markers, as and to classical A. L. I. B cells in human are memory Exp Immunol. 2016; PubMed Scopus Google Scholar Atypical B cells to and in activation of the receptor and and and S. Rivera-Correa J. Jenkins D. Flores Castro D. Giannopoulou E. Pernis A.B. Molecular mechanisms controlling age-associated B cells in autoimmunity.Immunol Rev. 2022; 307: 79-100Crossref PubMed Scopus (10) Google Scholar This cell population a of A.D. Kleberg L. Sundling C. Alternative B cell differentiation during infection and inflammation.Front Immunol. 2022; 13908034Crossref PubMed Scopus (5) Google Scholar are cells, develop plasma and antibodies in addition to a B-cell to produce proinflammatory and M.P. Age-associated B cells.Annu Rev Immunol. 2020; 38: 315-340Crossref PubMed Scopus (161) Google J. C.M. S. B cells during and antibodies with cell Immunol. 2022; PubMed Scopus Google J. of and differentiation of different B-cell Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar has been that this population a role in including immune system and to chronic I. S. A. on the of B cells in Exp Immunol. 2022; PubMed Google Scholar, E. 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