CD19+CD24hiCD38hi B Cells Exhibit Regulatory Capacity in Healthy Individuals but Are Functionally Impaired in Systemic Lupus Erythematosus Patients

The regulation of antibody production is linked to the generation and maintenance of plasmablasts and plasma cells from their B cell precursors. Plasmablasts are the rapidly produced and short-lived effector cells of the early antibody response, whereas plasma cells are the long-lived mediators of lasting humoral immunity. An extraordinary number of control mechanisms, at both the cellular and molecular levels, underlie the regulation of this essential arm of the immune response. Despite this complexity, the terminal differentiation of B cells can be described as a simple probabilistic process that is governed by a central gene-regulatory network and modified by environmental stimuli.

The generation of antibody-secreting plasma cells.

Plasma cells provide humoral immunity. They have traditionally been viewed mainly as short-lived end-stage products of B-cell differentiation that deserve little interest. This view is changing, however, because we now know that plasma cells can survive for long periods in the appropriate survival niches and that they are an independent cellular component of immunological memory. Studies of the biology of plasma cells reveal a mechanism of intriguing simplicity and elegance that focuses memory provided by plasma cells on recently encountered pathogens while minimizing the 'fading' of memory for pathogens encountered in the distant past. This mechanism is based on competition for survival niches between newly generated plasmablasts and older plasma cells.

Competence and competition : the challenge of becoming a long-lived plasma cell

In this Review, Nicole Baumgarth describes the development and functions of B-1 cells. These innate-like B cells serve as the major source of natural antibody in mice, and can have important roles in defence against mucosal pathogens and in maintaining tissue homeostasis. During their development, B and T cells with self-reactive antigen receptors are generally deleted from the repertoire to avoid autoimmune diseases. Paradoxically, innate-like B-1 cells in mice are positively selected for self-reactivity and form a pool of long-lived, self-renewing B cells that produce most of the circulating natural IgM antibodies. This Review provides an overview of the developmental processes that shape the B-1 cell pool in mice, outlines the functions of B-1 cells in both the steady state and during host defence, and discusses possible functional B-1 cell homologues that exist in humans.

The double life of a B-1 cell: self-reactivity selects for protective effector functions

The relevance of regulatory B cells in the maintenance of tolerance in healthy individuals or in patients with immune disorders remains understudied. In healthy individuals, CD19(+)CD24(hi)CD38(hi) B cells suppress CD4(+)CD25(-) T cell proliferation as well as the release of interferon-γ and tumor necrosis factor-α by these cells; this suppression is partially mediated through the production of interleukin-10 (IL-10). We further elucidate the mechanisms of suppression by CD19(+)CD24(hi)CD38(hi) B cells. Healthy CD19(+)CD24(hi)CD38(hi) B cells inhibited naive T cell differentiation into T helper 1 (T(H)1) and T(H)17 cells and converted CD4(+)CD25(-) T cells into regulatory T cells (T(regs)), in part through the production of IL-10. In contrast, CD19(+)CD24(hi)CD38(hi) B cells from patients with rheumatoid arthritis (RA) failed to convert CD4(+)CD25(-) T cells into functionally suppressive T(regs) or to curb T(H)17 development; however, they maintained the capacity to inhibit T(H)1 cell differentiation. Moreover, RA patients with active disease have reduced numbers of CD19(+)CD24(hi)CD38(hi) B cells in peripheral blood compared with either patients with inactive disease or healthy individuals. These results suggest that in patients with active RA, CD19(+)CD24(hi)CD38(hi) B cells with regulatory function may fail to prevent the development of autoreactive responses and inflammation, leading to autoimmunity.

CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation.

In man and in mouse, B-cell maturation occurs in steps, first in the bone marrow from hematopoietic precursors to immature/transitional B cells, then in the periphery from transitional to fully mature B cells. Each developmental step is tightly controlled by the expression and function of the B-cell receptor (BCR) and by the ability to interact with the microenvironment. Mature B cells collaborate with T cells in the adaptive immune response, leading to the production of high-affinity antibodies. This response is very accurate, but slow. Immediately after pathogen entry, however, antibodies already present in the serum reinforce the innate immune response and contribute to the first-line defense against infection. Low-affinity natural antibodies are produced by B-1a B cells in the mouse and immunoglobulin M (IgM) memory cells in man. These antibodies represent an immediate protection against all microorganisms and the only one against encapsulated bacteria. B-1a and IgM memory B cells may function as a link between the innate and adaptive immune response and thus perform a primordial B-cell function.

Peripheral development of B cells in mouse and man.

COPYRIGHT © 2022 Picchianti Diamanti, Luchetti, Nicastri, Rosado and Laganà. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 21 October 2022 DOI 10.3389/fimmu.2022.1058152

/pdf/editorial-chronic-autoimmune-arthritis-infections-and-rlxscxbf.pdf

M. Manuela Rosado

Papers

Peripheral development of B cells in mouse and man.

Editorial: Chronic autoimmune arthritis, infections and vaccines