Surrogate light chain is required for central and peripheral B‐cell tolerance and inhibits anti‐DNA antibody production by marginal zone B cells

Abstract

Selection of the primary antibody repertoire takes place in pro-/pre-B cells, and subsequently in immature and transitional B cells. At the first checkpoint, μ heavy (μH) chains assemble with surrogate light (SL) chain into a precursor B-cell receptor. In mice lacking SL chain, μH chain selection is impaired, and serum autoantibody levels are elevated. However, whether the development of autoantibody-producing cells is due to an inability of the resultant B-cell receptors to induce central and/or peripheral B-cell tolerance or other factors is unknown. Here, we show that receptor editing is defective, and that a higher proportion of BM immature B cells are prone to undergoing apoptosis. Furthermore, transitional B cells are also more prone to undergoing apoptosis, with a stronger selection pressure to enter the follicular B-cell pool. Those that enter the marginal zone (MZ) B-cell pool escape selection and survive, possibly due to the B-lymphopenia and elevated levels of B-cell activating factor. Moreover, the MZ B cells are responsible for the elevated IgM anti-dsDNA antibody levels detected in these mice. Thus, the SL chain is required for central and peripheral B-cell tolerance and inhibits anti-DNA antibody production by MZ B cells.Keywords: Autoantibodies r Autoimmunity r Light chain recombination r Marginal zone B cells r Pre-BCR Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction V(D)J recombination is a stochastic process that gives rise to a vast primary repertoire of B-cell receptors (BCRs), recognizing self (auto) and nonself antigens. To purge and control autoreactive B cells, several checkpoints are in place, in both central and peripheral lymphoid organs [1,2]. The main mechanism of central B-cell tolerance is receptor editing [3,4] and, as some autoreactivity remains among the cells that migrate to the periphery [5], they undergo further selection as transitional B cells in the spleen Correspondence: Prof. Inga-Lill Mårtensson e-mail: lill.martensson@rheuma.gu.se[6], mainly by clonal deletion. Extrinsic factors are also involved, for example, B lymphocyte activating factor (BAFF), also known as BLyS, a key factor that modulates survival of peripheral B cells [7]. Defective central and peripheral B-cell tolerance checkpoints, as well as elevated BAFF levels have all been associated with autoimmune diseases, for example, systemic lupus erythematosus and rheumatoid arthritis, and mouse models thereof, a hallmark of which is autoantibody production [8][9][10].Selection of the primary BCR repertoire takes place also at the pro-B to pre-B-cell transition based on antibody μ heavy (μH) * These authors contributed equally to this work. and κ germline configuration (GL) and λ2 germline transcripts (λ2 0 ) and λ1,2,3 rearrangements (RE). (E) Rag-1 and Rag-2 mRNA levels. Data are shown as mean ± SEM of three to five mice per group, and are from a single experiment representative of three independent experiments. p Values were determine...

The Role of the Pre-B Cell Receptor in B Cell Development, Repertoire Selection, and Tolerance

“…Whether this is a result of positive selection and proliferative expansion, in line with the above-mentioned requirement for poly-/autoreactivity is currently unclear ( 91 ), as at least some of the expansion is likely due to signaling through the IL-7R ( 66 , 76 ). Anyhow, negative selection at the immature B cell stage in SLC −/− mice is more prominent than in controls, inferred from a higher proportion of cells prone to apoptosis ( 96 ), and interpreted as a result of the expansion of “autoreactive” pre-B cells ( 95 ). Central B-cell tolerance is despite of this incomplete.…”

Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity

“…Interactions between integrins and their ligands are essential for maintaining the location of leukocytes in general, and mediate the extravasation of cells into tissues as well as their retention in peripheral lymphoid organs (1). In particular, marginal zone (MZ) B cells not only express higher levels of the LFA-1 (αLβ2) and VLA-4 (α4β1) integrins than do their neighbors the follicular (FO) B cells (2), but also depend on these receptors for their retention in the splenic marginal zone; MZ B cells retained in the spleen are released to the circulation when the interaction with ICAM-1 and VCAM-1 is blocked, both in wild-type and in autoimmune mice (2, 3). Appropriately, the LFA-1 and VLA-4 ligands, ICAM-1 and VCAM-1, are expressed in the splenic marginal sinus in mice (2), and VCAM-1 is expressed in the perifollicular and marginal zone in the human spleen (4).…”

“…As well as harboring MZ B cells, the spleen is an important reservoir for MBCs (7–9); although to date the mechanism of their retention there has not been identified, LFA-1 and/or VLA-4 integrins are obvious candidates for that role. Here we investigate this possibility using SLC −/− (surrogate light chain-deficient) mice, which share features with autoimmune mouse models, including spontaneous formation of germinal centers (GCs) and MBCs (3, 10–12). Furthermore, in humans we examine the expression pattern of the LFA-1 and VLA-4 integrins in B-cell subsets from secondary lymphoid organs as well as functional properties of these integrins in PB of healthy donors and patients with rheumatoid arthritis.…”

Age‐associated B cells expanded in autoimmune mice are memory cells sharing H‐CDR3‐selected repertoires

“…A CD21 −/low B‐cell population has been described in mice that lack the surrogate light chain (SLC −/− ) . This strain represents a model of autoimmunity that exhibits defective central and peripheral B‐cell tolerance , which results in the spontaneous formation of germinal centers (GCs), MBCs and plasma cells that produce typical lupus autoantibodies . In SLC −/− mice, a subset of the CD21 −/low population is the GC B cells, whereas the characteristics of the remainder, i.e.…”