Dataset Information

T-bet-expressing B cells contribute to the autoreactive plasma cell pool in Lyn^-/- mice.

ABSTRACT: Systemic Lupus Erythematosus (SLE) is characterized by pathogenic autoantibodies against nucleic acid-containing antigens. Understanding which B-cell subsets give rise to these autoantibodies may reveal therapeutic approaches for SLE that spare protective responses. Mice lacking the tyrosine kinase Lyn, which limits B and myeloid cell activation, develop lupus-like autoimmune diseases characterized by increased autoreactive plasma cells (PCs). We used a fate-mapping strategy to determine the contribution of T-bet⁺ B cells, a subset thought to be pathogenic in lupus, to the accumulation of PCs and autoantibodies in Lyn^-/- mice. Approximately, 50% of splenic PCs in Lyn^-/- mice originated from T-bet⁺ cells, a significant increase compared to WT mice. In vitro, splenic PCs derived from T-bet⁺ B cells secreted both IgM and IgG anti-dsDNA antibodies. To determine the role of these cells in autoantibody production in vivo, we prevented T-bet⁺ B cells from differentiating into PCs or class switching in Lyn^-/- mice. This resulted in a partial reduction in splenic PCs and anti-dsDNA IgM and complete abrogation of anti-dsDNA IgG. Thus, T-bet⁺ B cells make an important contribution to the autoreactive PC pool in Lyn^-/- mice.

SUBMITTER: Ottens K

PROVIDER: S-EPMC10524956 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

T-bet-expressing B cells contribute to the autoreactive plasma cell pool in Lyn<sup>-/-</sup> mice.

Ottens Kristina K Schneider Jalyn J Satterthwaite Anne B AB

European journal of immunology 20230514 8

Systemic Lupus Erythematosus (SLE) is characterized by pathogenic autoantibodies against nucleic acid-containing antigens. Understanding which B-cell subsets give rise to these autoantibodies may reveal therapeutic approaches for SLE that spare protective responses. Mice lacking the tyrosine kinase Lyn, which limits B and myeloid cell activation, develop lupus-like autoimmune diseases characterized by increased autoreactive plasma cells (PCs). We used a fate-mapping strategy to determine the con ...[more]

PMID: 37134326

Similar Datasets

Project description:IL10 plays a dual role in supporting humoral immunity and inhibiting inflammatory conditions. B cells producing IL10 are thought to play a key regulatory role in maintaining self-tolerance and suppressing excessive inflammation during autoimmune and infectious diseases, primarily by inhibiting associated T cell responses. The extent to which B cells, through the provision of IL10, might function to sustain or inhibit autoantibody production is less clear. We previously described transgenic mice expressing catalytically inactive RAG1 (dnRAG1 mice), which show expansion of an IL10-compentent CD5+ B cell subset that phenotypically resembles B10 B cells, hypogammaglobulinemia, and a restricted B cell receptor repertoire with features indicative of impaired B cell receptor editing. We show here that B10-like B cells in dnRAG1 mice bind the membrane-associated autoantigen phosphatidylcholine (PtC), and that in vitro lipopolysaccharide (LPS) stimulation of dnRAG1 splenocytes induces a robust IgM response enriched in reactivity toward lupus-associated autoantigens. This outcome was correlated with detection of sIgMhi B cell populations that were distinct from, but in addition to, sIgMint populations observed after similar treatment of wild-type splenocytes. Loss of IL10 expression in dnRAG1 mice had no significant effect on B10-like B cell expansion or the frequency of PtC+ B cells. Compared to IL10+/+ dnRAG1 mice, levels of serum IgM, but not serum IgG, were highly elevated in some naïve IL10-/- dnRAG1 mice, and was correlated with a significant increase in serum BAFF levels. Differentiation of sIgMint B cells from LPS-stimulated dnRAG1 splenocytes was enhanced by loss of IL10 expression and IL10 blockade, but was suppressed by treatment with recombinant IL10. In vitro LPS-induced differentiation and antibody production was inhibited by treatment with JAK/STAT inhibitors or a synthetic corticosteroid, independent of IL10 expression and genotype. Taken together, these data suggest that IL10 expression in dnRAG1 mice maintains suppression of IgM levels in part by inhibiting BAFF production, and that regulatory B10-like B cells, through the provision of IL10, constrains B cell differentiation in response to mitogenic stimuli. Furthermore, autoantibody profiling raises a possible link between CD5+ B cell expansion, mitogenic stimulation, and autoantibodies associated with autoimmune complications observed in lupus and lupus-related disorders.

Dataset Information

T-bet-expressing B cells contribute to the autoreactive plasma cell pool in Lyn^-/- mice.

Publications

T-bet-expressing B cells contribute to the autoreactive plasma cell pool in Lyn<sup>-/-</sup> mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

T-bet-expressing B cells contribute to the autoreactive plasma cell pool in Lyn-/- mice.

Publications

T-bet-expressing B cells contribute to the autoreactive plasma cell pool in Lyn<sup>-/-</sup> mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

T-bet-expressing B cells contribute to the autoreactive plasma cell pool in Lyn^-/- mice.