Random recombination of antibody heavy-and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs). Here we show that the naive follicular B-cell pool is enriched for cells expressing prototypic ANA heavy chains in these mice in a non-autoimmune background with a broad antibody repertoire. This results in the spontaneous formation of T-cell-dependent germinal centres that are enriched with B cells expressing prototypic ANA heavy chains. However, peripheral tolerance appears maintained by selection thresholds on cells entering the memory B-cell and plasma cell pools, as exemplified by the exclusion of cells expressing the intrinsically self-reactive V H 81X from both pools.
Age-associated B cells (ABCs) represent a distinct cell population expressing low levels of CD21 (CD21 ). The Ig repertoire expressed by ABCs in aged mice is diverse and exhibits signs of somatic hypermutation (SHM). A CD21 B-cell population is expanded in autoimmune diseases, e.g. systemic lupus erythematosus, as well as in lupus-prone NZB/W mice and in mice lacking a pre-B cell receptor (SLC ). However, the nature of the CD21 B cells (hereafter ABCs) in autoimmunity is not well understood. Here we show that in young SLC mice, the vast majority of the ABCs express memory B-cell (MBC) markers in contrast to wild-type controls. A similar population is present in lupus-prone MRL mice before and at disease onset. In SLC mice, a majority of the ABCs are IgM , their V genes have undergone SHM, show clonal diversification and clonal restriction at the H-CDR3 level. ABC hybridomas, established from SLC mice, secrete typical lupus autoantibodies, e.g. anti-Smith antigen, and some of those that bind to DNA comprise a H-CDR3 that is identical to previously described IgM anti-DNA antibodies from lupus-prone mice. Together, these results reveal that ABCs in autoimmune mice are comprised of autoreactive MBCs expressing highly restricted H-CDR3 repertoires.
Viral dsRNA can be found at the site of inflammation in RA patients, and intra-articular injection of dsRNA induces arthritis by activating type I IFN signaling in mice. Further, DCs, a major source of IFN-α, can be found in the synovium of RA patients. We therefore determined the occurrence of DCs in dsRNA-induced arthritis and their ability to induce arthritis. Here, we show, by immunohistochemistry, that cells expressing the pan-DC marker CD11c and the pDC marker 120G8 are present in the inflamed synovium in dsRNA-induced arthritis. Flt3L-generated and splenic DCs preactivated with dsRNA before intra-articular injection, but not mock-stimulated cells, clearly induced arthritis. Induction of arthritis was dependent on type I IFN signaling in the donor DCs, whereas IFNAR expression in the recipient was not required. Sorting of the Flt3L-DC population into cDCs (CD11c(+), PDCA-1(-)) and pDCs (CD11c(+), PDCA-1(+)) revealed that both subtypes were arthritogenic and produced type I IFN if treated with dsRNA. Taken together, these results demonstrate that viral nucleic acids can elicit arthritis by activating type I IFN signaling in DCs. Once triggered, autocrine type I IFN signaling in dsRNA-activated DCs is sufficient to propagate arthritis.
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...
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