CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse

Abstract

The tight-skin (TSK/+) mouse, a genetic model for human systemic sclerosis (SSc), develops cutaneous fibrosis and autoantibodies against SSc-specific target autoantigens. Although molecular mechanisms explaining the development of fibrosis and autoimmunity in SSc patients or TSK/+ mice remain unknown, we recently demonstrated that SSc patients overexpress CD19, an important regulatory molecule expressed by B lymphocytes. B cells from CD19-deficient mice are hyporesponsive to transmembrane signals, while B cells overexpressing CD19 are hyperresponsive and generate autoantibodies. In this study, TSK/+ B cells also exhibited a hyperresponsive phenotype with decreased surface IgM expression, enhanced serum Ig production, and spontaneous autoantibody production. Moreover, CD19 tyrosine phosphorylation was constitutively augmented in TSK/+ B cells. CD19-mediated [Ca 2+ ] i responses, Vav phosphorylation, and Lyn kinase activity were similarly enhanced. Studies of TSK/+ mice deficient in CD19 expression demonstrated that CD19 deficiency significantly decreased skin fibrosis in TSK/+ mice. Additionally, CD19 loss in TSK/+ mice upregulated surface IgM expression and completely abrogated hyper-γ-globulinemia and autoantibody production. CD19 deficiency also inhibited IL-6 production by TSK/+ B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling in TSK/+ mice leads to skin sclerosis possibly through IL-6 overproduction as well as autoimmunity.

Blockade of CD40/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse

“…As we have reported abnormalities of B cell responses in TSK/+ mice,11 25 the association of CD40/CD40L interactions with B cell hyperresponsiveness in TSK/+ mice was addressed. First, TSK/+ B cell proliferation to anti-IgM antibody, anti-CD40 mAb and LPS was assessed (fig 5A).…”

“…Adoptive transfer of both T and B cells from TSK/+ mice induces cutaneous collagen deposition and autoantibody production in wild-type mice, while the infusion of purified T cells alone does not lead to the development of TSK syndrome 6. Deficiency of CD19 as well as B cell depletion using anti-CD20 mAb result in markedly reduced skin fibrosis in TSK/+ mice 11 26. Furthermore, the development of skin fibrosis correlated closely with serum anti-topo I antibody levels in TSK/+ mice 27.…”

“…To determine immunoglobulin concentrations, ELISAs were carried out as described,11 using affinity-purified mouse IgM, IgG1, IgG2a, IgG2b, IgG3 and IgA (Southern Biotechnology Associates, Birmingham, Alabama, USA) to generate standard curves. Serum anti-topoisomerase (anti-topo) I autoantibody levels were determined with specific ELISA kits (Medical and Biological Laboratories, Nagoya, Japan) as described 11…”

Treatment with abatacept prevents experimental dermal fibrosis and induces regression of established inflammation-driven fibrosis

“…T-cell requirement may also explain the absence of efficacy of abatacept in Tsk-1 mice, given that bone marrow transplantation experiments have challenged the implication of T cells in this model 31 32. Indeed, the transfer of enriched T cells increased autoantibodies’ production but did not cause skin fibrosis and transfer of T lymphocytes led only to mild fibrotic lesions compared with massive fibrosis in Tsk-1 mice 33.…”

Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-β signalling to prevent fibrosis

“…In contrast, Tsk-1 mice represent later stages of SSc, in which inflammatory infiltrates have already resolved and fibroblasts have become endogenously activated 33 39. In addition, the Tsk-1 model also highlights the key role of B cells in SSc 40. The AdTBR model is independent of inflammation, and fibrosis is exclusively driven by enhanced TGF-β signalling in fibroblasts 5 33.…”