4.8 Article

CD38 Deficiency Ameliorates Chronic Graft-Versus-Host Disease Murine Lupus via a B-Cell-Dependent Mechanism

Journal

FRONTIERS IN IMMUNOLOGY
Volume 12, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.713697

Keywords

CD38; cGVHD lupus-like; T-bet(+) B cells; anti-ssDNA antibodies; GC B cells; STAT1; type I IFN-signature; inflammation

Categories

Funding

  1. Proyecto del Plan Estatal [SAF2017-89801-R]
  2. IPBLN-CSIC Proteomics Unit belonged to ProteoRed-ISCIII [PRB2, PRB3]
  3. CIB-CSIC
  4. IPBLN-CSIC [PT17/0019/0010]
  5. JAE-Intro (CSIC)
  6. Consejo Nacional de Ciencia y Tecnologia (CONACYT) of Mexico [502492]
  7. Andalusian Government
  8. IPBLN-CSIC [PT13/0001/0011]
  9. [SAF2017-82905-R]

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In a chronic graft-versus-host disease model, Cd38(-/-) mice exhibited milder lupus-like autoimmunity and lower levels of autoantibodies, along with decreased percentages of certain cell types compared to wild-type mice. This suggests that CD38 in B cells acts as a modulator receptor that controls autoimmune responses.
The absence of the mouse cell surface receptor CD38 in Cd38(-/-) mice suggests that this receptor acts as a positive regulator of inflammatory and autoimmune responses. Here, we report that, in the context of the chronic graft-versus-host disease (cGVHD) lupus inducible model, the transfer of B6.C-H2bm12/KhEg(bm12) spleen cells into co-isogenic Cd38(-/-) B6 mice causes milder lupus-like autoimmunity with lower levels of anti-ssDNA autoantibodies than the transfer of bm12 spleen cells into WT B6 mice. In addition, significantly lower percentages of Tfh cells, as well as GC B cells, plasma cells, and T-bet(+)CD11c(hi) B cells, were observed in Cd38(-/-) mice than in WT mice, while the expansion of Treg cells and Tfr cells was normal, suggesting that the ability of Cd38(-/-) B cells to respond to allogeneic help from bm12 CD4(+) T cells is greatly diminished. The frequencies of T-bet(+)CD11c(hi) B cells, which are considered the precursors of the autoantibody-secreting cells, correlate with anti-ssDNA autoantibody serum levels, IL-27, and sCD40L. Proteomics profiling of the spleens from WT cGVHD mice reflects a STAT1-driven type I IFN signature, which is absent in Cd38(-/-) cGVHD mice. Kidney, spleen, and liver inflammation was mild and resolved faster in Cd38(-/-) cGVHD mice than in WT cGVHD mice. We conclude that CD38 in B cells functions as a modulator receptor that controls autoimmune responses.

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