Antibodies from donor B cells perpetuate cutaneous chronic graft-versus-host disease in mice

Abstract

• Antibodies produced by donor B cells are required for thymic and lymphoid damage in mice with chronic GVHD.• Antibody-producing donor B cells associate with infiltration of Th17 cells in the skin and perpetuation of cutaneous chronic GVHD in mice.

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

“…This result could be attributed to XBP-1-dependent defects in dendritic cell-derived type I IFN signaling, which regulates T-cell survival, 10,66 from chemotactic signals such as CXCL16 produced by nonhematopoietic cells, also regulated by XBP-1, 67 or from antibody-mediated cutaneous infiltration of pathogenic Th17 cells. 29,65 In spleens, frequency of total granulocytes was significantly reduced after B-I09 administration in the B10.D2 to BALB/c model (data not shown), in agreement with previous reports indicating that XBP-1 is critically involved in the differentiation and recruitment of granulocyte subsets into tissues leading to inflammatory fibrosis, 11,68,69 and that these subsets are involved in cGVHD. 70,71 Current leading therapies for cGVHD directly target B cells or T cells, 31,60 whereas the current study and previous literature suggest that inhibition of the IRE-1a/ XBP-1 pathway via B-I09 could directly impact other cell subsets involved in cGVHD development in addition to B cells and T cells, 65 such as dendritic cells, 10 granulocytes, 11 and even nonhematopoietic cells.…”

“…56 In our study, XBP-1-deficient B cells produced significantly less IL-12p40 and IL-4/5 cytokines after LPS and IL-4 stimulation, suggesting that XBP-1 regulates both type 1 and 2 effector B-cell differentiation. Although some of our B-cell data can be connected to an intrinsic defect of BCR signaling and S1P1 from XBP-1 deficiency, 17 we have demonstrated that BM+Sp+B-I09 2.5 29 Here, XBP-1-deficient B cells secreted less antibodies in response to both in vitro and in vivo stimuli, and both in vitro and in vivo treatment with B-I09 phenocopied this effect. XBP-1 KO B cells also engaged in less class-switch recombination after allo-BMT compared with XBP-1 WT B cells, where higher retention of surface IgM was consistent with reduced levels of serum anti-dsDNA IgG, consistent with a previous report that XBP-1 KO B cells express less activation-induced cytidine deaminase.…”

“…19,[28][29][30][31] We hypothesized conditional deletion of XBP-1 on donor allogeneic B lymphocytes would impair B-cell activation and development of cGVHD. To test this hypothesis, we used a BO model of pulmonary cGVHD (B6 to B10.BR) mediated by donor T cells and antigen-presenting cells (APCs).…”

“…58 T FH are a T-cell subset that has recently been shown to be correlated with cGVHD pathogenesis. 32,34 Although the role of T FH and GC B cells in murine models of cGVHD is still under debate, 29,59 Forcade et al recently indicated a key role of T FH , which strongly correlated with cGVHD in human patients. 33 Accordingly, in our study murine recipients of XBP-1 KO B cells displayed an indirect impact on T FH cell differentiation, where donor T FH cells were reduced in the spleens.…”

Genetic risk factors for sclerotic graft-versus-host disease

“…30 A recent study showed that antibodies from donor B cells perpetuate cutaneous sclerotic GVHD in mice. 31 Functional activation of T cells depends on surface expression of TCR-CD3 complexes. CD247 encodes the TCR z (CD3z) subunit and plays a crucial role in coupling antigen recognition to several intracellular signal-transduction pathways.…”