Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease

Abstract

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplant reflects a complex immune response resulting in chronic damage to multiple tissues. Previous studies indicated that donor B cells and the antibodies they produce play an important role in the development of cGVHD. To understand the pathogenic role of antibodies in cGVHD, we focused our studies on posttransplant production of immunoglobulin G antibodies targeting cell surface antigens expressed in multiple cGVHD affected tissues, due to their potential functional impact on living cells in vivo. Using plate-bound cell membrane proteins as targets, we detected a significantly higher level of antibodies reactive with these membrane antigens in patients who developed cGVHD, compared with those who did not and healthy donors. Plasma-reactive antibody levels increased significantly prior to the clinical diagnosis of cGVHD and were reduced following cGVHD therapies including prednisone, interleukin-2, or extracorporeal photophoresis. Using cell-based immunoprecipitation with plasma from cGVHD patients and mass spectrometry, we identified 43 membrane proteins targeted by these antibodies. The presence of antibodies in cGVHD patients' plasma that specifically target 6 of these proteins was validated. Antibodies reactive with these 6 antigens were more frequently detected in patients with cGVHD compared with patients without cGVHD and healthy donors. These results indicate that antibodies that target membrane antigens of living cells frequently develop in cGVHD patients and further support a role for B cells and antibodies in the development of cGVHD.

Double-Negative T Cell Levels Correlate with Chronic Graft-versus-Host Disease Severity

“…B cells also play important roles in the immune reaction leading to cGVHD [10][11][12]. Interestingly, BAFF plasma levels have been shown to correlate with cGVHD development [22,54], with excess BAFF promoting survival of self-reactive B cells [25,26].…”

“…Whereas aGVHD is triggered by direct T cell recognition of histocompatibility antigens, the pathophysiology of cGVHD is reminiscent of classical autoimmune disorders, involving both alloreactive T cells and B cells [10][11][12][13][14][15]. More specifically, B cells participate in antigen presentation to T cells, germinal center formation, and alloantibody and autoantibody production, all of which contribute to disease pathophysiology [10][11][12]. As a result, both T cell-and B cell-targeted therapies have been used to treat cGVHD.…”

Anti-Ro52 Autoantibodies Are Related to Chronic Graft-vs.-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

“…Chronic GVHD is an autoimmune-like syndrome caused by the interactions of donor CD4 + T and B cells and production of IgG (7)(8)(9)(10)(11). Recently, antibodies have been reported to play an important role in the development of cGVHD (12)(13)(14)(15)(16)(17)(18)(19). Previous studies showed that donor B cellderived antibodies augmented the development of bronchiolitis obliterans and perpetuated cutaneous cGVHD in mice (7,9).…”

Adrenal crisis in a 14-year-old boy 12 years after hematopoietic stem cell transplantation

“…Most common presentations are autoimmune cytopenias, Hashimoto thyroiditis or myasthenia gravis ( 24 , 25 , 26 , 27 , 28 ). Multiple autoantibodies have been associated with chronic GvHD ( 29 , 30 ). Assessing the prevalence of autoimmune diseases after HSCT, it has to be considered that HSCT is a curative treatment for both malignant diseases and many nonmalignant disorders, such as autoimmune diseases ( 31 ).…”