Cytomegalovirus-Induced Cd13-Specific Autoimmunity-a Possible Cause of Chronic Graft-Versus-Host Disease1

Abstract

Cytomegalovirus (CMV) infection has been suggested to be associated with certain autoimmune phenomena as well as with the development of chronic graft-versus-host disease (cGVHD) following allogeneic bone marrow transplantation. Earlier we found that the CMV-associated host protein CD13 is immunogenic during CMV infection in allogeneic bone marrow transplant patients, resulting in production of CD13-specific antibodies (7). Here we found a close correlation between CD13-specific immunity and later development of cGVHD in 26 of 33 patients who could be evaluated for this disease. Of seven patients with CMV disease, six developed extensive cGVHD, all of whom had CD13 specific antibodies (P=0.0002). All 14 patients who were CD13-immune later developed either limited or extensive cGVHD (P=0.0008). Antibodies in sera from the CD13-immune patients suffering from cGVHD recognized normal structures in cryosectioned skin biopsies from control individuals, producing a staining pattern similar to that of CD13-specific monoclonal antibodies. The antibody binding could be specifically blocked by preincubation of the skin sections with a mixture of monoclonal antibodies against CD13, and was also abolished after preabsorption of sera to mouse cells expressing human CD13. No other common autoantibodies were identified in more than single patients. Furthermore, in vivo binding of IgM antibodies in a CD13-like fashion was preferentially demonstrated in skin and oral mucosa biopsies from the CD13-immune patients suffering from cGVHD. Thus, we suggest that CMV-induced CD13-specific autoimmunity contribute to tissue damage in chronic graft-versus-host reactions.

Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation

“…38,40 The use of alternative donors increases the risk of CMV infection and acute GVHD. CMV infection has been associated with an increased risk of chronic GVHD, 20,57,58 and chronic GVHD has been associated with late CMV infection. 34 Despite these interactions, our results show that these factors have independent impacts on the risk of late death from infectious disease.…”

Clonal gammopathies following alemtuzumab-based reduced intensity conditioning haematopoietic stem cell transplantation: association with chronic graft-versus-host disease and improved overall survival

“…[4][5][6]15 There have been various observational reports on the development of autoantibodies and gammopathies post-HSCT coinciding with CMV reactivation or presence of GvHD. 16 Indeed, viral infections have been associated with the development of chronic GvHD or autoimmunity through various mechanisms such as aberrant expression of intracellular antigens on virus-infected cells triggering a specific immune response, or molecular mimicry between virally encoded peptides and self-peptides. 17 While the use of alemtuzumabbased RIC regimens has been associated with an increased incidence of viral infections post-HSCT, 18,19 in our cohort, there was no increased incidence of viral infections between patients with and without gammopathies (P ¼ 0.431).…”

“…There is increasing evidence to suggest that chronic GvHD shares many similarities with autoimmune disorders. 15,16 T cells and dendritic cells play an important role in B-cell maturation and the development of humoral response, and antibody responses against minor histocompatibility antigens such as H-Y antigens have been implicated in chronic GvHD and GvL effect following HSCT. 21 The role of humoral responses following transplantation is still undefined.…”

Response to steroids inde novoautoimmune hepatitis after liver transplantation

“…Bystander activation of macrophages and T lymphocytes, superantigen effects of bacterial products, and molecular mimicry processes are other factors that may occur during infection. 24,28,29 A distinctive feature of LTX is the need of immunosuppression, usually achieved by the use of calcineurin inhibitors. The possible relationship between cyclosporine and autoimmune phenomena is supported by several clinical and experimental features.…”