Immunoproteomic Analysis of Potentially Severe Non-Graft-Versus-Host Disease Hepatitis After Allogenic Bone Marrow Transplantation

Abstract

The development of potentially severe non-graft-versus-host disease (GVHD) hepatitis resembling autoimmune hepatitis (AIH) has been reported after bone marrow transplantation (BMT). The aim of this study was to better characterize this form of hepatitis, particularly through the identification of autoantigens recognized by patient sera. Five patients who received an allogeneic BMT for the treatment of hematological diseases developed liver dysfunction with histological features suggestive of AIH. Before and during the onset of hepatic dysfunction, sera were tested on immunoblottings performed with cytosolic, microsomal, mitochondrial, and nuclear proteins from rat liver homogenate and resolved by two-dimensional electrophoresis. Antigenic targets were identified by mass spectrometry. During the year that followed BMT, all patients presented with GVHD. Acute hepatitis then occurred after the withdrawal, or during the tapering, of immunosuppressive therapy. At that time, no patients had a history of liver toxic drug absorption, patent viral infection, or any histopathological findings consistent with GVHD. Immunoreactive spots stained by sera collected at the time of hepatic dysfunction were more numerous and more intensely expressed than those stained by sera collected before. Considerable patient-dependent pattern heterogeneity was observed. Among the 259 spots stained exclusively by sera collected at the time of hepatitis, a total of 240 spots were identified, corresponding to 103 different proteins. Twelve of them were recognized by sera from 3 patients. Conclusions: This is the first immunological description of potentially severe non-GVHD hepatitis occurring after BMT, determined using a proteomic approach and enabling a discussion of the mechanisms that transform an alloimmune reaction into an autoimmune response. Any decision to withdraw immunosuppression after allogeneic BMT should be made with caution.

Antigenicity of Bovine Pericardium Determined by a Novel Immunoproteomic Approach

“…Indeed, in the present study, since animal models are expected to generate a robust immune response, it is intriguing that a relatively small subset of proteins within BP was identified as antigenic. Furthermore, 31 of the antigens identified in the current study have also been implicated as antigens in the pathogenesis of human diseases 30–35 , the majority of them through identification of their antigen specific antibodies 23–25, 36–49 . A Basic Local Alignment Search Tool (BLAST) search between rabbit and bovine for these previously identified antigens showed them to share between 40–99% homology 50 , with 11 of the antigens sharing greater than 93% homology.…”

“…For example, Beleoken et al . found twelve hepatic autoantigens associated with graft versus host disease, however, no integral membrane antigens were identified 23 . Similarly, Biswas et al ., identified 18 rheumatoid arthritis autoantigens, none of which were integral membrane antigens 24 .…”

Autoimmune-Like Hepatitis

“…Furthermore, the diagnostic score according to the AIH group criteria was 19, classifying the case as definite AIH; however, there were no autoantibodies present, which is one of the major criteria for AIH. 17 There was also no response to steroids. Therefore, we believe this case represents AILH, or an AILH variant of “hepatitic” GVHD, which has been infrequently described.…”

Development of a novel histologic diagnostic algorithm for hepatic graft-versus-host disease

“…30 Hepatic graft-versus-host disease may also be associated with de novo liver diseases. Beleoken et al 31 noted several hepatic graft-versushost disease patients who went on to develop an autoimmune hepatitis presentation after tapering or cessation of immunosuppression, and suggest that hepatic graft-versus-host disease may be a factor in the pathogenesis of de novo autoimmune liver disease. A primary biliary cholangitis-like picture has been similarly noted in murine models.…”