Complement component 4d immunostaining in liver allografts of patients with de novo immune hepatitis

Abstract

De novo immune hepatitis (DNIH) is a form of late graft dysfunction after liver transplantation. The fine mechanisms leading to the development of DNIH are not known, and whether this hepatitis is a form of rejection or a result of an auto/alloimmune injury has not been established. In our patients, DNIH was always preceded by the production of donor-specific antibodies against the glutathione S-transferase T1 (GSTT1) enzyme because of a genetic mismatch in which the donors carried the wild-type gene and the recipients displayed the null genotype. Complement component 4d (C4d) immunopositivity in 12 paraffin-embedded liver biopsy samples from 8 patients diagnosed with DNIH associated with anti-GSTT1 antibodies was retrospectively evaluated. Six patients with a diagnosis of chronic rejection (CR) and 7 patients with hepatitis C virus recurrence were included as control groups. Among the patients with DNIH, 7 showed C4d-positive immunostaining localized in the portal tracts, whereas in the tested biopsy samples of the 2 control groups, this staining pattern was absent. Four biopsy samples of the CR group showed C4d-positive sinusoidal staining. This study confirms the activation of the complement pathway in the presence of donor-specific antibodies, which was shown by the deposition of C4d elements in liver biopsy samples of patients with DNIH. The use of C4d as a marker of antibody-mediated rejection in liver allografts in the presence of antidonor antibodies is discussed, and it may contribute to improved differential diagnoses based on biopsy findings.

Donor-Specific HLA Antibodies in Living Versus Deceased Donor Liver Transplant Recipients

“…Consequently, it is reasonable to hypothesize that, given the nature of the procedure, DDLT recipients may be more sensitive to the detrimental effects of HLA antibodies in comparison to LDLT recipients. That said, similar to recent reports, DSA is likely to have an impact in both donor settings because our multivariate analysis demonstrated an independent association between DSA and graft failure regardless of donor type (5)(6)(7)(8)10,(19)(20)(21).…”

“…Not until the recent seminal work of multiple investigators has the interest in alloantibodies in LT become reinvigorated (6,7,10,20,26,27). Significant associations have been made between preformed and de novo DSA and liver transplant rejection, alloimmune hepatitis and patient and graft survival (4)(5)(6)(7)(8)(9)(10)19,21,26). Still, controversy exists because some reports have refuted these findings (27), and the current data have emanated mainly from singlecenter studies.…”

Complement component 4d immunohistochemistry in the assessment of liver allograft biopsy samples: Applications and pitfalls

“…We have not demonstrated portal venule staining or terminal hepatic venule staining with any significant frequency in native or allograft liver tissues with the fresh-frozen IF technique. This is consistent with the results of Aguilera et al 1 (see their Table 2), who found that biopsy samples from patients with non-de novo immune hepatitis did not demonstrate C4d in portal areas. We have found that IF staining for C4d is similar to the staining demonstrated by Aguilera et al in their chronic rejection group (see their Fig.…”

“…We read the article by Aguilera et al 1 and the accompanying editorial by Bellamy 2 with great interest. As Bellamy indicates, our group has documented complement component 4d (C4d) staining in ABO-compatible liver allograft recipients in 2 recent publications.…”

Histopathological Syndromes of Liver Allograft Rejection and Recurrent Disease

“…Portal vein and capillary C4d deposits can also be detected in other circumstances, including biliary obstruction [98], recurrent HBV infection [99], recurrent HCV infection [101], and de novo AIH [107]. C4d staining has also been described in portal venous and capillary, sinusoidal, central vein, and arterial endothelial cells, in lymphoid nodules, and in periductal and portal stromal cells in native pediatric livers with HBV, HCV, AIH, and overlap syndromes between AIH and PSC [108].…”