Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance

Abstract

Autoimmune hepatitis has been described as recurrent or de novo disease after transplantation. The legitimacy of these diagnoses and the bases for their occurrence are unknown. To better understand these aspects of allograft dysfunction, the purported pathogenic mechanisms of classical autoimmune hepatitis were reviewed and extrapolated to recurrent and de novo disease after transplantation. Loss of self-tolerance may relate to defects in the negative selection of autoreactive immunocytes and the clonal expansion of promiscuous lymphocytes that are cross-reactive to homologous antigens (molecular mimicry). Repopulation of the allograft with recipient antigen-presenting cells and the presence of primed promiscuous cytotoxic T cells within the recipient are likely factors for recurrent disease. Targets may be the same peptides that triggered the original disease, donor-derived class II antigens of the major histocompatibility complex, or homologous antigens associated with unidentified hepatotrophic viruses. De novo disease is probably due to similar mechanisms, but its predilection for children suggests that thymic dysfunction associated with cyclosporine treatment may be a factor. Corticosteroid therapy is effective in each condition. In conclusion, recurrent and de novo autoimmune hepatitis after transplantation are examples of self-intolerance. The mechanisms that perturb immunologic homeostasis in this human model of the classical disease must be studied more rigorously. (Liver Transpl 2002;8:505-513.)

Rejection and Steroid Dependence: Unique Risk Factors in the Development of Pediatric Posttransplant De Novo Autoimmune Hepatitis

“…Prior hypotheses have included immunosuppression-induced autoimmunity (35)(36)(37)(38), molecular mimicry (17,39), autoantibodies directed against glutathione-S-transferase T1 (16,40) and a preponderance of acute cellular rejection to lead to the development of d-AIH (17,(41)(42)(43). Many of these theories have only been examined in animal models, and clearly additional work is needed to understand mechanisms involved in d-AIH.…”

Liver biopsy interpretation for causes of late liver allograft dysfunction

“…2 Acute rejection is also the most likely diagnosis when central perivenulitis involves a majority of central veins with minimal or absent portal inflammation, except if the original disease was AIH. In this situation, isolated central perivenulitis may represent early recurrent AIH 34,42,74,75 or new-onset AIH. In native livers presenting with acute AIH central perivenulitis, chronic portal inflammation and interface activity usually develop over time.…”

“…Donor livers undoubtedly contain nonmajor histocompatibility complex antigens not expressed in the native liver, and theoretically all forms of AIH after transplantation could be classified as rejection. 34,42 Serological and histological findings used to distinguish AIH from rejection may reflect the nature, density, and location of antigenic targets. There are no conventional clinical tests that differentiate an autoimmune response from rejection, and distinctions based on clinical and histopathological findings may not reflect the true pathogenesis.…”

“…Criteria used to distinguish rejection from AIH can be melded into generalized criteria applicable to other causes of late liver allograft dysfunction, [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] including: (1) histopathological evidence of liver injury showing a pattern compatible with the diagnosis (liver tests are usually elevated in a pattern consistent with the diagnosis); (2) positive serological, molecular biological, immunological, or radiographic evidence of pathogen or possible cause of injury; and (3) other causes of similar histopathological changes and elevated liver tests, if present, have been reasonably excluded. Table 1 shows approximate incidences, risk factors, and clinical, immunological, and radiological observations for common causes of late dysfunction.…”

Autoimmune Hepatitis After Liver Transplantation

“…The pathogenesis of recurrent AIH is uncertain, although it is widely accepted that a strong genetic predisposition may affect its occurrence, behavior and outcome (Czaja, 2008a), as well as its risk of recurrence (Czaja, 1999b(Czaja, , 2002(Czaja, , 2009. HLA mismatching between donor and recipient has been proposed as a factor in recurrent disease (Wright, 1992), but its importance continues to be disputed (Gonzales-Koch et al, 2001;Ayata et al, 2000;Milkiewicz, 1999, Reich, 2000, Devlin, 1995.…”