Differential IgG4-Producing Plasma Cell Infiltration in Non- and Post-Transplant Plasma Cell Hepatitis

Abstract

Autoimmune hepatitis (AIH), post-transplant recurrent AIH (rAIH), and plasma cell-rich rejection (PCR) are clinical diagnoses with the shared histopathologic hallmark of plasma cell hepatitis (PCH). As these histologically and serologically indistinguishable diagnoses are differentiated by clinical context, it remains uncertain whether they represent distinct immunologic phenomena. Improved understanding of immunoglobulin subclass 4-producing plasma cells (IgG4-PC) has brought attention to IgG4 as an immunophenotypic biomarker. To date, degree and clinical significance of IgG4-PC infiltration in PCH remain elusive. This retrospective, single-center study assessed IgG4-PC infiltration in AIH, rAIH, and PCR via standardized immunohistochemistry analysis. Identified cases from 2005 to 2020 (n = 47) included AIH (treatment-naïve AIH (tnAIH): n = 15 and AIH-flare on treatment (fAIH); n = 10), rAIH (n = 8), and PCR (n = 14) were analyzed and correlated with clinical characteristics. IgG4-Positivity (# IgG4-PC/# pan-IgG-expressing cells) distribution was heterogenous and overlapping [tnAIH: 0.060 (IQR 0.040–0.079), fAIH: 0.000 (0.000–0.033), rAIH: 0.000 (0.000–0.035), PCR: 0.228 (0.039–0.558)]. IgG4-Positivity was inversely correlated with corticosteroid use (p < 0.001). IgG4-Positivity ≥0.500 was associated with rapid AST improvement (p = 0.03). The variable IgG4-Positivity of AIH, rAIH and PCR suggests diverse and overlapping immunopathologic mechanisms and that current diagnostic schemes inadequately capture PCH immunopathology. We propose incorporation of IgG4-Positivity to refine current PCH classification and treatment strategies.

Reply to: Comments on: Differential IgG4-Producing Plasma Cell Infiltration in Non- and Post-Transplant Plasma Cell Hepatitis

“…Additionally, their work also suggests that serologic evaluation of anti-GSTT1 antibodies may be a useful marker in PCR diagnosis and disease response to corticosteroid therapy (1). It is satisfying that the findings from our histopathologic assessment of post-transplant plasma cell hepatitis correlates with their observations (2).…”

“…A study in which IgG4 Positivity and anti-GSTT1 antibodies are identified in the same subjects is warranted. Additionally, as our works only evaluated a combined 28 cases of PCR and rAIH, further studies with a larger cohort are needed (1,2).…”