Immune traits in combination with inflammatory proteins revealing the pathogenesis of autoimmune liver diseases: A Mendelian randomization study

Abstract

Background

Prior observational research has shown relationships between immune cells, inflammatory proteins, and autoimmune liver diseases (AILD), but their causal associations remain controversial. Therefore, we aimed to clarify the causal association between them.

Methods

We carried out a comprehensive Mendelian randomization (MR) analysis to clarify causal associations between 731 immune traits, 91 circulating inflammatory proteins, and AILD, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH). A two-step MR analysis was used to explore the mediating role of circulating inflammatory proteins. Additionally, we performed sensitivity analyses to evaluate the robustness of the results.

Results

CD27 on IgD⁺ CD24⁺ B cell, CD27 on IgD⁻ CD38^dim B cell, CD27 on unswitched memory B cell, CD27 on switched memory B cell, and CD27 on CD24⁺ CD27⁺ B cell were risk factors for PBC. However, we detected protective effects of CD25 on IgD⁻ CD27⁻ B cell against PBC and CD28 on resting CD4⁺ Treg cell against PSC. Circulating CD40, Interleukin-33, and Delta and Notch-like epidermal growth factor-related receptor were protective factors for PBC. Furthermore, CD40 mediated the association between immune traits and PBC, with the mediated proportions ranging from 18.3 % to 35.4 %. Tumor necrosis factor superfamily member 12 was identified as a risk factor for PSC, and monocyte chemotactic protein 3 was identified as a protective factor for PSC. Additionally, PBC and PSC had effects on eleven immune traits, which are suggested to be the consequences of them. We found no causal association between immune traits, circulating inflammatory proteins, and AIH. Sensitivity analyses demonstrated our results were robust.

Conclusions

Our results demonstrate the causal roles of immune traits and inflammatory proteins in PBC and PSC, which reveals their pathogenesis. It is necessary to investigate the specific mechanism by which immune cells and inflammatory proteins affecting the occurrence of AILD.