Transfer of PBMC From SSc Patients Induces Autoantibodies and Systemic Inflammation in Rag2-/-/IL2rg-/- Mice.

Xiaoyang Yue,Antje Müller,Junping Yin,Xinhua Yu,Harald Heidecke,Jacqueline Wax,Junie D Tchudjin Magatsin,Brigitte Kasper,Yaqing Shu,Marjan Ahmadi,Gabriela Riemekasten,Peter Lamprecht,Xiaoqing Wang,Frank Petersen

doi:10.3389/fimmu.2021.677970

Abstract

ObjectiveThe contribution of sustained autologous autoantibody production by B cells to the pathogenesis of systemic sclerosis (SSc) and granulomatosis with polyangiitis (GPA) is not fully understood. To investigate this, a humanized mouse model was generated by transferring patient-derived peripheral blood mononuclear cells (PBMC) into immunocompromised mice.MethodsPBMC derived from patients with SSc and GPA as well as healthy controls (HD) were isolated, characterized by flow cytometry, and infused into Rag2-/-/IL2rg-/- mice. In addition, PBMC from SSc patients treated with rituximab were transferred into mice. Twelve weeks later, human autoantibodies were determined in blood of the recipient mice and affected tissues were analyzed for pathological changes by histology and immunohistochemistry.ResultsMice engrafted with PBMC derived from SSc patients developed autoantibodies such as antinuclear antibodies (ANA) mimicking the pattern of the respective donors. Moreover, cellular infiltrates dominated by B cells were observed in lung, kidney and muscles of the recipient mice. By contrast, PBMC derived from HD or GPA patients survived in recipient mice after transfer, but neither human autoantibodies nor inflammatory infiltrates in tissues were detected. Furthermore, these pathological changes were absent in mice transferred with PBMC from rituximab-treated SSc patients.ConclusionThis humanized mouse model is indicative for cross-reactivity of human lymphocytes to murine autoantigens and argues for a pivotal role of B cells as well as of sustained autoimmunity in the pathogenesis of SSc. It provides a powerful tool to study interstitial lung disease and so far, under-recognized disease manifestations such as myositis and interstitial nephritis.

Highlights

Systemic sclerosis (SSc) and granulomatosis with polyangiitis (GPA) are systemic autoimmune diseases affecting multiple organs
peripheral blood mononuclear cells (PBMC) derived from patients with SSc (n=6), patients with GPA (n=3) and from healthy donors (HD) (n=) were transferred into 8, 6 and 9 Rag2-/-/ IL2rg-/- mice, respectively
Sera of all mice transferred with PBMC derived from HD were negative for Antinuclear antibodies (ANA), whereas ANA were detected in sera of 2 out of 6 mice which received SSc-PBMC (Figure 2B)

Summary

Introduction

Systemic sclerosis (SSc) and granulomatosis with polyangiitis (GPA) are systemic autoimmune diseases affecting multiple organs. They are characterized by distinct disease phenotypes with respect to immunopathology, extent of organ involvement and clinical symptoms [1, 2]. In GPA, the pivotal role of anti-neutrophil cytoplasmic autoantibodies targeting proteinase-3 (PR3-ANCA) for the aberrant activation of cytokine-primed neutrophils was shown in studies in vitro and in vivo [2]. This concept is further supported by the therapeutic effect of rituximab, a B cell-depleting antibody, in GPA. The contribution of B cells and the humoral immune response needs to be proven

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Conclusion