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Comprehensive Profiling of Peripheral Blood Mononuclear Cells Reveals Monocyte-CD8+ T cell-B cell Communication as Central Cell-cell Interaction and pathogenesis in IgA Vasculitis

ABSTRACT: IgA vasculitis (IgAV) is a common vasculitis which often occurs in children. IgAV is characterized by the vasculitis caused by IgA deposition in the walls of small vessels. The mechanisms of immune disorders in IgAV, as well as the innmue network regulation between immune cells is still unclear. Dissecting the IgA-secreting B cells is crucial for understanding the pathegenesis mechanisms of IgA deposition in IgA vasculitis (IgAV). Here, we used single-cell RNA sequencing to profile immune cells in peripheral blood mononuclear cells of IgAV. MIF induced IgA secretion in IgAV, and monocyte-CD8+ T cell-B cell communication regulated MIF pathway. ICAMs pathway regulated monocyte-CD8+ T cell-B cell communication, and promoted B cells adhension in IgAV. CD8+ T cell was the key cell in monocyte-CD8+ T cell-B cell communication. TCR repertoire analysis identified a specific CD8+ Temra cluster with specific TCR clonetypes. BCR repertoire analysis revealed the existence of IgA Fc-specific IgG in serum of IgAV nephritis. These findings reveals complicated immune regulation in IgAV, emphrazing the importance of MIF and ICAMs pathways in cell-cell interaction, discovering CD8+ T cells’ crucial function for IgAV pathogenesis, and bringing new insights into the pathegenesis of IgA deposition in IgAV.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243002 | GEO | 2024/09/05

REPOSITORIES: GEO

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Project description:The discovery of hepatitis C virus (HCV) in 1989 revealed the virus as the etiology of 40%-90% of the “essential” mixed cryoglobulinemia, where immune complex forms deposit called cryoprecipitate at temperatures below 37 °C. Cryoprecipitate constitutes monoclonal IgM and polyclonal IgG, some of which has reactivity against HCV core and NS3 epitopes. Resultant immune complex is considered entrapped on microvascular endothelium via C1q receptor, leading to complement activation and organ injury presenting predominantly as dermopathy, peripheral neuropathy and nephropathy. However, currently little is known on whether auto-reactive, cold-precipitating IgG components enriched in cryoprecipitate may play some role on the deposition of immune complex and subsequent complement-mediated injury of specific organs. Recently, with the advent of high-throughput immune repertoire sequencing and mass spectrometry, technical feasibility is growing to delineate antibodies of interest and their sequences directly from serum. To date, vast majority of studies actually utilized the antigen column for affinity purification of antibodies of interest, although this strategy is not applicable to disease entity with unknown antigen involvement. In such cases, disease-specific and organ-specific immune deposits may be a good alternative source of etiological antibodies. Herein, targeting HCV cryoglobulinemic vasculitis as a model, we conducted a proof-of-concept study aiming at characterizing the IgG components most prone to cryoprecipitation. To this end, we longitudinally studied one patient with cryoglobulinemic vasculitis with chronic HCV infection. After obtaining informed consent, cryoprecipitate and supernatant were separated from peripheral blood sample. Fab fragments from Protein G-purified IgG were recovered after papain digestion for isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomics. Simultaneously, total RNA was isolated from peripheral blood, and immunoglobulin heavy chain variable region (IGHV) was PCR-amplified with unique molecular identifier (UMI) strategy to construct a personal IGHV sequence library of immunoglobulin variable region. Sequencing output from MiSeq was bioinformatically converted into mass spectrometry database. Search was performed using MaxQuant software.

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Comprehensive Profiling of Peripheral Blood Mononuclear Cells Reveals Monocyte-CD8+ T cell-B cell Communication as Central Cell-cell Interaction and pathogenesis in IgA Vasculitis

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