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IgG 4 -related disease (IgG 4 -RD) is an immune-mediated fibrotic disorder that has been linked to CD4+ cytotoxic T lymphocytes (CD4+CTLs). The effector phenotype of CD4+CTLs and the relevance of both CD8+ cytotoxic T lymphocytes (CD8+CTLs) and apoptotic cell death remain undefined in IgG 4 -RD. We sought to define CD4+CTL heterogeneity, characterize the CD8+CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG 4 -RD. Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data. We establish that among circulating CD4+CTLs in IgG 4 -RD, CD27loCD28loCD57hi cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A–expressing CD8+CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8+ T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR. CD4+CTLs and CD8+CTLs may induce apoptotic cell death in tissues of patients with IgG 4 -RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin. [ABSTRACT FROM AUTHOR]

ImmunoglobulinG4-related disease (IgG4-RD) is a recently recognized disease and, as such, there is a pressing need to identify biomarkers for diagnosis, monitoring disease activity, and predicting prognosis and response to therapy. Here, we review the recent development and identification of biomarkers for IgG4-RD. Through extensive literature review and analysis, we updated the biomarkers for IgG4-RD and further put forward our own viewpoints. In addition to traditional biomarkers, such as serum IgG4 concentration and typical histological characteristics, several novel indicators, including IgG2, serum soluble IL-2 receptor (sIL2R), and cc-chemokine ligand 18 (CCL18), indicate inflammation and fibrosis and can be used to accurately diagnose and predict treatment response. Studies to identify target autoantigens in IgG4-RD have shed light on the unmet need for biomarkers that can identify this disorder. Additionally, both serological and histopathologic immune cells involved in antigen-induced responses, innate immune cells (macrophages, mast cells, and the I-IFN/ IL-33 pathway), as well as subsequent acquired immune cells (T and B cell subsets), may also serve as new biomarkers for IgG4-RD. Since IgG4-RD often clinically manifests with multiple organs involvement, non-invasive PET-CT can improve diagnosis and antidiastole levels. These novel biomarkers provide information to help diagnose IgG4-RD, monitor disease activity, as well as predict prognosis and response to therapy. [ABSTRACT FROM AUTHOR]

How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T-cell–dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs in patients with elevated tissue expression levels of IgE (Kimura disease, KD) and those of IgG 4 (IgG 4 -related disease, IgG 4 -RD) can provide important insights regarding cytokine expression by Tfh cells. We sought to identify disease-specific Tfh cell subsets in secondary and tertiary lymphoid organs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in 2 distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). Single-cell RNA sequencing, in situ sequencing, and multicolor immunofluorescence analysis were used to investigate B cells, Tfh cells, and infiltrating type 2 cells in lesion tissues from patients with KD or IgG 4 -RD. Infiltrating Tfh cells in tertiary lymphoid organs from IgG 4 -RD were divided into 6 main clusters. We encountered abundant infiltrating IL-10 –expressing LAG3 + Tfh cells in patients with IgG 4 -RD. Furthermore, we found that infiltrating AICDA + CD19 + B cells expressing IL-4 , IL-10 , and IL-21 receptors correlated with IgG 4 expression. In contrast, we found that infiltrating IL-13–expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13–expressing Tfh cells in tissues from patients with IgG 4 -RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG 4 -RD; in contrast, type 2 immune cells were abundant in KD. Our analysis revealed a novel subset of IL- 10 + LAG3 + Tfh cells infiltrating the affected organs of IgG 4 -RD patients. In contrast, IL-13+ Tfh cells and type 2 immune cells infiltrated those of KD patients. [Display omitted] [ABSTRACT FROM AUTHOR]