IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder capable of affecting nearly any organ. While previous research implicates both innate and adaptive immunity in its pathogenesis, a comprehensive synthesis of findings from emerging single-cell analyses was lacking. This systematic review aimed to consolidate and evaluate the current evidence from single-cell studies on IgG4-RD to enhance the understanding of its cellular and molecular mechanisms, identify key pathogenic cell subsets, and highlight future research directions.

A systematic literature review was conducted following the PRISMA guidelines. Searches were performed across four databases (PubMed, Embase, Cochrane Library, and Web of Science) in June 2025, using keywords including "IgG4-related disease", "IgG4-RD", and "single cell". Studies were included if they involved single-cell analysis of samples from IgG4-RD patients, with comparators being healthy individuals or patients with other conditions. Two reviewers independently screened titles, abstracts, and full texts. Data on study design, sample type, cellular findings, and key outcomes were extracted. The quality of included studies was assessed, and only those rated as "good" were incorporated. The review was finalized in September 2025.

The search identified 12 high-quality studies for inclusion, published between 2021 and 2025, encompassing a total of 382 patients. The analyzed samples included peripheral blood mononuclear cells (PBMCs, 6 studies), submandibular glands (SMGs, 6 studies), retroperitoneal tissue from IgG4-related retroperitoneal fibrosis (1 study), and cerebrospinal fluid (CSF, 1 study). The review revealed widespread cellular activation and dysfunction across multiple compartments. In PBMCs, studies reported abnormalities in various immune cells. Cytotoxic T lymphocytes (CTLs), including both CD4⁺ and CD8⁺ subsets, were expanded and exhibited enhanced chemotaxis, cytotoxicity, and the ability to induce mesenchymal cell apoptosis. B cells showed upregulation of pathways related to protein processing, oxidative phosphorylation, and the unfolded protein response. A unique extrafollicular IgD^-CD27^-CXCR5^-CD11c^-DN3 B cell subset was identified. Monocytes demonstrated increased TNF production and expression of profibrotic factors like RETN, while also secreting BAFF to support B cell survival. Dendritic cells (DCs) were enriched for chemotaxis-related genes, and natural killer (NK) cells showed upregulation of activation and cytotoxicity-associated genes. In SMGs, research highlighted the involvement of tissue-resident and infiltrating cells. Novel T follicular helper (Tfh)-like cell populations were identified, including IL-10⁺LAG3⁺ Tfh cells potentially involved in IgG4 class-switching, and granzyme K-expressing cytotoxic Tfh cells within tertiary lymphoid structures. CD4⁺ CTLs expressing amphiregulin and TGF-β were found to interact with proliferating (MKI67⁺) B cells. Specific B cell subsets, such as TOP2A_B cells (poised to become IgG4+ plasma cells) and ICOS_PD-1_B cells (a transitional state), were described. Furthermore, fibroblasts expressing collagen type XV were identified as a potential disease-characterizing non-immune cell population. In retroperitoneal tissue, a single study found a notable increase in CD4⁺CXCR5^-PD-1hi peripheral helper T (Tph) cells, which highly expressed IL-21 and TIGIT. Experimental evidence suggested these Tph cells promote B cell maturation and differentiation into plasmablasts via the TIGIT-IL-21 signaling pathway. In CSF, analysis of a single case identified an oligoclonal T-cell response. CD8⁺ effector memory T cells (TEM) were implicated in driving the migration and proliferation of pathogenic B cells via MIF-CD74 signaling and recruiting CD4⁺ CTLs via CCL5.

This systematic review synthesizes evidence that IgG4-RD pathogenesis involves a complex interplay of activated and dysfunctional immune and non-immune cells across different tissues. Key findings include the prominent roles of cytotoxic CD4⁺ and CD8⁺ T cells, distinct helper T cell subsets (Tfh, Tph), aberrant B cell activation and differentiation, and the contribution of stromal cells like fibroblasts. While single-cell RNA sequencing has been instrumental in revealing this cellular heterogeneity and inferring pathogenic interactions, the field has yet to fully leverage spatial transcriptomics to elucidate the tissue microenvironment's architecture. Future research integrating spatial context with single-cell data is anticipated to provide a more comprehensive understanding of cellular interactions in IgG4-RD, paving the way for more precise therapeutic strategies.