Age-associated B cell infiltration in salivary glands represents a hallmark of Sjögren's-like disease in aging mice.

Sjögren's disease (SjD), characterized by circulating autoantibodies and exocrine gland inflammation, is typically diagnosed in women over 50 years of age. However, the contribution of age to SjD pathogenesis is unclear. C57BL/6 female mice at different ages were studied to investigate how aging influences the dynamics of salivary gland inflammation. Salivary glands were characterized for immune cell infiltration, inflammatory gene expression, and saliva production. At 8 months, gene expression of several chemokines involved in immune cell trafficking was significantly elevated. At this age, age-associated B cells (ABCs), a unique subset of B cells expressing the myeloid markers CD11b and/or CD11c, were preferentially enriched in the salivary glands compared to other organs like the spleen or liver. The salivary gland ABCs increased with age and positively correlated with increased CD4 T follicular helper cells. By 14 months, lymphocytic foci of well-organized T and B cells spontaneously developed in the salivary glands. In addition, the mice progressively developed high titers of serum autoantibodies. A subset of aged mice developed salivary gland dysfunction mimicking SjD patients. Our data demonstrates that aging is a significant confounding factor for SjD. Thus, aged female C57BL/6 mice are more appropriate and a valuable preclinical model for investigating SjD pathogenesis and novel therapeutic interventions.

Age-associated B cell infiltration in salivary glands represents a hallmark of Sjögren's-like disease in aging mice.

Sjögren's disease (SjD), characterized by circulating autoantibodies and exocrine gland inflammation, is typically diagnosed in women over 50 years of age. However, the contribution of age to SjD pathogenesis is unclear. C57BL/6 female mice at different ages were studied to investigate how aging influences the dynamics of salivary gland inflammation. Salivary glands were characterized for immune cell infiltration, inflammatory gene expression, oxidative stress, and saliva production. At 8 months, gene expression of several chemokines involved in immune cell trafficking was significantly elevated. At this age, Age-associated B cells (ABCs), a unique subset of B cells expressing the myeloid markers CD11b and/or CD11c, were preferentially enriched in the salivary glands compared to other organs like the spleen or liver. The salivary gland ABCs increased with age and positively correlated with increased CD4 T follicular helper cells. By 14 months, lymphocytic foci of well-organized T and B cells spontaneously developed in the salivary glands. In addition, the mice progressively developed high titers of serum autoantibodies. A subset of aged mice developed salivary gland dysfunction mimicking SjD patients. Our data demonstrates that aging is a significant confounding factor for SjD. Thus, aged female C57BL/6 mice are more appropriate and a valuable preclinical model for investigating SjD pathogenesis and novel therapeutic interventions.

STING Agonist-Induced Skin Inflammation Is Exacerbated with Prior Systemic Innate Immune Activation.

Activation of the Stimulator of Interferon Genes (STING) protein has paradoxical outcomes in skin disease. STING activation exacerbates psoriatic skin disease and delays wound healing in diabetic mice, yet it also facilitates wound healing in normal mice. To address the role of localized STING activation in the skin, mice were injected subcutaneously with a STING agonist, diamidobenzimidazole STING Agonist-1 (diAbZi). The effect of a prior inflammatory stimulus on STING activation was addressed by pre-treating mice intraperitoneally with poly (I:C). The skin at the injection site was evaluated for local inflammation, histopathology, immune cell infiltration, and gene expression. Serum cytokine levels were measured to assess systemic inflammatory responses. Localized diABZI injection induced severe skin inflammation with erythema, scaling, and induration. However, the lesions were self-limiting and resolved within 6 weeks. At the peak of inflammation, the skin showed epidermal thickening, hyperkeratosis, and dermal fibrosis. Neutrophils, CD3 T cells, and F4/80 macrophages were present in the dermis and subcutaneous layers. Gene expression was consistent with increased local interferon and cytokine signaling. Interestingly, the poly (I:C)-pre-treated mice showed higher serum cytokine responses and developed worse inflammation with delayed wound resolution. Our study demonstrates that prior systemic inflammation amplifies STING-mediated inflammatory responses and skin disease.

Antibody deposition on vascular endothelial cells contributes to localized inflammation in salivary glands.

BACKGROUND: Oral and ocular dryness due to reduced saliva and tear production, exocrine gland inflammation, and autoantibodies to multiple cellular proteins are the cardinal features of Sjögren's Disease. Among the autoantibody specificities, anti-Ro52 is linked with higher disease severity. We have previously reported that mice immunized with recombinant Ro52 developed IgG deposits in salivary and lacrimal glands and showed reduced saliva and tear production. Furthermore, passive transfer of sera from Ro52-immunized mice rapidly induced glandular dysfunction without immune cell infiltration in recipient mice. METHODS: To identify mechanisms driving antibody-mediated salivary gland dysfunction, hyperimmune rabbit antiserum to mouse Ro52 was passively transferred into NZM2758 female mice, pretreated with alum adjuvant. Alum-pretreated mice given hyperimmune rabbit antiserum to maltose-binding protein served as controls. Antibody deposition and its distribution in the salivary glands were studied by immunofluorescence staining for rabbit IgG, nerve fibers, and endothelial cells. The nCounter inflammation panel was used to determine differentially expressed genes in the salivary gland. RESULTS: Rabbit IgG deposits were detected in salivary glands of anti-Ro52 immune sera recipients. The rabbit IgG was present on the endothelial cells in small blood vessels, and it did not co-localize with nerve fibers. Ingenuity pathway analysis of the gene expression dataset predicted the canonical vascular endothelial growth factor (VEGF) pathway as the most activated and Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) as the most inhibited pathway in the salivary glands of anti-Ro52 sera recipients. CONCLUSION: Our study suggests that autoantibody deposition on salivary gland endothelial cells might play a critical role in the pathogenesis of Sjögren's Disease.

Systemic immune response to vimentin and granuloma formation in a model of pulmonary sarcoidosis.

A characteristic feature of sarcoidosis is a dysregulated immune response to persistent stimuli, often leading to the formation of non-necrotizing granulomas in various organs. Although genetic susceptibility is an essential factor in disease development, the etiology of sarcoidosis is not fully understood. Specifically, whether autoimmunity contributes to the initiation or progression of the disease is uncertain. In this study, we investigated systemic autoimmunity to vimentin in sarcoidosis. IgG antibodies to human vimentin were measured in sera from sarcoidosis patients and healthy controls. Mice immunized with recombinant murine vimentin were challenged intravenously with vimentin-coated beads to mimic pulmonary sarcoidosis. Lungs from treated mice were studied for cellular infiltration, granuloma formation, and gene expression. Immune cells in the bronchoalveolar lavage fluid were evaluated by flow cytometry. Compared to healthy controls, sarcoidosis patients had a higher frequency and levels of circulating anti-vimentin IgG. Vimentin-immunized mice developed lung granulomas following intravenous challenge with vimentin-coated beads. These sarcoidosis-like granulomas showed the presence of Langhans and foreign body multinucleated giant cells, CD4 T cells, and a heterogeneous collection of MHC II positive and arginase 1-expressing macrophages. The lungs showed upregulated pro-inflammatory gene expression, including Ifng, Il17, and Tnfa, reflecting TH1/TH17 responses typical of sarcoidosis. In addition, genes in the TH2 canonical pathway were also upregulated, congruent with increased numbers of ILC2 in the bronchoalveolar lavage. Overall, these results further validate vimentin as an autoantigen in sarcoidosis and provide evidence for an anti-vimentin immune response in disease pathogenesis. Our study also highlights the possible role of ILC2-driven TH2-like responses in the formation of lung granulomas in sarcoidosis.