Innate Immunity and Biological Therapies for the Treatment of Sjögren’s Syndrome

Srivastava, Amrita; Makarenkova, Helen P.

doi:10.3390/ijms21239172

Cited by 30 publications

(27 citation statements)

References 305 publications

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“…In stark contrast to the control SMG, the NOD.B10 sample consisted of reduced numbers of cells that comprise the epithelial cell populations with the NOD.B10 mice having a total of 3,626 epithelial cells (or ~34%) compared to 4,955 epithelial cells (or ~41%) observed in the control glands ( Figure 4 ). This finding is not surprising given that the loss of these cell populations is commonly observed in pSS and has been attributed to the loss of salivary flow in patients ( 76 ). Overall, our scRNA-seq analyses has revealed the degree of cellular heterogeneity and the broad range of cell types associated with pSS diseased state.…”

Section: Resultsmentioning

confidence: 63%

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

et al. 2021

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Sjögren’s Syndrome (SS) is a chronic autoimmune disease of unknown etiology which primarily affects the salivary and lacrimal glands resulting in the loss of secretory function. Treatment options for SS have been hampered due to the lack of a better understanding of the underlying gene regulatory circuitry and the interplay between the myriad pathological cellular states that contribute to salivary gland dysfunction. To better elucidate the molecular nature of SS, we have performed RNA-sequencing analysis of the submandibular glands (SMG) of a well-established primary Sjögren’s Syndrome (pSS) mouse model. Our comprehensive examination of global gene expression and comparative analyses with additional SS mouse models and human datasets, have identified a number of important pathways and regulatory networks that are relevant in SS pathobiology. To complement these studies, we have performed single-cell RNA sequencing to examine and identify the molecular and cellular heterogeneity of the diseased cell populations of the mouse SMG. Interrogation of the single-cell transcriptomes has shed light on the diversity of immune cells that are dysregulated in SS and importantly, revealed an activated state of the salivary gland epithelial cells that contribute to the global immune mediated responses. Overall, our broad studies have not only revealed key pathways, mediators and new biomarkers, but have also uncovered the complex nature of the cellular populations in the SMG that are likely to drive the progression of SS. These newly discovered insights into the underlying molecular mechanisms and cellular states of SS will better inform targeted therapeutic discoveries.

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Section: Resultsmentioning

confidence: 63%

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

et al. 2021

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“…The hallmarks of pSS are progressive focal infiltration of immune cells (mainly T and B cells), hypergammaglobulinemia, and the presence of autoantibodies, underscoring the importance of adaptive immunity in SS pathophysiology (62,63). However, recent findings have suggested that innate immunity-especially NK cells-plays a role in SS pathogenesis (64)(65)(66). The relative and total numbers of circulating NK cells and CD56 dim NK cells were lower while the number of CD56 bright NK cells was higher in pSS patients compared to healthy control subjects (67,68).…”

Section: Nk Cells and Sjögren's Syndromementioning

confidence: 99%

NK Cells in Autoimmune Diseases: Protective or Pathogenic?

2021

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Autoimmune diseases generally result from the loss of self-tolerance (i.e., failure of the immune system to distinguish self from non-self), and are characterized by autoantibody production and hyperactivation of T cells, which leads to damage of specific or multiple organs. Thus, autoimmune diseases can be classified as organ-specific or systemic. Genetic and environmental factors contribute to the development of autoimmunity. Recent studies have demonstrated the contribution of innate immunity to the onset of autoimmune diseases. Natural killer (NK) cells, which are key components of the innate immune system, have been implicated in the development of multiple autoimmune diseases such as systemic lupus erythematosus, type I diabetes mellitus, and autoimmune liver disease. However, NK cells have both protective and pathogenic roles in autoimmunity depending on the NK cell subset, microenvironment, and disease type or stage. In this work, we review the current knowledge of the varied roles of NK cell subsets in systemic and organic-specific autoimmune diseases and their clinical potential as therapeutic targets.

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“…Results of function analysis using murine SS models have elucidated that 1, 2, and 17 cells are of great significance in the occurrence and development of SS, which play roles in regulating the differentiation, amplification, and functions of self-reactive T and B cells [7][8][9]. Furthermore, inflammatory cytokines balance the epithelial homeostasis and modulates the functions of B and T cells [3]. Ectopic expressions of CXC chemokines (CXCL9, CXCL10, CXCL11, and CXCL13), interleukins (IL-1/2/4/6/10/12/17/ 22/23), IFN-c, and TNF-α occur in the minor salivary glands of SS patients as compared to healthy individuals [10,11].…”

Section: Introductionmentioning

confidence: 99%

Integrated Network Pharmacology and Mice Model to Investigate Qing Zao Fang for Treating Sjögren’s Syndrome

Zeng

Liu

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Sjögren’s syndrome (SS) is an autoimmune disease, and its conventional treatment has exhibited limited therapeutic efficacy. Qing Zao Fang (QZF), a traditional Chinese medicine formula, is used in the treatment of Sjögren’s syndrome, but its chemical composition is complex, and its pharmacological mechanism is not clear. Therefore, this study aims to explore the potential mechanism of QZF in the treatment of Sjögren’s syndrome based on network pharmacology and SS mouse model. The main active components and predicted targets of QZF were analyzed by network pharmacology. The SS mouse model was constructed and divided into 6 groups: control, SS, SS + hydroxychloroquine (HCQ)-treated, SS + low-dose QZF-treated, SS + medium-dose QZF-treated, and SS + high-dose QZF-treated group. Immunohistochemical, ELISA, and qRT-PCR assays were performed to detect the expressions of targets associated with SS. TUNEL staining was used to detect apoptosis. Cumulatively, 230 active compounds and 1883 targets of QZF were identified. There were 227 common targets for QZF and SS. The effective active ingredients were stigmasterol, neocryptotanshinone II, neotanshinone C, miltionone I, and beta-pinene. It mainly acts on biological processes such as inflammatory response, chemokine metabolic process, and immune response as well as pathways such as FoxO signaling pathway, Yersinia infection, HIF-1 signaling pathway, and TNF signaling pathway. In SS mice, levels of AKT1, HIF-1α, TNF-α, IL-6, and IL-17A were increased, while decreased after QZF treatment. In contrast, IL-10 levels were decreased in SS mice and increased in QZF-treated mice. In addition, QZF reduced apoptosis in the submandibular gland tissue compared to SS mice. It can be concluded that the QZF in treatment of SS is the result of the combined action of multiple components, multiple targets, and multiple pathways. This study improves the understanding of the link between QZF and SS on molecular mechanisms.

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Innate Immunity and Biological Therapies for the Treatment of Sjögren’s Syndrome

Cited by 30 publications

References 305 publications

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

NK Cells in Autoimmune Diseases: Protective or Pathogenic?

Integrated Network Pharmacology and Mice Model to Investigate Qing Zao Fang for Treating Sjögren’s Syndrome

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