Identifying the Signature Immune Phenotypes Present in Pediatric Localized Scleroderma

Mirizio, Emily; Marathi, Archana; Hershey, Nicole; Ross, Caroline; Schollaert, Kaila L.; Salgado, Cláudia; Reyes‐Múgica, Miguel; Torok, Kathryn S.

doi:10.1016/j.jid.2018.09.025

Cited by 29 publications

(40 citation statements)

References 15 publications

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“…We found significant increases in numbers of epidermal T cells ( Fig 2B), dermal T cells, and dermal antigen presenting cells (APCs, including populations of CD11b+CD11c+ and CD11b+ macrophages and CD11c+ dendritic cells) but not B cells ( Fig 2C). These findings mirror those found in human morphea lesions, namely increased T cell and macrophage signatures (Higashi-Kuwata et al 2009;Mirizio et al 2019) .…”

Section: T Cells Antigen Presenting Cells and Fibroblasts Are Increasupporting

confidence: 84%

“…Our previous work, as well as others, has shown that the interferon (IFN)-inducible chemokines CXCL9 and CXCL10 are highly expressed in lesional skin and serum from morphea patients, and may serve as biomarkers for disease activity and severity (Mertens et al 2018;Mirizio et al 2019;O'Brien et al 2017) . Together with CXCL11, CXCL9 and CXCL10 bind to a shared receptor, CXCR3 (Colvin et al 2004) .…”

Section: Introductionmentioning

confidence: 99%

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An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3

Patel

Watanabe

et al. 2019

Preprint

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Morphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. We first characterized which cells produce the CXCR3 ligands in the skin using the Reporter of Expression of CXCR3 ligands mouse (REX3). We found that fibroblasts contribute the bulk of CXCL9 and CXCL10, whereas endothelial cells are key dual chemokine producers. Macrophages, which have high MFI of chemokine expression, upregulated CXCL9 production over time, fibroblasts CXCL10 production, and T cells dual chemokine expression. To determine whether bleomycin treatment could directly induce expression of these chemokines, we treated cultured REX3 mouse dermis monolayers in vitro with bleomycin or IFNγ with TNF and found that bleomycin could induce low amounts of CXCL9 directly in fibroblasts, whereas the cytokines were required for optimal CXCL9 and CXCL10 production. To determine whether these chemokines are mechanistically involved in pathogenesis, we induced fibrosis in CXCL9, CXCL10, or CXCR3 deficient mice and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9, but not CXCL10, to cultured mouse fibroblasts induces collagen 1a1 mRNA expression, indicating the chemokine itself can contribute to fibrosis. Taken together, our studies provide evidence that acute intradermal bleomycin administration in mice can model inflammatory morphea, and that CXCL9 and its receptor CXCR3 are mechanistically involved in pathogenesis.

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Section: T Cells Antigen Presenting Cells and Fibroblasts Are Increasupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3

Patel

Watanabe

et al. 2019

Preprint

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“…Developed in 2003 and 2007, respectively, the NRCOS (University of Pittsburgh, PI - Torok) and MAC (University of Texas Southwestern, PI – Jacobe) cohorts collect and link patient data with biological specimens through well-developed, standardized methods for recruitment, data capture, data management, and handling of biological specimens, with the personnel and infrastructure to support these activities [ 8 , 10 – 12 , 25 – 28 ]. Research participants in both cohorts are required to meet the diagnostic criteria of LS [ 29 ] and undergo an IRB-approved consent process to collect predefined case report forms and biospecimens (blood, skin, saliva) [ 8 , 10 – 12 , 25 – 28 ]. Pediatric-onset disease is defined as onset at < 18 years of age.…”

Section: Methodsmentioning

confidence: 99%

Single-cell transcriptome conservation in a comparative analysis of fresh and cryopreserved human skin tissue: pilot in localized scleroderma

et al. 2020

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Background The purpose of this study was to assess variability in cell composition and cell-specific gene expression in the skin of patients with localized scleroderma (LS) utilizing CryoStor® CS10 in comparison to RPMI to produce adequate preservation of tissue samples and cell types of interest for use in large-scale multi-institutional collaborations studying localized scleroderma and other skin disorders. Methods We performed single-cell RNA sequencing on paired skin biopsy specimens from 3 patients with LS. Each patient with one sample cryopreserved in CryoStor® CS10 and one fresh in RPMI media using 10× Genomics sequencing. Results Levels of cell viability and yield were comparable between CryoStor® CS10 (frozen) and RPMI (fresh) preserved cells. Furthermore, gene expression between preservation methods was collectively significantly correlated and conserved across all 18 identified cell cluster populations. Conclusion Comparable cell population and transcript expression yields between CryoStor® CS10 and RPMI preserved cells support the utilization of cryopreserved skin tissue in single-cell analysis. This suggests that employing standardized cryopreservation protocols for the skin tissue will help facilitate multi-site collaborations looking to identify mechanisms of disease in disorders characterized by cutaneous pathology.

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“…In both adult and pediatric LS analyses, lymphocytes and their associated cytokine and chemokine populations are observed in both the blood and skin. Flow cytometry studies of the circulating cellular phenotype of LS (pediatric and adult) have shown a predominance of CD4 + T helper cells along with decreased functional T regulatory cells (61–63). This decrease in T regulatory cells, possibly reflecting a more “permissive state,” was also seen in pediatric SSc without increases in other T cell populations (64).…”

Section: Potential Pathogenic Etiologiesmentioning

confidence: 99%

“…This decrease in T regulatory cells, possibly reflecting a more “permissive state,” was also seen in pediatric SSc without increases in other T cell populations (64). Furthermore, when comparing paired active to inactive PBMC phenotypes in LS, those with active disease states demonstrated much higher populations of IFNγ-expressing T cells (reflecting T H 1 cells; CD4 + IFNγ + T cells) (63). An expanded study utilizing multiparameter mass cytometry by time-of-flight spectrometry (CyTOF) also supported increased IFNγ expression from CD4 + T cells, as well as NK cell populations, in active LS PBMC samples (65).…”

Section: Potential Pathogenic Etiologiesmentioning

confidence: 99%

Immunopathogenesis of Pediatric Localized Scleroderma

Torok

Jacobe

et al. 2019

Front. Immunol.

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Localized scleroderma (LS) is a complex disease characterized by a mixture of inflammation and fibrosis of the skin that, especially in the pediatric population, also affects extracutaneous tissues ranging from muscle to the central nervous system. Although developmental origins have been hypothesized, evidence points to LS as a systemic autoimmune disorder, as there is a strong correlation to family history of autoimmune disease, the presence of shared HLA types with rheumatoid arthritis, high frequency of auto-antibodies, and elevated circulating chemokines and cytokines associated with T-helper cell, IFNγ, and other inflammatory pathways. This inflammatory phenotype of the peripheral blood is reflected in the skin via microarray, RNA Sequencing and tissue staining. Research is underway to identify the key players in the pathogenesis of LS, but close approximation of inflammatory lymphocytic and macrophage infiltrate with collagen and fibroblasts deposition supports the notion that LS is a disease of inflammatory driven fibrosis. The immune system is dynamic and undergoes changes during childhood, and we speculate on how the unique features of the immune system in childhood could potentially contribute to some of the differences in LS between children and adults. Interestingly, the immune phenotype in pediatric LS resembles to some extent the healthy adult cellular phenotype, possibly supporting accelerated maturation of the immune system in LS. We discuss future directions in better understanding the pathophysiology of and how to better treat pediatric LS.

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Identifying the Signature Immune Phenotypes Present in Pediatric Localized Scleroderma

Cited by 29 publications

References 15 publications

An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3

An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3

Single-cell transcriptome conservation in a comparative analysis of fresh and cryopreserved human skin tissue: pilot in localized scleroderma

Immunopathogenesis of Pediatric Localized Scleroderma

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