Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis

Hu, Dan; Notarbartolo, Samuele; Croonenborghs, Tom; Patel, Bonny; Cialic, Ron; Yang, Tun-Hsiang; Aschenbrenner, Dominik; Andersson, Karin; Gattorno, Marco; Pham, Minh; Kivisäkk, Pia; Pierre, Isabelle V.; Lee, Youjin; Kiani, Karun; Bokarewa, Maria; Tjon, Emily; Pochet, Nathalie; Sallusto, Federica; Kuchroo, Vijay K.; Weiner, Howard L.

doi:10.1038/s41467-017-01571-8

Cited by 97 publications

(82 citation statements)

References 64 publications

(87 reference statements)

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“…Moreover, LGALS8 was shown to be present in CSF of MS patients, and RRMS patients with antibodies against LGALS8 showed EDSS progression and worse disease prognosis . Interestingly, potential imbalance in peripheral Th17 and Th1 cells has also been shown to be associated with reduced gene expression of several different cytokines and chemokines in MS patients, among which CCL3 . It is possible that the observed decrease in both LGALS8 and CCL3 reflect imbalance in T helper cells, which promote a pro‐inflammatory self‐antigen reaction and MS progression.…”

Section: Discussionmentioning

confidence: 99%

Plasma proteome in multiple sclerosis disease progression

Malekzadeh¹,

Leurs

Wieringen³

et al. 2019

Ann Clin Transl Neurol

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Background: The pathophysiology of multiple sclerosis disease progression remains undetermined. The aim of this study was to identify differences in plasma proteome during different stages of MS disease progression. Methods:We used a multiplex aptamer proteomics platform (Somalogic) for sensitive detection of 1129 proteins in plasma. MS patients were selected and categorized based on baseline and a 4-year follow-up EDSS (delta EDSS) scores; relapseonset (RO) slow progression (n = 31), RO with rapid progression (n = 29), primary progressive (n = 30), and healthy controls (n = 20). The relation of baseline plasma protein levels with delta EDSS and different MRI progression parameters were assessed using linear regression models. Results: Regression analyses of plasma proteins with delta EDSS showed six significant associations. Strong associations were found for the proteins LGLAS8 (P = 7.64 9 10 À5 , q = 0.06), CCL3 (P = 0.0001, q = 0.06), and RGMA (P = 0.0005, q = 0.09). In addition, associations of plasma proteins were found with percentage brain volume for C3 (P = 2,08 9 10 À9 , q = 1,70 9 10 À6 ), FGF9 (P = 3,42 9 10 À9 , q = 1,70 9 10 À6 ), and EHMT2 (P = 0.0007, q = 0.01). Most of the significant markers were associated with cell-cell and cell-extracellular matrix adhesion, immune system communication, immune system activation, and complement pathways. Conclusions: Our results revealed eight novel biomarkers related to clinical and radiological progression in MS. These results indicate that changes in immune system, complement pathway and ECM remodeling proteins contribute to MS progression and may therefore be further explored for use in prognosis of MS. 1582

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Section: Discussionmentioning

confidence: 99%

Plasma proteome in multiple sclerosis disease progression

Malekzadeh¹,

Leurs

Wieringen³

et al. 2019

Ann Clin Transl Neurol

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“…Based on the immunohistochemistry results presented in this study, another mechanism that might be important for psoriasis resolution could be induction of a relative increase in numbers of BLIMP-1/IL-10-producing T cells. Pathogenic/effector T H 17 T cells are capable of being converted to nonpathogenic IL-10-expressing T cells in model systems when IL-23 signaling is low 30 and IL-10 production is regulated by BLIMP-1 31 ; thus the increase in numbers of BLIMP-1/IL-10-producing T cells might support psoriasis resolution. Further evaluation of this T-cell subset, its function in the context of psoriasis resolution, and its potential for durability of response will need to be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

Psoriatic skin molecular and histopathologic profiles after treatment with risankizumab versus ustekinumab

Visvanathan

Baum

Vinisko

et al. 2019

Journal of Allergy and Clinical Immunology

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Background: IL-23 contributes to the activation, maintenance, and proliferation of T H 17 cells and plays a major role in psoriasis pathophysiology. IL-23p19 inhibition with risankizumab resulted in superior clinical responses in patients with psoriasis compared with ustekinumab (dual IL-12/IL-23 inhibitor), but comparative molecular effects have not been established. Objective: We investigated the similarities and differences in molecular and histopathologic profiles in skin lesions from patients with psoriasis receiving risankizumab versus ustekinumab at an early time point. Methods: Lesional skin biopsy samples from 81 patients with moderate-to-severe plaque psoriasis participating in 2 different studies (a phase I risankizumab study and a phase II study of risankizumab vs ustekinumab) were analyzed by using histopathology, immunohistochemistry, and RNA sequencing. Results: Risankizumab induced a rapid decrease in levels of proteins and transcriptomic biomarkers associated with the IL-23 pathway, which were maintained through 8 weeks. At week 4, risankizumab decreased histopathologic expression of biomarkers, including K16, Ki67, CD3, lipocalin-2, CD11c, dendritic cell lysosome-associated membrane glycoprotein, b-defensin 2, and S100A7; global histopathologic scoring revealed that 54% and 69% of patients treated with 90 or 180 mg of risankizumab, respectively, were graded as experiencing ''excellent improvement'' versus 29% of patients treated with ustekinumab. At week 4, there was a common decrease in expression of 2645 genes expressed in lesional skin between patients receiving risankizumab and ustekinumab and a significant decrease in 2682 genes unique to risankizumab treatment. Risankizumab more strongly downregulated expression of genes associated with keratinocytes, epidermal cells, and monocytes, versus ustekinumab. Conclusion: Risankizumab demonstrated more pronounced changes in the molecular and histopathologic profile of psoriatic skin lesions compared with ustekinumab at week 4. (J Allergy Clin

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“…Additionally, Th17 cells were able to produce TNF, IL‐22, IL‐21, and GM‐CSF . An increasing number of studies have indicated that Th17 cells are involved in the maintenance of immune homeostasis, particularly at mucosal surfaces in the intestine, and contribute to chronic inflammation in autoimmune diseases, such as RA and multiple sclerosis . In RA patients, Th17 cells were shown to play an essential role in RA pathogenesis, particularly at the early phase of disease via immune dysfunction …”

Section: Phenotype and Differentiation Of Th17 Cellsmentioning

confidence: 99%

Th17 cell pathogenicity and plasticity in rheumatoid arthritis

Yang

Qian

Zhang

et al. 2019

Journal of Leukocyte Biology

113

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CD4 + Th cells play an important role in the development of rheumatoid arthritis (RA) by regulating adaptive immune response. As major subsets of CD4 + Th cells, Th17 cells can produce a large number of hallmark cytokines such as IL-17A and IL-17F, which participate in host defense and immune homeostasis. However, increasing researches have shown that Th17 cells are unstable and exhibit a certain degree of plasticity, which aggravates their pathogenicity. Furthermore, the plasticity and pathogenicity of Th17 cells are closely related with the disease activity in RA. In this paper, the characteristics including phenotype, differentiation, plasticity, and pathogenicity of Th17 cells in RA will be systematically summarized. This will contribute to clarify the immunologic mechanism of RA and further provide a novel strategy for the clinical treatment of autoimmune diseases. K E Y W O R D S pathogenicity, plasticity, rheumatoid arthritis, Th17 cells 1

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Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis

Cited by 97 publications

References 64 publications

Plasma proteome in multiple sclerosis disease progression

Plasma proteome in multiple sclerosis disease progression

Psoriatic skin molecular and histopathologic profiles after treatment with risankizumab versus ustekinumab

Th17 cell pathogenicity and plasticity in rheumatoid arthritis

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