Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis

Al-Mossawi, Hussein; Chen, L.; Fang, Hai; Ridley, A; Wit, Jelle de; Yager, Nicole; Hammitzsch, Ariane; Pulyakhina, Irina; Fairfax, Benjamin P.; Simone, Davide; Yi, Yao; Bandyopadhyay, Soham; Doig, Karen; Gundle, R; Kendrick, Benjamin; Powrie, Fiona; Knight, Julian C.; Bowness, Paul

doi:10.1038/s41467-017-01771-2

Cited by 118 publications

(106 citation statements)

References 61 publications

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“…Notably, our proposed mechanism with the disease associated allele increasing monocyte-derived sIL7R in inflammation would likely act via its known effect on potentiating the bioavailability of IL-7 4 . Importantly, this model is in keeping with a role for IL-7 in T-cell driven pathogenesis 25 and is compatible with the genetics, where large datasets are unable to demonstrate a direct effect of this allele on T-cell expression.…”

Section: Discussionsupporting

confidence: 69%

Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele

Al-Mossawi

Yager

Taylor

et al. 2018

Preprint

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IL-7 is a key factor in T-cell immunity and IL7R polymorphisms are implicated in autoimmune pathogenesis. IL7R mRNA is induced in stimulated monocytes in a genetically determined manner, yet a role for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level across multiple cell subsets and conditions in healthy individuals. We find monocyte surface and soluble IL7R (sIL7R) protein are markedly expressed in response to lipopolysaccharide (LPS). We further demonstrate alleles of rs6897932, a non-synonymous IL7R polymorphism associated with susceptibility to Multiple Sclerosis, Ankylosing Spondylitis and Primary Biliary Cirrhosis, form the key determinant of both surface IL7R and sIL7R in the context of inflammation. No effect of this allele was observed in unstimulated monocytes or across lymphoid subsets. Production of sIL7R by monocytes greatly exceeded that of CD4 + T-cells, and was strongly associated with both rs6897932 genotype and expression of the splicing factor gene DDX39A. Stimulated monocytes were sensitive to exogenous IL-7, which elicits a defined transcriptional signature. Flow cytometry and single-cell sequencing of synovial fluid derived monocytes from patients with spondyloarthritis showed an enlarged subset of IL7R + monocytes with a unique transcriptional profile that markedly overlaps that induced by IL-7 in-vitro and shows similarity to the previously described 'Mono4' subset. These data demonstrate diseaseassociated genetic variants at IL7R specifically impact monocyte surface IL7R and sIL7R following innate immune stimulation, suggesting a previously unappreciated key role for monocytes in IL-7 pathway biology and IL7R-associated diseases.

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Section: Discussionsupporting

confidence: 69%

Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele

Al-Mossawi

Yager

Taylor

et al. 2018

Preprint

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“…In SpA, IL-17+ CD4+ T cells are present in higher frequencies in the peripheral blood of patients with PsA and AS than in healthy controls 135,136 . Furthermore, several studies have demonstrated the presence of IL-17+ CD4+ T cells in the synovial fluid of patients with PsA, AS or reactive arthritis 91,134,137,138 . As well as identifying increased IL-17+ CD4+ T cell frequencies in the peripheral blood of patients with psoriasis or PsA compared to healthy controls, increased frequencies of IL-17+ CD4+ T cells have also been identified in psoriatic lesional skin compared with skin from healthy individuals 139 .…”

Section: Il-17a+ Cd4+ T (T H 17) Cells In Spamentioning

confidence: 99%

IL-17 in the immunopathogenesis of spondyloarthritis

et al. 2018

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Spondyloarthritis (SpA) is a term that refers to a group of inflammatory diseases that includes psoriatic arthritis, axial SpA and nonradiographic axial SpA, reactive arthritis, enteropathic arthritis and undifferentiated SpA. The disease subtypes share clinical and immunological features, including joint inflammation (peripheral and axial skeleton); skin, gut and eye manifestations; and the absence of diagnostic autoantibodies (seronegative). The diseases also share genetic factors. The aetiology of SpA is still the subject of research by many groups worldwide. Evidence from genetic, experimental and clinical studies has accumulated to indicate a clear role for the IL-17 pathway in the pathogenesis of SpA. The IL-17 family consists of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F, of which IL-17A is the best studied. IL-17A is a pro-inflammatory cytokine that also has the capacity to promote angiogenesis and osteoclastogenesis. Of the six family members, IL-17A has the strongest homology with IL-17F. In this Review, we discuss how IL-17A and IL-17F and their cellular sources might contribute to the immunopathology of SpA.

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“…In adult humans NKp44+ ILC3s reside in tonsil and intestine and represent an important source of IL-22 (17)(18)(19)(20), while IL-17-producing NKp44− ILC3s have been described only in fetal developing lymph nodes (21,22). In contrast to basic science studies, recent translational rheumatology studies demonstrated the presence of IL-17-producing NKp44+ ILC3s in the gut (23) and synovial fluid (SF) (24) of patients with SpA, in the intestine of patients with Crohn's disease (25), and in the normal enthesis (26), but not in the synovial membrane (27), the primary site of inflammation in SpA. The reason for this apparent discrepancy remains to be clarified; however, lack of stringent ILC phenotyping, high functional plasticity of ILCs, and potential contamination with T cells during isolation may play an important role.…”

Section: Introductionmentioning

confidence: 99%

Expansion of Interleukin‐22– and Granulocyte–Macrophage Colony‐Stimulating Factor–Expressing, but Not Interleukin‐17A–Expressing, Group 3 Innate Lymphoid Cells in the Inflamed Joints of Patients With Spondyloarthritis

Blijdorp

Menegatti

Mens

et al. 2019

Arthritis & Rheumatology

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Objective Clinical trials of the anti–interleukin‐17A (anti– IL ‐17A) antibody secukinumab have demonstrated a crucial role of the cytokine IL ‐17A in the pathogenesis of spondyloarthritis (SpA); however, its cellular source in this condition remains a matter of controversy. Group 3 innate lymphoid cells ( ILC 3s) have been recently identified as potent producers of proinflammatory cytokines, including IL ‐17A and IL ‐22, in a number of different tissues. This study was undertaken to characterize the presence and composition of ILC s, and investigate whether these cells are an important source of IL ‐17A, in the synovial tissue ( ST ) of patients with SpA. Methods Matched ST , synovial fluid, and peripheral blood ( PB ) samples were obtained from SpA patients with actively inflamed knee joints. ILC subsets were characterized by flow cytometry. Gene expression analysis at the single‐cell level was performed directly ex vivo and after in vitro activation. An IL ‐17A enzyme‐linked immunospot assay was used to detect IL ‐17A–secreting cells. Results ILC s, and particularly NK p44+ ILC 3s, were expanded in inflamed arthritic joints. Single‐cell expression analysis demonstrated that ST ILC s were clearly distinguishable from ST T cells and from their PB counterparts. Expression of the Th17 signature transcripts RORC , AHR , and IL 23R was detected in a large proportion of ST ILC 3s. These cells were capable of inducing expression of IL 22 and CSF 2 , but not IL 17A , in response to in vitro restimulation. Conclusion Our findings demonstrate that absolute and relative numbers of ILC 3s are enriched in the synovial joints of patients with SpA. However, these cells are not a significant source of IL ‐17A in this disease.

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Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis

Cited by 118 publications

References 61 publications

Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele

Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele

IL-17 in the immunopathogenesis of spondyloarthritis

Expansion of Interleukin‐22– and Granulocyte–Macrophage Colony‐Stimulating Factor–Expressing, but Not Interleukin‐17A–Expressing, Group 3 Innate Lymphoid Cells in the Inflamed Joints of Patients With Spondyloarthritis

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