Pathogenic, glycolytic PD-1+ B cells accumulate in the hypoxic RA joint

Floudas, Achilleas; Neto, Nuno; Marzaioli, Viviana; Murray, Kieran; Moran, Barry; Monaghan, Michael G.; Low, Candice; Mullan, Ronan; Rao, Navin; Krishna, Vinod; Nagpal, Sunil; Veale, Douglas J.; Fearon, Ursula

doi:10.1172/jci.insight.139032

Cited by 50 publications

(49 citation statements)

References 35 publications

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“…It has also been described that PD-L1-expressing Bregs have high avidity for BAFF and that these cells are spared after B cell depletion in EAE mice, an intervention that raises BAFF serum levels, revealing a novel aspect of a therapy that is successfully used in patients with MS ( 446 ). Furthermore, alterations in PD-L1 + , PD-L2 + , and PD-1 + Bregs have been reported in patients with autoimmune conditions ( 237 , 434 , 447 – 450 ).…”

Section: Suppressive Mechanisms Of Bregs By Cell Surface-expressed Momentioning

confidence: 98%

Immunosuppressive Mechanisms of Regulatory B Cells

et al. 2021

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Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

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Section: Suppressive Mechanisms Of Bregs By Cell Surface-expressed Momentioning

confidence: 98%

Immunosuppressive Mechanisms of Regulatory B Cells

et al. 2021

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“…Li et al showed that the expression of PD-1 on the surface of CD4 + T and CD8 + T cells and the level of soluble PD-1 (soluble PD-1, sPD-1) in serum were significantly decreased in patients with RA (99). According to recent studies, T cells and pathogenic PD-1 + B cells accumulate in RA joints, and the expression of CXCR3 and GM-CSF in PD-1 + B cells is higher than in PD-1 -B cells (100).…”

Section: Treg Cells In Ramentioning

confidence: 99%

Function and Role of Regulatory T Cells in Rheumatoid Arthritis

et al. 2021

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Rheumatoid arthritis (RA) is a systemic and heterogeneous autoimmune disease with symmetrical polyarthritis as its critical clinical manifestation. The basic cause of autoimmune diseases is the loss of tolerance to self or harmless antigens. The loss or functional deficiency of key immune cells, regulatory T (Treg) cells, has been confirmed in human autoimmune diseases. The pathogenesis of RA is complex, and the dysfunction of Tregs is one of the proposed mechanisms underlying the breakdown of self-tolerance leading to the progression of RA. Treg cells are a vital component of peripheral immune tolerance, and the transcription factor Foxp3 plays a major immunosuppressive role. Clinical treatment for RA mainly utilizes drugs to alleviate the progression of disease and relieve disease activity, and the ideal treatment strategy should be to re-induce self-tolerance before obvious tissue injury. Treg cells are one of the ideal options. This review will introduce the classification, mechanism of action, and characteristics of Treg cells in RA, which provides insights into clinical RA treatment.

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“…RA patient arthroscopies were performed under local anaesthetic using Wolf 2.7 mm needle arthroscopy or ultrasound guided biopsy as previously described [ 16 ]. Synovial tissue isolation and generation of single cell suspension for further analysis was performed as described previously [ 17 ]. Briefly, approximately 15 synovial biopsies were isolated per patient and enzymatically and mechanically digested using the GentleMACS Tumor Dissociation Kit, human (Miltenyi Biotech, Bergisch Gladbach, Germany) as per manufacturers’ instructions.…”

Section: Methodsmentioning

confidence: 99%

ACPA Status Correlates with Differential Immune Profile in Patients with Rheumatoid Arthritis

Floudas

Canavan

McGarry

et al. 2021

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Rheumatoid arthritis (RA) is a progressive erosive autoimmune disease that affects 1% of the world population. Anti-citrullinated protein autoantibodies (ACPA) are routinely used for the diagnosis of RA, however 20–30% of patients are ACPA negative. ACPA status is a delineator of RA disease endotypes with similar clinical manifestation but potentially different pathophysiology. Profiling of key peripheral blood and synovial tissue immune populations including B cells, T follicular helper (Tfh) cells and CD4 T cell proinflammatory cytokine responses could elucidate the underlying immunological mechanisms involved and inform a treat to target approach for both ACPA-positive and ACPA-negative RA. Detailed high dimensionality flow cytometric analysis with supervised and unsupervised algorithm analysis revealed unique RA patient peripheral blood B cell and Tfh cell profiles. Synovial tissue single cell analysis of B cell subpopulation distribution was similar between ACPA− and ACPA+ RA patients, highlighting a key role for specific B cell subsets in both disease endotypes. Interestingly, synovial tissue single cell analysis of CD4 T cell proinflammatory cytokine production was markedly different between ACPA− and APCA+ RA patients. RNAseq analysis of RA patient synovial tissue highlighted disease endotype specific gene signatures. ACPA status associates with unique immune profile signatures that reinforce the need for a treat to target approach for both endotypes of RA.

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Pathogenic, glycolytic PD-1+ B cells accumulate in the hypoxic RA joint

Cited by 50 publications

References 35 publications

Immunosuppressive Mechanisms of Regulatory B Cells

Immunosuppressive Mechanisms of Regulatory B Cells

Function and Role of Regulatory T Cells in Rheumatoid Arthritis

ACPA Status Correlates with Differential Immune Profile in Patients with Rheumatoid Arthritis

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