Review Article | Published:

Leukocyte trafficking between stromal compartments: lessons from rheumatoid arthritis

Nature Reviews Rheumatologyvolume 14pages476487 (2018) | Download Citation

Abstract

The trafficking of leukocytes from their site of production in the bone marrow through the circulation and into peripheral tissues is a highly coordinated and tightly regulated process in healthy individuals. Lymphocytes are long-lived cells that visit many lymphoid and peripheral tissues over their lifetime and can even recirculate back to the bone marrow, whereas granulocytes and monocytes are not thought to recirculate so widely. Using rheumatoid arthritis (RA) as an example, this Review explores the migratory journey of leukocytes during the establishment and resolution of disease — from the blood, through the lymphoid tissues and into peripheral sites such as the lungs and the gut before their entry into the synovium. This Review explores our current understanding of differences in the molecular processes that regulate leukocyte trafficking at different phases of disease and in different stromal compartments, which could help to explain the disease heterogeneity seen in patients with RA. Expanding our knowledge of these processes will open new avenues in the clinical management of RA, paving the way for personalized medicine that is founded on the pathological molecular signature of each patient, which varies according to their phase of disease or disease subtype.

Key points

  • Patients with rheumatoid arthritis (RA) have defects in at least one, if not multiple, checkpoints that regulate leukocyte entry into and exit from lymphoid and peripheral tissues, including the joints.

  • Even at the earliest phases of disease, patients with RA have impaired thymic output and naive T cells that have an immunosenescent phenotype.

  • Individuals at risk of RA show signs of alterations in the phenotype of lymphocytes trafficking through the draining lymph nodes of the joints.

  • Genetic predisposition and metabolic alterations in T cells can render them ‘sticky’ and hypermotile, contributing to aberrant lymphocyte trafficking throughout the body.

  • Interactions between fibroblasts and endothelial cells in the synovium evolve with disease, changing the shape and nature of the inflammatory infiltrate at each phase of RA.

  • Lymphatic vessels change during experimental inflammatory arthritis and represent a potential novel therapeutic target.

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Acknowledgements

The work of the authors is supported by an Arthritis Research UK Career Development Fellowship (grant number 19899 to H.M.M.) and by an Arthritis Research UK programme grant (grant number 19791 to C.D.B.). The Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence is partially funded by Arthritis Research UK (grant number 20298); this centre is a collaboration between the University of Glasgow, the University of Newcastle and the University of Birmingham in the UK. The MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research (grant number MR/P021220/1) is a collaboration between the University of Birmingham, the University of Nottingham and Oxford University in the UK.

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Nature Reviews Rheumatology thanks S. Jalkanen, M. Perretti and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Rheumatology Research Group, Arthritis Research UK Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK

    • Christopher D. Buckley
    •  & Helen M. McGettrick
  2. Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK

    • Christopher D. Buckley

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H.M.M. researched data for this article. Both authors provided substantial contributions to discussions of its content, wrote the article and reviewed or edited the manuscript before submission.

Competing interests

C.D.B. declares that he has received research funding from Roche. H.M.M. declares that she has received research funding from Pfizer.

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Correspondence to Helen M. McGettrick.

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https://doi.org/10.1038/s41584-018-0042-4