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Effector and regulatory B cells in immune-mediated kidney disease

Nature Reviews Nephrology volume 15, pages 11–26 (2019)Cite this article

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Abstract

B cells have a central role in many autoimmune diseases, including in those with renal involvement, as well as in the immunological response to kidney transplantation. The majority of B cell studies have focused on their pathological role as antibody producers. However, these cells have broad functions in immune responses beyond immunoglobulin secretion, including antigen presentation to T cells and cytokine production. Importantly, not all B cell subsets enhance immune responses. Regulatory B (Breg) cells attenuate inflammation and contribute to the maintenance of immune tolerance. Breg cells are numerically deficient and/or dysfunctional in several autoimmune diseases that can affect the kidneys, including systemic lupus erythematosus and anti-neutrophil cytoplasmic antibody-associated vasculitis, as well as in some groups of renal transplant recipients with alloimmune graft damage. B cell-targeting biologics have been trialled with promising results in diverse immune-mediated renal conditions. These therapies can affect both pro-inflammatory B cells and Breg cells, potentially limiting their long-term efficacy. Future strategies might involve the modulation of pro-inflammatory B cells in combination with the stimulation of regulatory subsets. Additionally, the monitoring of individual B cell subsets in patients may lead to the discovery of novel biomarkers that could help to predict disease relapse or progression.

Key points

  • B cells can promote disease through the production of antibodies, the release of pro-inflammatory cytokines and the presentation of antigen to T cells, which leads to T cell activation and polarization

  • Regulatory B (Breg) cell subsets can attenuate disease through the action of the immunomodulatory cytokine IL-10 and various other mechanisms

  • An imbalance in the numbers or function of pro-inflammatory and regulatory B cell subsets is found in various immune-mediated renal diseases and in renal transplant cohorts

  • Quantitative and qualitative assessment of B cell subsets may lead to the identification of biomarkers that could predict disease outcomes or relapse and instruct therapeutic strategies

  • B cell depletion has been successfully used for the treatment of various autoimmune diseases that affect the kidneys; the utility of B cell depletion therapy in kidney transplantation remains uncertain

  • As the available agents that are used for total B cell depletion remove Breg cells as well as pro-inflammatory B cells, a need exists for more targeted approaches using novel agents or combination therapies

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Fig. 1: B cell differentiation pathways and Breg cell subsets.
Fig. 2: B cell immune functions.
Fig. 3: Targets of B cell-directed therapies.
Fig. 4: Proposed mechanism of B cell depletion therapy in autoimmune disease and transplantation.

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Acknowledgements

A.D.S. is supported by Kidney Research UK.

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Nature Reviews Nephrology thanks S. Hillion and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. These authors contributed equally: Claudia Mauri and Alan D. Salama

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  1. Division of Medicine, University College London, London, UK

    Kristine Oleinika & Claudia Mauri

  2. UCL Centre for Nephrology, Royal Free Hospital, London, UK

    Alan D. Salama

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Glossary

Nephrotic syndrome

A triad of symptoms, namely oedema, proteinuria >3.5 g/day and hypoalbuminaemia, which result from glomerular podocyte damage. Patients often present with marked hypercholesterolaemia.

Minimal change disease

A common cause of nephrotic syndrome in children and adults, which is characterized by minimal histological abnormalities visible by light microscopy, but in which podocyte effacement can be observed by electron microscopy.

Membranous glomerulonephritis

A glomerular disease that is characterized by subepithelial immune complexes, which cause nephrotic syndrome and is frequently associated with the presence of autoantibodies to phospholipase A2 receptor or thrombospondin type 1 domain-containing protein 7A.

Induction therapy

The initial immunosuppressive therapy used at the time of transplantation or the initial therapy used to treat autoimmune diseases.

Germinal centre reaction

The process through which high-affinity, class-switched plasma cells and memory B cells are generated.

Type 1 response

An immune response in which mainly T helper 1 (TH1) cells produce cytokines, such as IFNγ and IL-12.

Type 2 response

An immune response in which mainly T helper 2 (TH2) cells produce cytokines, such as IL-4.

Tertiary lymphoid tissue

Organized lymphoid structures that develop in non-lymphoid tissues.

Invariant natural killer T cell

(iNKT cell). A CD1d-restricted T cell that expresses a semi-invariant T cell receptor and recognizes lipid antigens.

Operational tolerance

Long-term allograft acceptance without the requirement for continuous immunosuppression.

Maintenance therapy

Continuous immunosuppression to maintain stable graft function or remission in cases of autoimmunity.

Cryoglobulinaemia

A syndrome of circulating cryoglobulins, which are immunoglobulins that precipitate at temperatures below 37oC, leading to skin, kidney and neurological disease.

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Oleinika, K., Mauri, C. & Salama, A.D. Effector and regulatory B cells in immune-mediated kidney disease. Nat Rev Nephrol 15, 11–26 (2019). https://doi.org/10.1038/s41581-018-0074-7

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