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IgG4-related disease: an update on pathophysiology and implications for clinical care

Nature Reviews Rheumatology volume 16, pages 702–714 (2020)Cite this article

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Abstract

IgG4-related disease (IgG4-RD) has only existed as a unique disease entity since 2003, yet remarkable progress has already been achieved in describing the essential features of the disease. A framework for systematic clinical studies has been created by the development of a quantitative disease activity tool (the IgG4-RD Responder Index) and the validation of classification criteria, both of which were the products of international, multi-centre investigations. In addition, substantial strides have been made in understanding the pathophysiology of IgG4-RD. In particular, the central role of B cells in the disease has been demonstrated by both the robust clinical responsiveness of IgG4-RD to B cell depletion and by the identification of multiple self-antigens that promote B cell expansion. CD4+ T cells have also been investigated in detail; CD4+ cytotoxic T lymphocytes (suspected of promoting disease) and a specific T follicular helper cell subset that contributes to IgG4 isotype switching have both been defined by multiple groups. The mechanisms by which these immune cells converge on target tissues, interact with fibroblasts and promote tissue remodelling are beginning to be understood and will be an important research focus in the coming years.

Key points

  • IgG4-related disease (IgG4-RD) is an insidiously progressive immune-mediated fibrotic disease typified by tumour-like mass formation in many affected organs.

  • High serum IgG4 concentrations or increased numbers of IgG4+ plasma cells in tissue must be paired with appropriate clinical, histopathological and (often) radiological information for a diagnosis of IgG4-RD.

  • B cell-depletion therapy is a highly effective treatment for IgG4-RD, confirming the importance of B cells in the pathophysiology of this disease.

  • CD4+ cytotoxic T lymphocytes (CTLs) dominate the immune cell infiltrate in IgG4-RD and decline after B cell-targeted therapy, suggesting that B cells present antigen to and thereby activate CD4+ CTLs.

  • M2 macrophages, activated B cells, CD4+ CTLs and fibroblasts probably all contribute to generating the inflammatory masses composed of immune cells and fibrotic tissue that occur in IgG4-RD.

  • Novel therapeutic approaches to targeting B cells and/or CD4+ CTLs are being evaluated for the treatment of IgG4-RD.

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Fig. 1: The manifestations of IgG4-related disease.
Fig. 2: Clinical, radiological and histopathological characteristics of IgG4-related disease.
Fig. 3: T cell–B cell collaboration and immunoglobulin class switching in IgG4-related disease.
Fig. 4: Potential mechanism of immune-mediated fibrosis in IgG4-related disease.

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Acknowledgements

The work of C.A.P. is supported by a Scientist Development Award from the Rheumatology Research Foundation and a New Investigator Award from the Scleroderma Foundation. The work of J.H.S. is supported by an Autoimmunity Center of Excellence award from the National Institute of Allergy and Infectious Diseases (UM1 AI-144295).

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  1. Massachusetts General Hospital, Division of Rheumatology, Allergy and Immunology, Boston, MA, USA

    Cory A. Perugino & John H. Stone

  2. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA

    Cory A. Perugino

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C.A.P. declares no competing interests. J.H.S. declares that he has received grants and consultation fees related to IgG4-related disease from Principia Biopharma, Roche and Viela Bio.

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Nature Reviews Rheumatology thanks H. Umehara, W. Zhang and J. van Laar for their contribution to the peer review of this work.

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Glossary

Dacryoadenitis

Enlarged lacrimal glands that are generally not tender.

Obliterative phlebitis

Targeted destruction of veins as opposed to arteries.

Hypergammaglobulinaemia

Raised concentrations of immunoglobulins in the blood.

Fab-arm exchange

The swapping of half-antibody fragments between antibody molecules, a property that is unique to IgG4 among the different IgG subclasses.

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Perugino, C.A., Stone, J.H. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat Rev Rheumatol 16, 702–714 (2020). https://doi.org/10.1038/s41584-020-0500-7

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