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Clonal haematopoiesis and dysregulation of the immune system

Nature Reviews Immunology volume 23, pages 595–610 (2023)Cite this article

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Abstract

Age-related diseases are frequently linked to pathological immune dysfunction, including excessive inflammation, autoreactivity and immunodeficiency. Recent analyses of human genetic data have revealed that somatic mutations and mosaic chromosomal alterations in blood cells — a condition known as clonal haematopoiesis (CH) — are associated with ageing and pathological immune dysfunction. Indeed, large-scale epidemiological studies and experimental mouse models have demonstrated that CH can promote cardiovascular disease, chronic obstructive pulmonary disease, chronic liver disease, osteoporosis and gout. The genes most frequently mutated in CH, the epigenetic regulators TET2 and DNMT3A, implicate increased chemokine expression and inflammasome hyperactivation in myeloid cells as a possible mechanistic connection between CH and age-related diseases. In addition, TET2 and DNMT3A mutations in lymphoid cells have been shown to drive methylation-dependent alterations in differentiation and function. Here we review the observational and mechanistic studies describing the connection between CH and pathological immune dysfunction, the effects of CH-associated genetic alterations on the function of myeloid and lymphoid cells, and the clinical and therapeutic implications of CH as a target for immunomodulation.

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Fig. 1: Features of clonal haematopoiesis.
Fig. 2: Functional effects of clonal haematopoiesis-associated mutations in myeloid cells.
Fig. 3: Impact of TET2 and DNMT3A loss in lymphocytes.

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Author information

Authors and Affiliations

  1. Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA

    Roger Belizaire

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Waihay J. Wong, Michelle L. Robinette & Benjamin L. Ebert

  3. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Waihay J. Wong

  4. Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, MA, USA

    Michelle L. Robinette

  5. Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA, USA

    Benjamin L. Ebert

Authors
  1. Roger Belizaire
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  2. Waihay J. Wong
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  3. Michelle L. Robinette
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  4. Benjamin L. Ebert
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Benjamin L. Ebert.

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Competing interests

B.L.E. has received research funding from Celgene, Deerfield, Novartis and Calico and consulting fees from GRAIL. He is a member of the scientific advisory board of and a shareholder of Neomorph, TenSixteen Bio, Skyhawk Therapeutics and Exo Therapeutics. The other authors have no competing interests.

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Nature Reviews Immunology thanks J. DeGregori, M. De Dominici, J. Mistry, J. Trowbridge and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Belizaire, R., Wong, W.J., Robinette, M.L. et al. Clonal haematopoiesis and dysregulation of the immune system. Nat Rev Immunol 23, 595–610 (2023). https://doi.org/10.1038/s41577-023-00843-3

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