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IMMUNE DYSREGULATION

The sickening consequences of too much SYK signaling

Nature Genetics volume 53, pages 432–434 (2021)Cite this article

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Immune responses require a delicate balance: a weak response can cause immunodeficiency, whereas an excessive response can lead to hyperinflammatory disease and hematological malignancy. Because spleen tyrosine kinase has roles in multiple signaling pathways, its gain-of-function alterations in humans cause hypogammaglobulinemia as well as autoinflammation and predisposition to B cell lymphoma.

SYK is an essential regulator of BCR-mediated signaling. Enhanced BCR signaling and autoreactive B cells have been implicated in the pathogenesis of autoimmune diseases, B lineage leukemias and lymphomas. Molecular mechanisms underpinning the malignant transformation events in B cells have been investigated mainly in animal models. A new study by Wang et al. provides insights into how constitutive SYK signaling affects human health3. The authors report six patients with monoallelic missense gain-of-function variants who presented with recurrent infections; inflammation of the skin, joints, intestines and central nervous system; and a propensity to develop diffuse B cell lymphomas3.

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Fig. 1: Activating germline SYK mutations affect many cellular functions.

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  1. Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD, USA

    Ivona Aksentijevich

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  1. Ivona Aksentijevich
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Correspondence to Ivona Aksentijevich.

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Aksentijevich, I. The sickening consequences of too much SYK signaling. Nat Genet 53, 432–434 (2021). https://doi.org/10.1038/s41588-021-00837-8

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