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Cited by 4Immunodeficiency and Autoimmune DisordersBlood disorders and treatmentsT-cell and B-cell Immunology

Hem1 inborn errors of immunity: waving goodbye to coordinated immunity in mice and humans

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Christodoulou, Alexandra, Tsai, Julia Y., Suwankitwat, Nutthakarn, Anderson, Andreas, Iritani, Brian M.·2024·Frontiers in Immunology
DOI 10.3389/fimmu.2024.1402139PMC PMC11254771
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Abstract

Inborn errors of immunity (IEI) are a group of diseases in humans that typically present as increased susceptibility to infections, autoimmunity, hyperinflammation, allergy, and in some cases malignancy. Among newly identified genes linked to IEIs include 3 independent reports of 9 individuals from 7 independent kindreds with severe primary immunodeficiency disease (PID) and autoimmunity due to loss-of-function mutations in the NCKAP1L gene encoding Hematopoietic protein 1 (HEM1). HEM1 is a hematopoietic cell specific component of the WASp family verprolin homologous (WAVE) regulatory complex (WRC), which acts downstream of multiple immune receptors to stimulate actin nucleation and polymerization of filamentous actin (F-actin). The polymerization and branching of F-actin is critical for creating force-generating cytoskeletal structures which drive most active cellular processes including migration, adhesion, immune synapse formation, and phagocytosis. Branched actin networks at the cell cortex have also been implicated in acting as a barrier to regulate inappropriate vesicle (e.g. cytokine) secretion and spontaneous antigen receptor crosslinking. Given the importance of the actin cytoskeleton in most or all hematopoietic cells, it is not surprising that HEM1 deficient children present with a complex clinical picture that involves overlapping features of immunodeficiency and autoimmunity. In this review, we will provide an overview of what is known about the molecular and cellular functions of HEM1 and the WRC in immune and other cells. We will describe the common clinicopathological features and immunophenotypes of HEM1 deficiency in humans and provide detailed comparative descriptions of what has been learned about Hem1 disruption using constitutive and immune cell-specific mouse knockout models. Finally, we discuss future perspectives and important areas for investigation regarding HEM1 and the WRC.

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Cited by

Sorted by citations

Authors
Christodoulou, A., Tsai, J. Y., Suwankitwat, N., Anderson, A., & Iritani, B. M.
Affiliations
University of Washington (US)
Corresponding author
Iritani, Brian M.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2024-07-04
Volume
15
Pages
1402139-1402139
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2024.1402139
PMC
PMC11254771
OpenAlex
W4400335304
Cited by
4
References
5
Citations by year
2025: 4
FWCI
0.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (RO1 AI09020, RO1AI158353, R21AI156243)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
WAVE regulatory complex, primary immunodeficiency, autoimmunity, actin cytoskeleton, actin nucleation, F-actin polymerization, immunological synapse, phagocytosis, cytokine production, mouse knockout models, loss-of-function mutations
MeSH terms
Animals, Humans, Immunologic Deficiency Syndromes, Mice

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