Murine ARPC1B deficiency as a novel model for human hyper IgE syndrome — ASN Events
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  2. Workshop 5: Lymphocyte biology 2
  3. Murine ARPC1B deficiency as a novel model for human hyper IgE syndrome

Murine ARPC1B deficiency as a novel model for human hyper IgE syndrome (#60)

Brigette Boast 1 , Katrina Randall 1 , Gaetan Burgio 1 , Taco Kuijpers 2 , Klaus Schwarz 3 , Anselm Enders 1
  1. Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
  2. Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  3. The Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany

Actin Related Protein 2/3 Complex Subunit B (ARPC1B) is a subunit of the Arp2/3 complex, which is essential for F-actin polymerisation. The Arp2/3 complex is downstream of the DOCK and WASP signalling cascade. Binding of WASP to ARPC1B is crucial for activating Arp2/3. Recently, mutations in ARPC1B have been identified to cause human Hyper IgE syndrome (HIGE). Affected patients have an increased susceptibility to viral skin infections, and elevated levels of IgE and IgA similar to DOCK8 deficiency. To gain an understanding of how the lack of ARPC1B leads to immunodeficiency and immune dysregulation, we have performed the first functional study of Arpc1b mutant mice, and contrast results with murine DOCK8 deficiency and present the results here.

Whilst both ARPC1B and DOCK8 deficient patients have HIGE, only Arpc1b mutant mice show elevated IgE in sera. Furthermore, naïve Arpc1b mutants have an increased number of IgE+ B cells compared with wild-type littermates. Surface IgM and IgD expression is significantly decreased on naïve Arpc1b mutant B cells, while IgM and IgD is unaffected in Dock8 mice. This reduction in BCR expression in Arpc1b mutants is not due to reduction in cell size caused by an abnormal cytoskeleton.

In contrast to Dock8 mutants, Arpc1b mutant mice have normal numbers of marginal zone (MZ) B cells and are able to form persistent germinal centres (GCs). Interestingly, total numbers of GC B cells are higher in Arpc1b mutant mice than they are in wild-type littermates.

As mice deficient in ARPC1B do not share a phenotype with mice deficient in DOCK8, this indicates that Arp2/3 activity in resting B cells can occur independently of DOCK8 activation. Conversely, the DOCK8-specific lack of MZ and GC B cells suggests a previously unknown role of DOCK8 independent from its function as an activator of the Arp2/3 complex through WASP.

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