Abstract
Hematopoietic protein-1 (Hem-1) is a member of the actin-regulatory WASp family verprolin homolog (WAVE) complex. Loss-of-function variants in the NCKAP1L gene encoding Hem-1 were recently discovered to result in primary immunodeficiency disease (PID) in children, characterized by poor specific Ab responses, increased autoantibodies, and high mortality. However, the mechanisms of how Hem-1 deficiency results in PID are unclear. In this study, we utilized constitutive and B cell–specific Nckap1l-KO mice to dissect the importance of Hem-1 in B cell development and functions. B cell–specific disruption of Hem-1 resulted in reduced numbers of recirculating follicular (FO), marginal zone (MZ), and B1 B cells. B cell migration in response to CXCL12 and -13 were reduced. T-independent Ab responses were nearly abolished, resulting in failed protective immunity to Streptococcus pneumoniae challenge. In contrast, T-dependent IgM and IgG2c, memory B cell, and plasma cell responses were more robust relative to WT control mice. B cell–specific Hem-1–deficient mice had increased autoantibodies against multiple autoantigens, and this correlated with hyperresponsive BCR signaling and increased representation of CD11c+T-bet+ age-associated B cell (ABC cells) — alterations associated with autoimmune diseases. These results suggest that dysfunctional B cells may be part of a mechanism explaining why loss-of-function Hem-1 variants result in recurring infections and autoimmunity.
Authors
Alan Avalos, Jacob T. Tietsort, Nutthakarn Suwankitwat, Jonathan D. Woods, Shaun W. Jackson, Alexandra Christodoulou, Christopher Morrill, H. Denny Liggitt, Chengsong Zhu, Quan-Zhen Li, Kevin K. Bui, Heon Park, Brian M. Iritani
Figure 5
Hem-1 is required for optimal TI Ab production and protection against
