Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell–specific manner
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 r...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-05-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.153597 |
| _version_ | 1811238001530896384 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Alan Avalos |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:34:14Z |
| format | Article |
| id | doaj.art-7b1c015f36ab4961996e21a2e851809a |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T12:34:14Z |
| publishDate | 2022-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-7b1c015f36ab4961996e21a2e851809a2022-12-22T03:32:57ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-05-0179Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell–specific mannerAlan AvalosJacob T. TietsortNutthakarn SuwankitwatJonathan D. WoodsShaun W. JacksonAlexandra ChristodoulouChristopher MorrillH. Denny LiggittChengsong ZhuQuan-Zhen LiKevin K. BuiHeon ParkBrian M. IritaniHematopoietic 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.https://doi.org/10.1172/jci.insight.153597Immunology |
| spellingShingle | 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 Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell–specific manner JCI Insight Immunology |
| title | Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell–specific manner |
| title_full | Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell–specific manner |
| title_fullStr | Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell–specific manner |
| title_full_unstemmed | Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell–specific manner |
| title_short | Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell–specific manner |
| title_sort | hem 1 regulates protective humoral immunity and limits autoantibody production in a b cell specific manner |
| topic | Immunology |
| url | https://doi.org/10.1172/jci.insight.153597 |
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