Germline-activating mutations in PIK3CD compromise B cell development and function

Publication Date:
2018-08-07
Publisher:
Rockefeller University Press
Print ISSN:
0022-1007
Electronic ISSN:
1540-9538
Topics:
Medicine
Keywords:
Immunodeficiency, Human Disease Genetics
Published by:
http://www.rupress.org/
_version_ 1836399022933278720
autor Avery, D. T., Kane, A., Nguyen, T., Lau, A., Nguyen, A., Lenthall, H., Payne, K., Shi, W., Brigden, H., French, E., Bier, J., Hermes, J. R., Zahra, D., Sewell, W. A., Butt, D., Elliott, M., Boztug, K., Meyts, I., Choo, S., Hsu, P., Wong, M., Berglund, L. J., Gray, P., OSullivan, M., Cole, T., Holland, S. M., Ma, C. S., Burkhart, C., Corcoran, L. M., Phan, T. G., Brink, R., Uzel, G., Deenick, E. K., Tangye, S. G.
beschreibung Gain-of-function (GOF) mutations in PIK3CD , encoding the p110 subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd . In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110 inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110 inhibitors.
citation_standardnr 6315468
datenlieferant ipn_articles
feed_id 96
feed_publisher Rockefeller University Press
feed_publisher_url http://www.rupress.org/
insertion_date 2018-08-07
journaleissn 1540-9538
journalissn 0022-1007
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher Rockefeller University Press
quelle Journal of Experimental Medicine
relation http://jem.rupress.org/cgi/content/short/215/8/2073?rss=1
schlagwort Immunodeficiency, Human Disease Genetics
search_space articles
shingle_author_1 Avery, D. T., Kane, A., Nguyen, T., Lau, A., Nguyen, A., Lenthall, H., Payne, K., Shi, W., Brigden, H., French, E., Bier, J., Hermes, J. R., Zahra, D., Sewell, W. A., Butt, D., Elliott, M., Boztug, K., Meyts, I., Choo, S., Hsu, P., Wong, M., Berglund, L. J., Gray, P., OSullivan, M., Cole, T., Holland, S. M., Ma, C. S., Burkhart, C., Corcoran, L. M., Phan, T. G., Brink, R., Uzel, G., Deenick, E. K., Tangye, S. G.
shingle_author_2 Avery, D. T., Kane, A., Nguyen, T., Lau, A., Nguyen, A., Lenthall, H., Payne, K., Shi, W., Brigden, H., French, E., Bier, J., Hermes, J. R., Zahra, D., Sewell, W. A., Butt, D., Elliott, M., Boztug, K., Meyts, I., Choo, S., Hsu, P., Wong, M., Berglund, L. J., Gray, P., OSullivan, M., Cole, T., Holland, S. M., Ma, C. S., Burkhart, C., Corcoran, L. M., Phan, T. G., Brink, R., Uzel, G., Deenick, E. K., Tangye, S. G.
shingle_author_3 Avery, D. T., Kane, A., Nguyen, T., Lau, A., Nguyen, A., Lenthall, H., Payne, K., Shi, W., Brigden, H., French, E., Bier, J., Hermes, J. R., Zahra, D., Sewell, W. A., Butt, D., Elliott, M., Boztug, K., Meyts, I., Choo, S., Hsu, P., Wong, M., Berglund, L. J., Gray, P., OSullivan, M., Cole, T., Holland, S. M., Ma, C. S., Burkhart, C., Corcoran, L. M., Phan, T. G., Brink, R., Uzel, G., Deenick, E. K., Tangye, S. G.
shingle_author_4 Avery, D. T., Kane, A., Nguyen, T., Lau, A., Nguyen, A., Lenthall, H., Payne, K., Shi, W., Brigden, H., French, E., Bier, J., Hermes, J. R., Zahra, D., Sewell, W. A., Butt, D., Elliott, M., Boztug, K., Meyts, I., Choo, S., Hsu, P., Wong, M., Berglund, L. J., Gray, P., OSullivan, M., Cole, T., Holland, S. M., Ma, C. S., Burkhart, C., Corcoran, L. M., Phan, T. G., Brink, R., Uzel, G., Deenick, E. K., Tangye, S. G.
shingle_catch_all_1 Germline-activating mutations in PIK3CD compromise B cell development and function
Immunodeficiency, Human Disease Genetics
Gain-of-function (GOF) mutations in PIK3CD , encoding the p110 subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd . In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110 inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110 inhibitors.
Avery, D. T., Kane, A., Nguyen, T., Lau, A., Nguyen, A., Lenthall, H., Payne, K., Shi, W., Brigden, H., French, E., Bier, J., Hermes, J. R., Zahra, D., Sewell, W. A., Butt, D., Elliott, M., Boztug, K., Meyts, I., Choo, S., Hsu, P., Wong, M., Berglund, L. J., Gray, P., OSullivan, M., Cole, T., Holland, S. M., Ma, C. S., Burkhart, C., Corcoran, L. M., Phan, T. G., Brink, R., Uzel, G., Deenick, E. K., Tangye, S. G.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_catch_all_2 Germline-activating mutations in PIK3CD compromise B cell development and function
Immunodeficiency, Human Disease Genetics
Gain-of-function (GOF) mutations in PIK3CD , encoding the p110 subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd . In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110 inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110 inhibitors.
Avery, D. T., Kane, A., Nguyen, T., Lau, A., Nguyen, A., Lenthall, H., Payne, K., Shi, W., Brigden, H., French, E., Bier, J., Hermes, J. R., Zahra, D., Sewell, W. A., Butt, D., Elliott, M., Boztug, K., Meyts, I., Choo, S., Hsu, P., Wong, M., Berglund, L. J., Gray, P., OSullivan, M., Cole, T., Holland, S. M., Ma, C. S., Burkhart, C., Corcoran, L. M., Phan, T. G., Brink, R., Uzel, G., Deenick, E. K., Tangye, S. G.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_catch_all_3 Germline-activating mutations in PIK3CD compromise B cell development and function
Immunodeficiency, Human Disease Genetics
Gain-of-function (GOF) mutations in PIK3CD , encoding the p110 subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd . In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110 inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110 inhibitors.
Avery, D. T., Kane, A., Nguyen, T., Lau, A., Nguyen, A., Lenthall, H., Payne, K., Shi, W., Brigden, H., French, E., Bier, J., Hermes, J. R., Zahra, D., Sewell, W. A., Butt, D., Elliott, M., Boztug, K., Meyts, I., Choo, S., Hsu, P., Wong, M., Berglund, L. J., Gray, P., OSullivan, M., Cole, T., Holland, S. M., Ma, C. S., Burkhart, C., Corcoran, L. M., Phan, T. G., Brink, R., Uzel, G., Deenick, E. K., Tangye, S. G.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_catch_all_4 Germline-activating mutations in PIK3CD compromise B cell development and function
Immunodeficiency, Human Disease Genetics
Gain-of-function (GOF) mutations in PIK3CD , encoding the p110 subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd . In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110 inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110 inhibitors.
Avery, D. T., Kane, A., Nguyen, T., Lau, A., Nguyen, A., Lenthall, H., Payne, K., Shi, W., Brigden, H., French, E., Bier, J., Hermes, J. R., Zahra, D., Sewell, W. A., Butt, D., Elliott, M., Boztug, K., Meyts, I., Choo, S., Hsu, P., Wong, M., Berglund, L. J., Gray, P., OSullivan, M., Cole, T., Holland, S. M., Ma, C. S., Burkhart, C., Corcoran, L. M., Phan, T. G., Brink, R., Uzel, G., Deenick, E. K., Tangye, S. G.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_title_1 Germline-activating mutations in PIK3CD compromise B cell development and function
shingle_title_2 Germline-activating mutations in PIK3CD compromise B cell development and function
shingle_title_3 Germline-activating mutations in PIK3CD compromise B cell development and function
shingle_title_4 Germline-activating mutations in PIK3CD compromise B cell development and function
timestamp 2025-06-30T23:36:22.542Z
titel Germline-activating mutations in PIK3CD compromise B cell development and function
titel_suche Germline-activating mutations in PIK3CD compromise B cell development and function
topic WW-YZ
uid ipn_articles_6315468