Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy

Bernice Lo, Kejian Zhang, Wei Lu, Lixin Zheng, Qian Zhang, Chrysi Kanellopoulou, Yu Zhang, Zhiduo Liu, Jill M. Fritz, Rebecca Marsh, Ammar Husami, Diane Kissell, Shannon Nortman, Vijaya Chaturvedi, Hilary Haines, Lisa R. Young, Jun Mo, Alexandra H. Filipovich, Jack J. Bleesing, Peter MustilloMichael Stephens, Cesar M. Rueda, Claire A. Chougnet, Kasper Hoebe, Joshua McElwee, Jason D. Hughes, Elif Karakoc-Aydiner, Helen F. Matthews, Susan Price, Helen C. Su, V. Koneti Rao, Michael J. Lenardo, Michael B. Jordan

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248 Citations (Scopus)


Mutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. The biological role of LRBA in immunologic disease is unknown. We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)-immunoglobulin fusion drug. Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor. We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3+ regulatory and activated conventional T cells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway.

Original languageEnglish
Pages (from-to)436-440
Number of pages5
Issue number6246
Publication statusPublished - 24 Jul 2015
Externally publishedYes


ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Lo, B., Zhang, K., Lu, W., Zheng, L., Zhang, Q., Kanellopoulou, C., Zhang, Y., Liu, Z., Fritz, J. M., Marsh, R., Husami, A., Kissell, D., Nortman, S., Chaturvedi, V., Haines, H., Young, L. R., Mo, J., Filipovich, A. H., Bleesing, J. J., ... Jordan, M. B. (2015). Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science, 349(6246), 436-440.