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 Mustillo & 13 others Michael 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

Research output: Contribution to journalArticle

197 Citations (Scopus)

Abstract

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
JournalScience
Volume349
Issue number6246
DOIs
Publication statusPublished - 24 Jul 2015
Externally publishedYes

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CTLA-4 Antigen
Therapeutics
Proteins
Abatacept
Immune System Diseases
Chloroquine
Lysosomes
Autoimmunity
Lipopolysaccharides
Immunoglobulins
T-Lymphocytes
Mutation

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. / Lo, Bernice; Zhang, Kejian; Lu, Wei; Zheng, Lixin; Zhang, Qian; Kanellopoulou, Chrysi; Zhang, Yu; Liu, Zhiduo; Fritz, Jill M.; Marsh, Rebecca; Husami, Ammar; Kissell, Diane; Nortman, Shannon; Chaturvedi, Vijaya; Haines, Hilary; Young, Lisa R.; Mo, Jun; Filipovich, Alexandra H.; Bleesing, Jack J.; Mustillo, Peter; Stephens, Michael; Rueda, Cesar M.; Chougnet, Claire A.; Hoebe, Kasper; McElwee, Joshua; Hughes, Jason D.; Karakoc-Aydiner, Elif; Matthews, Helen F.; Price, Susan; Su, Helen C.; Rao, V. Koneti; Lenardo, Michael J.; Jordan, Michael B.

In: Science, Vol. 349, No. 6246, 24.07.2015, p. 436-440.

Research output: Contribution to journalArticle

Lo, B, Zhang, K, Lu, W, Zheng, L, Zhang, Q, Kanellopoulou, C, Zhang, Y, Liu, Z, Fritz, JM, Marsh, R, Husami, A, Kissell, D, Nortman, S, Chaturvedi, V, Haines, H, Young, LR, Mo, J, Filipovich, AH, Bleesing, JJ, Mustillo, P, Stephens, M, Rueda, CM, Chougnet, CA, Hoebe, K, McElwee, J, Hughes, JD, Karakoc-Aydiner, E, Matthews, HF, Price, S, Su, HC, Rao, VK, Lenardo, MJ & Jordan, MB 2015, 'Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy', Science, vol. 349, no. 6246, pp. 436-440. https://doi.org/10.1126/science.aaa1663
Lo, Bernice ; Zhang, Kejian ; Lu, Wei ; Zheng, Lixin ; Zhang, Qian ; Kanellopoulou, Chrysi ; Zhang, Yu ; Liu, Zhiduo ; Fritz, Jill M. ; Marsh, Rebecca ; Husami, Ammar ; Kissell, Diane ; Nortman, Shannon ; Chaturvedi, Vijaya ; Haines, Hilary ; Young, Lisa R. ; Mo, Jun ; Filipovich, Alexandra H. ; Bleesing, Jack J. ; Mustillo, Peter ; Stephens, Michael ; Rueda, Cesar M. ; Chougnet, Claire A. ; Hoebe, Kasper ; McElwee, Joshua ; Hughes, Jason D. ; Karakoc-Aydiner, Elif ; Matthews, Helen F. ; Price, Susan ; Su, Helen C. ; Rao, V. Koneti ; Lenardo, Michael J. ; Jordan, Michael B. / Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. In: Science. 2015 ; Vol. 349, No. 6246. pp. 436-440.
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AU - Zhang, Kejian

AU - Lu, Wei

AU - Zheng, Lixin

AU - Zhang, Qian

AU - Kanellopoulou, Chrysi

AU - Zhang, Yu

AU - Liu, Zhiduo

AU - Fritz, Jill M.

AU - Marsh, Rebecca

AU - Husami, Ammar

AU - Kissell, Diane

AU - Nortman, Shannon

AU - Chaturvedi, Vijaya

AU - Haines, Hilary

AU - Young, Lisa R.

AU - Mo, Jun

AU - Filipovich, Alexandra H.

AU - Bleesing, Jack J.

AU - Mustillo, Peter

AU - Stephens, Michael

AU - Rueda, Cesar M.

AU - Chougnet, Claire A.

AU - Hoebe, Kasper

AU - McElwee, Joshua

AU - Hughes, Jason D.

AU - Karakoc-Aydiner, Elif

AU - Matthews, Helen F.

AU - Price, Susan

AU - Su, Helen C.

AU - Rao, V. Koneti

AU - Lenardo, Michael J.

AU - Jordan, Michael B.

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N2 - 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.

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