The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects
Open accessAbstract
Background: Cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. Objective: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. Methods: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. Results: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T‐, B‐, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA‐4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. Conclusions: Affected mutation carriers with CTLA‐4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV‐ and cytomegalovirus‐associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Control of Regulatory T Cell Development by the Transcription Factor Foxp3
Hori, S., Nomura, T., & Sakaguchi, S. (2003) · Science · doi:10.1126/science.1079490 · Cited by 8,187 · cited 2×
“In subjects presenting with immunodeficiency, autoimmunity, and lymphoproliferation with impaired Treg cell development or function, in addition to CTLA-4 insufficiency, also mutations in FOXP3,LRBA, IL2RA,FASL,FAS,PI3K,NFKB1,NFKB2, STAT3, and STAT5B should be considered as a differential diagnosis.(6,23,25-32) Mutati…”
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells
Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003) · Nature Immunology · doi:10.1038/ni904 · Cited by 7,745
The Role of Tumoral FOXP3 on Cell Proliferation, Migration, and Invasion in Gastric Cancer
Zhang, L., Xu, J., Zhang, X., Zhang, Y., Wang, L., Huang, X., & Xu, Z. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479442 · Cited by 4,088
CTLA-4 Control over Foxp3 + Regulatory T Cell Function
Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., & Sakaguchi, S. (2008) · Science · doi:10.1126/science.1160062 · Cited by 2,956
Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T. W., & Sakaguchi, S. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.2.303 · Cited by 2,233
Read, S., Malmström, V., & Powrie, F. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.2.295 · Cited by 2,205
Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4
Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., Baker, J., Jeffery, L. E., Kaur, S., Briggs, Z., et al. (2011) · Science · doi:10.1126/science.1202947 · Cited by 1,860 · cited 2×
“CTLA-4 binds these ligands with a higher affinity and avidity than CD28 and removes them from the surfaces of APCs through transendocytosis, resulting in reduction in APC-mediated activation of conventional T cells.(12,13) CTLA4 encodes for 4 exons: exon 1 encodes the signal peptide, exon 2 encodes the ligand-binding…”
Picard, C., Al-Herz, W., Bousfiha, A., Casanova, J.-L., Chatila, T., Conley, M. E., Cunningham-Rundles, C., Etzioni, A., Holland, S. M., Klein, C., et al. (2015) · Journal of Clinical Immunology · doi:10.1007/s10875-015-0201-1 · Cited by 1,197
Self-citationImmune dysregulation in human subjects with heterozygous germline mutations in CTLA4
Kuehn, H. S., Ouyang, W., Lo, B., Deenick, E. K., Niemela, J. E., Avery, D. T., Schickel, J.-N., Tran, D. Q., Stoddard, J., Zhang, Y., et al. (2014) · Science · doi:10.1126/science.1255904 · Cited by 848
Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations
Schubert, D., Bode, C., Kenefeck, R., Hou, T. Z., Wing, J. B., Kennedy, A., Bulashevska, A., Petersen, B.-S., Schäffer, A. A., Grüning, B. A., et al. (2014) · Nature Medicine · doi:10.1038/nm.3746 · Cited by 832
Self-citation
Cited by
Moving towards personalized treatments of immune-related adverse events
Esfahani, K., Elkrief, A., Calabrese, C., Lapointe, R., Hudson, M., Routy, B., Miller, W. H., & Calabrese, L. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0352-8 · Cited by 351
Wei, S. C., Meijers, W. C., Axelrod, M. L., Anang, N.-A. A. S., Screever, E. M., Wescott, E. C., Johnson, D. B., Whitley, E., Lehmann, L., Courand, P.-Y., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0856 · Cited by 290
Early-onset autoimmunity associated with SOCS1 haploinsufficiency
Hadjadj, J., Castro, C. N., Tusseau, M., Stolzenberg, M.-C., Mazerolles, F., Aladjidi, N., Armstrong, M., Ashrafian, H., Cutcutache, I., Ebetsberger-Dachs, G., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18925-4 · Cited by 156
Self-citationPrimary immune regulatory disorders: a growing universe of immune dysregulation
Chan, A. Y., & Torgerson, T. R. (2020) · Current Opinion in Allergy & Clinical Immunology · doi:10.1097/aci.0000000000000689 · Cited by 111
Incomplete penetrance in primary immunodeficiency: a skeleton in the closet
Gruber, C., & Bogunovic, D. (2020) · Human Genetics · doi:10.1007/s00439-020-02131-9 · Cited by 97
Metadata
- Authors
- Schwab, C., Gabrysch, A., Olbrich, P., Patiño, V., Warnatz, K., Wolff, D., Hoshino, A., Kobayashi, M., Imai, K., Takagi, M., Dybedal, I., Haddock, J. A., Sansom, D. M., Lucena, J. M., Seidl, M., Schmitt-Graeff, A., Reiser, V., Emmerich, F., Frede, N., Bulashevska, A., Salzer, U., Schubert, D., Hayakawa, S., Okada, S., Kanariou, M., Kucuk, Z. Y., Chapdelaine, H., Petruzelkova, L., Sumnik, Z., Sediva, A., Slatter, M., Arkwright, P. D., Cant, A., Lorenz, H.-M., Giese, T., Lougaris, V., Plebani, A., Price, C., Sullivan, K. E., Moutschen, M., Litzman, J., Freiberger, T., van de Veerdonk, F. L., Recher, M., Albert, M. H., Hauck, F., Seneviratne, S., Pachlopnik Schmid, J., Kolios, A., Unglik, G., Klemann, C., Speckmann, C., Ehl, S., Leichtner, A., Blumberg, R., Franke, A., Snapper, S., Zeissig, S., Cunningham-Rundles, C., Giulino-Roth, L., Elemento, O., Dückers, G., Niehues, T., Fronkova, E., Kanderová, V., Platt, C. D., Chou, J., Chatila, T. A., Geha, R., McDermott, E., Bunn, S., Kurzai, M., Schulz, A., Alsina, L., Casals, F., Deyà-Martinez, A., Hambleton, S., Kanegane, H., Taskén, K., Neth, O., & Grimbacher, B.
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 142
- Issue
- 6
- Pages
- 1932-1946
- ISSN
- 0091-6749 (ISSN-L)
- OpenAlex
- W2801254160
- Cited by
- 438
- References
- 41
- FWCI
- 17.35
- Type
- journal article
- Language
- en
- Open access
- bronze
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
How to cite
Cite CoChat for the checks on this page, and the paper for its own findings.
- This page
- CoChat. (2026). Citation check: Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects. https://app.cochat.ai/papers/10.1016/j.jaci.2018.02.055
- The paper
- Schwab, C., Gabrysch, A., Olbrich, P., Patiño, V., Warnatz, K., Wolff, D., Hoshino, A., Kobayashi, M., Imai, K., Takagi, M., Dybedal, I., Haddock, J. A., Sansom, D. M., Lucena, J. M., Seidl, M., Schmitt-Graeff, A., Reiser, V., Emmerich, F., Frede, N., . . . Grimbacher, B. (2018). Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2018.02.055
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
