Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects

Schwab, Charlotte; Gabrysch, Annemarie; Olbrich, Peter; Patiño, Virginia; Warnatz, Klaus; Wolff, Daniel; Hoshino, Akihiro; Kobayashi, Masao; Imai, Kohsuke; Takagi, Motoki; Dybedal, Ingunn; Haddock, J; Sansom, David M.; Lucena, José Manuel; Seidl, Maximilian; Schmitt‐Graeff, Annette; Reiser, Veronika; Emmerich, Florian; Frede, Natalie; Bulashevska, Alla; Salzer, Ulrich; Schubert, Desirée; Hayakawa, Seiichi; Okada, Satoshi; Kanariou, Maria; Kucuk, Zeynep Yesim; Chapdelaine, Hugo; Petruželková, Lenka; Šumnı́k, Zdenĕk; Šedivá, Anna; Slatter, Mary; Arkwright, Peter D.; Cant, Andrew J.; Lorenz, Hanns‐Martin; Giese, Thomas; Lougaris, Vassilios; Plebani, Alessandro; Price, Christina; Sullivan, Kathleen E.; Moutschen, Michel; Litzman, Jiří; Freiberger, Tomáš; Veerdonk, Frank L. van de; Recher, Mike; Albert, Michael H.; Hauck, Fabian; Seneviratne, Suranjith L.; Schmid, Jana Pachlopnik; Kolios, Antonios; Unglik, Gary; Klemann, Christian; Speckmann, Carsten; Ehl, Stephan; Leichtner, Alan M.; Blumberg, Richard S.; Franke, André; Snapper, Scott B.; Zeißig, Sebastian; Cunningham‐Rundles, Charlotte; Giulino‐Roth, Lisa; Elemento, Olivier; Dückers, Gregor; Niehues, Tim; Froňková, Eva; Kanderová, Veronika; Platt, Craig D.; Chou, Janet; Chatila, Talal A.; Geha, Raif S.; McDermott, Elizabeth; Bunn, Su; Kurzai, Monika; Schulz, Ansgar; Alsina, Laia; Casals, Ferrán; Deyà‐Martínez, Àngela; Hambleton, Sophie; Kanegane, Hirokazu; Taskén, Kjetil; Neth, Olaf; Grimbacher, Bodo

doi:10.1016/j.jaci.2018.02.055

Cited by 357 publications

(541 citation statements)

References 41 publications

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“…No mutation was found in exon 4, and any motifs in which gene mutations accumulated in a specific region were not clearly provided. A heterozygous 2q33.2‐2q33.3 deletion was reported in two individuals with a CTLA‐4 insufficiency‐like phenotype, indicating that the study for detecting large deletion in this region is necessary in addition to the sequencing of the 4 exons in CTLA4 . No correlation between genotype and onset, penetrance, or disease phenotype has been represented .…”

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

“…Schwab et al characterized the clinical features in 133 CTLA4 mutation carriers. Based on this large clinical analysis, the patients suffered from autoimmune diseases, including cytopenia, enteropathy, and T1D, respiratory manifestations, and neurological symptoms, as first symptoms . The median age of disease onset was 11 years.…”

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

“…Main symptoms, present in more than half of patients, were hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenia, nonmalignant lymphoproliferation, respiratory tract infections, diarrhea, and atopic dermatitis (Table ). Neurological features including autoimmune encephalitis and brain infiltrations, endocrinopathy, and arthritis were also presented, although less frequent . In addition, CTLA‐4‐insufficient patients had infections dominated by bacterial infections in the respiratory tract, and Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) reactivations, including EBV‐induced hemophagocyticlymphohistiocytosis (HLH) and CMV‐associated diarrhea or gastritis .…”

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

“…Neurological features including autoimmune encephalitis and brain infiltrations, endocrinopathy, and arthritis were also presented, although less frequent . In addition, CTLA‐4‐insufficient patients had infections dominated by bacterial infections in the respiratory tract, and Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) reactivations, including EBV‐induced hemophagocyticlymphohistiocytosis (HLH) and CMV‐associated diarrhea or gastritis . Approximately 12% of the affected CTLA4 mutation carriers had malignancies: the most frequent malignancy observed in CTLA4 mutation carriers was lymphoma, including EBV‐associated diffuse large B cell lymphoma, Burkitt lymphoma, and Hodgkin lymphoma .…”

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

“…In addition, CTLA‐4‐insufficient patients had infections dominated by bacterial infections in the respiratory tract, and Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) reactivations, including EBV‐induced hemophagocyticlymphohistiocytosis (HLH) and CMV‐associated diarrhea or gastritis . Approximately 12% of the affected CTLA4 mutation carriers had malignancies: the most frequent malignancy observed in CTLA4 mutation carriers was lymphoma, including EBV‐associated diffuse large B cell lymphoma, Burkitt lymphoma, and Hodgkin lymphoma . Egg et al showed that seven of ten CTLA‐4‐insufficient patients with lymphoma and three of five patients with gastric cancers were EBV‐associated.…”

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

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What did we learn from CTLA‐4 insufficiency on the human immune system?

Mitsuiki

Schwab

Grimbacher

2018

Immunological Reviews

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127

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Summary Cytotoxic‐T‐lymphocyte‐antigen‐4 (CTLA‐4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated on activated T cells. CTLA‐4 inhibits T cell activation by various suppressive functions including competition with CD28, regulation of the inhibitory function of Treg cells, such as transendocytosis, and the control of adhesion and motility. Intrinsic CTLA‐4 signaling has been controversially discussed, but so far no distinct signaling pathway has been identified. The CTLA‐4‐mediated Treg suppression plays an important role in the maintenance of peripheral tolerance and the prevention of autoimmune diseases. Human CTLA‐4 insufficiency is caused by heterozygous germline mutations in CTLA4 and characterized by a complex immune dysregulation syndrome. Clinical studies on CTLA4 mutation carriers showed a reduced penetrance and variable expressivity, suggesting modifying factor(s). One hundred and forty‐eight CTLA4 mutation carriers have been reported; patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphocytic infiltration into multiple organs. The CTLA‐4 expression level in Treg cells was reduced, while the frequency of Treg cells was increased in CTLA‐4‐insufficient patients. The transendocytosis assay is a specific functional test for the assessment of newly identified CTLA4 gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, and targeted therapy such as with CTLA‐4 fusion proteins and mechanistic target of rapamycin (mTOR) inhibitors were applied; patients with life‐threatening, treatment‐resistant symptoms underwent hematopoietic stem cell transplantation. The fact that in humans CTLA‐4 insufficiency causes severe disease taught us that the amount of CTLA‐4 molecules present in/on T cells matters for immune homeostasis. However, whether the pathology‐causing activated T lymphocytes in CTLA‐4‐insufficient patients are antigen‐specific is an unsolved question. CTLA‐4, in addition, has a role in autoimmune diseases and cancer. Anti‐CTLA‐4 drugs are employed as checkpoint inhibitors to target various forms of cancer. Thus, clinical research on human CTLA‐4 insufficiency might provide us a deeper understanding of the mechanism(s) of the CTLA‐4 molecule and immune dysregulation disorders.

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Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

Section: Human Ctla‐4 Insufficiencymentioning

confidence: 99%

See 3 more Smart Citations

What did we learn from CTLA‐4 insufficiency on the human immune system?

Mitsuiki

Schwab

Grimbacher

2018

Immunological Reviews

Self Cite

127

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Cytotoxic T-Lymphocyte Antigen–4 Haploinsufficiency Cutaneous Manifestations

et al. 2021

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Adult-Onset Genetic Central Nervous System Disorders Masquerading as Acquired Neuroinflammatory Disorders

et al. 2022

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ImportanceAdult-onset genetic disorders may present with clinical and magnetic resonance imaging (MRI) features suggestive of acquired inflammatory diseases. An ever-growing number of potentially treatable adult-onset genetic neuroinflammatory disorders have been described in the past few years that need to be rapidly identified.ObservationsAdult-onset acquired neuroinflammatory disorders encompass a large group of central nervous system (CNS) diseases with varying presentation, MRI characteristics, and course, among which the most common is multiple sclerosis. Despite recent progress, including the discovery of specific autoantibodies, a significant number of adult-onset neuroinflammatory disorders with progressive or relapsing course still remain without a definite diagnosis. In addition, some patients with genetic disorders such as leukodystrophies, hemophagocytic lymphohistiocytosis, or genetic vasculopathies can mimic acquired neuroinflammatory disorders. These genetic disorders, initially described in pediatric populations, are increasingly detected in adulthood thanks to recent progress in molecular genetics and the larger availability of high-throughput sequencing technologies.Conclusions and RelevanceGenetic adult-onset neuroinflammatory diseases are at the border between primary CNS inflammatory diseases and systemic disorders with multiorgan involvement and predominantly neurologic manifestations. Neurologists must be aware of the main clues and red flags so they can confirm a diagnosis early, when some of these genetic disorders can be successfully treated.

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Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects

Cited by 357 publications

References 41 publications

What did we learn from CTLA‐4 insufficiency on the human immune system?

What did we learn from CTLA‐4 insufficiency on the human immune system?

Cytotoxic T-Lymphocyte Antigen–4 Haploinsufficiency Cutaneous Manifestations

Adult-Onset Genetic Central Nervous System Disorders Masquerading as Acquired Neuroinflammatory Disorders

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