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Preponderance of CTLA4 Variation Associated With Autosomal Dominant Immune Dysregulation in the MYPPPY Motif


One of the primary targets of immune checkpoint inhibition is the negative immune regulatory molecule CTLA-4. Immune-related adverse events are commonly observed following CTLA-4 inhibition in melanoma treatment, and a spectrum of these conditions are also observed in individuals with germline haploinsufficiency of CTLA4. Here we describe a heterozygous de novo missense variant of CTLA4 in a young girl with childhood-onset autoimmune hepatitis and polyarthritis, the latter responding to treatment with CTLA-4-Ig fusion protein. This variant lay within the highly conserved MYPPPY motif of CTLA-4: a critical structural determinant of ligand binding, which is also bound by the anti-CTLA-4 monoclonal antibody ipilimumab. Within the spectrum of CTLA4 variants reported, missense variants in the MYPPPY motif were overrepresented when compared to variants within a control population, highlighting the physiological importance of this motif in both the genetic and pharmacological regulation of autoimmunity and anti-tumor immunity.

Type Journal
ISBN 1664-3224 (Electronic) 1664-3224 (Linking)
Authors Siggs, O. M.; Russell, A.; Singh-Grewal, D.; Wong, M.; Chan, P.; Craig, M. E.; O'Loughlin, T.; Stormon, M.; Goodnow, C. C.
Responsible Garvan Author Prof Christopher Goodnow
Publisher Name Frontiers in Immunology
Published Date 2019-07-23
Published Volume 10
Published Pages 1544
Status Always Electronic
DOI 10.3389/fimmu.2019.01544
URL link to publisher's version