Publications

Publications Search

Search for publications by author
Search for publications by abstract keyword(s)

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

Abstract

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 https://www.ncbi.nlm.nih.gov/pubmed/31396201