Frontiers in Immunology (Jul 2019)

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

  • Owen M. Siggs,
  • Owen M. Siggs,
  • Amanda Russell,
  • Davinder Singh-Grewal,
  • Melanie Wong,
  • Pearl Chan,
  • Maria E. Craig,
  • Ted O'Loughlin,
  • Michael Stormon,
  • Christopher C. Goodnow,
  • Christopher C. Goodnow

DOI
https://doi.org/10.3389/fimmu.2019.01544
Journal volume & issue
Vol. 10

Abstract

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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.

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