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

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

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01544

DOI=10.3389/fimmu.2019.01544

ISSN=1664-3224

ABSTRACT=<p>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 <italic>CTLA4</italic>. Here we describe a heterozygous <italic>de novo</italic> missense variant of <italic>CTLA4</italic> 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 <italic>CTLA4</italic> 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.</p>