TY - JOUR
T1 - Preponderance of CTLA4 Variation Associated With Autosomal Dominant Immune Dysregulation in the MYPPPY Motif
AU - Siggs, Owen M.
AU - Russell, Amanda
AU - Singh-Grewal, Davinder
AU - Wong, Melanie
AU - Chan, Pearl
AU - Craig, Maria E.
AU - O'Loughlin, Ted
AU - Stormon, Michael
AU - Goodnow, Christopher C.
PY - 2019/7/23
Y1 - 2019/7/23
N2 - 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.
AB - 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.
KW - abatacept
KW - autoimmune hepatitis
KW - CTLA-4
KW - CTLA4
KW - de novo variant
KW - ipilimumab
KW - juvenile rheumatoid arthritis (JRA)
UR - http://www.scopus.com/inward/record.url?scp=85071280268&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1108800
U2 - 10.3389/fimmu.2019.01544
DO - 10.3389/fimmu.2019.01544
M3 - Article
C2 - 31396201
AN - SCOPUS:85071280268
SN - 1664-3224
VL - 10
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 1544
ER -