CTLA4 Message Reflects Pathway Disruption in Monogenic Disorders and Under Therapeutic Blockade. Front Immunol 2019;10:998
Date
06/04/2019Pubmed ID
31156616Pubmed Central ID
PMC6532297DOI
10.3389/fimmu.2019.00998Scopus ID
2-s2.0-85067103184 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
CTLA-4 is essential for immune tolerance. Heterozygous CTLA4 mutations cause immune dysregulation evident in defective regulatory T cells with low levels of CTLA-4 expression. Biallelic mutations in LRBA also result in immune dysregulation with low levels of CTLA-4 and clinical presentation indistinguishable from CTLA-4 haploinsufficiency. CTLA-4 has become an immunotherapy target whereby its blockade with a monoclonal antibody has resulted in improved survival in advanced melanoma patients, amongst other malignancies. However, this therapeutic manipulation can result in autoimmune/inflammatory complications reminiscent of those seen in genetic defects affecting the CTLA-4 pathway. Despite efforts made to understand and establish disease genotype/phenotype correlations in CTLA-4-haploinsufficiency and LRBA-deficiency, such relationships remain elusive. There is currently no specific immunological marker to assess the degree of CTLA-4 pathway disruption or its relationship with clinical manifestations. Here we compare three different patient groups with disturbances in the CTLA-4 pathway-CTLA-4-haploinsufficiency, LRBA-deficiency, and ipilimumab-treated melanoma patients. Assessment of CTLA4 mRNA expression in these patient groups demonstrated an inverse correlation between the CTLA4 message and degree of CTLA-4 pathway disruption. CTLA4 mRNA levels from melanoma patients under therapeutic CTLA-4 blockade (ipilimumab) were increased compared to patients with either CTLA4 or LRBA mutations that were clinically stable with abatacept treatment. In summary, we show that increased CTLA4 mRNA levels correlate with the degree of CTLA-4 pathway disruption, suggesting that CTLA4 mRNA levels may be a quantifiable surrogate for altered CTLA-4 expression.
Author List
Garcia-Perez JE, Baxter RM, Kong DS, Tobin R, McCarter M, Routes JM, Verbsky J, Jordan MB, Dutmer CM, Hsieh EWYAuthors
John M. Routes MD Chief, Professor in the Pediatrics department at Medical College of WisconsinJames Verbsky MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAutoimmune Diseases
CTLA-4 Antigen
Haploinsufficiency
Humans
Ipilimumab
Melanoma
Mutation
Signal Transduction
T-Lymphocytes, Regulatory
