CTLA4 Message Reflects Pathway Disruption in Monogenic Disorders and Under Therapeutic Blockade.

Josselyn E Garcia-Perez,Richard Tobin,Cullen M Dutmer,James Verbsky,Elena W Y Hsieh,Daniel S Kong,John M Routes,Ryan M Baxter,Michael B Jordan,Martin Mccarter

doi:10.3389/fimmu.2019.00998

Abstract

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.

Highlights

The regulation of immune responses to self and foreign antigens balances immune tolerance and antimicrobial defense
To CTLA4 haploinsufficient patients, LRBA deficient patients have a wide range of phenotypic presentations, including inflammatory bowel disease-like enteropathy, autoimmune hemolytic anemia, and immune thrombocytopenic purpura [23, 24]
When CTLA4 mRNA expression levels from peripheral blood mononuclear cells (PBMCs) were evaluated, the relative quantification of mRNA seemed to correlate with degree of CTLA-4 pathway disruption

Summary

INTRODUCTION

The regulation of immune responses to self and foreign antigens balances immune tolerance and antimicrobial defense. To CTLA4 haploinsufficient patients, LRBA deficient patients have a wide range of phenotypic presentations, including inflammatory bowel disease-like enteropathy, autoimmune hemolytic anemia, and immune thrombocytopenic purpura [23, 24] They often have hypogammaglobulinemia and increased CD21lo B cells [21, 25]. When CTLA4 mRNA expression levels from peripheral blood mononuclear cells (PBMCs) were evaluated, the relative quantification of mRNA seemed to correlate with degree of CTLA-4 pathway disruption To make this an unbiased assessment, and considering how LRBA deficiency evokes a CTLA-4 haploinsufficiency phenotype, we included two patients with mutations in LRBA Future studies evaluating larger patient cohorts are required to further expand this finding and potentially uncover a reliable biomarker for clinical management of these disorders

MATERIALS AND METHODS

Findings

ETHICS STATEMENT