Elevated Type I interferon signature in patients with Chronic Granulomatous Disease

Abstract Background Chronic granulomatous disease (CGD) patients develop repeated infections and inflammatory complications. Underlying pathogenesis of hyperinflammation in CGD is not clearly characterised. Objective To assess type-1 interferon signature and measure Siglec-1/CD169 expression on monocytes in patients with CGD. Methods mRNA sequencing of PBMCs in 5 CGD patients and 3 controls was analysed for differentially expressed genes. Subsequently, 20 patients with CGD, 10 heterozygous carriers of CYBB mutations, 11 healthy controls and 11 patients of systemic lupus erythematosus (disease controls) were enrolled. Expression of CD169 on monocytes was measured using flowcytometry. Expression of 5 type-1 interferon signature genes (ISGs) was measured using RT-PCR. Results On transcriptome analysis of peripheral blood mononuclear cells, increased expression of type-1 ISGs were seen in CGD patients. Monocyte CD169 expression was compared across 3 subgroups of CGD patients (10=Inflammatory disease, 5=Infectious disease, 5=Asymptomatic disease). CD169 expression on monocytes (percentage and ΔMFI) was significantly high in inflammatory disease subgroup in comparison to asymptomatic disease subgroup of CGD (p=0.001 and p=0.001). Similarly, the expression was significantly high in inflammatory disease subgroup when compared to infection subgroup of CGD (p=0.033 and p=0.017). An elevated type-1 interferon score by RT-PCR was found in inflammatory disease subgroup in comparison to infection subgroup of CGD (p=0.029) and healthy controls (p=0.021). Percentage and ΔMFI of monocyte CD169 correlated with type-1 interferon scores, rp=0.38 (p=0.049) and rp=0.46 (p=0.017), respectively. Conclusion CGD patients with hyperinflammatory manifestations exhibited a high type-1 interferon signature. CD169 is a reliable surrogate marker for estimation of type-1 interferon signature.