Tryptophan-kynurenine metabolites associate with inflammation and immunologic phenotypes in common variable immunodeficiency.

Abstract

A large proportion of patients with common variable immunodeficiency (CVID) have autoimmune and inflammatory manifestations characterized by chronic T-cell- and monocyte/macrophage activation of unknown etiology. The tryptophan-kynurenine pathway has previously been linked to immune activation involving T cells and monocytes/macrophages, as well as with gut microbial dysbiosis in some inflammatory diseases. We aimed to characterize the tryptophan-kynurenine pathway in CVID and its potential association with clinical/immunologic phenotype and gut microbial dysbiosis. Serum concentrations of a set of tryptophan-kynurenine pathway metabolites and neopterin were measured using liquid chromatography-tandem mass spectrometry in a discovery cohort (n = 40), a validation cohort (n = 53), and healthy controls (n = 60). B-cell phenotype was analyzed in both cohorts, whereas inflammatory markers (enzyme immunoassay), lipopolysaccharide, gut microbial composition, and food frequency questionnaire were measured in the discovery cohort. Compared to healthy controls, CVID patients had increased metabolism of the tryptophan-kynurenine pathway as assessed by increased kynurenine/tryptophan ratio, quinolinic acid, and 3-hydroxykynurenine in both the discovery and validation cohorts. The findings were most pronounced in the subgroup with autoimmune/inflammatory complications but was to some degree also observed in CVID patients with infection only. In CVID, the metabolites in the tryptophan-kynurenine pathway associated with soluble (s) markers of monocyte (sCD14, sCD163, neopterin) and T-cell (sCD25) activation as well as B-cell phenotype (eg, naïve B cells). Individual gut microbial taxa may influence tryptophan-kynurenine pathway metabolites, but not lipopolysaccharide or diet. We found altered levels of several metabolites in the tryptophan-kynurenine pathway in two different CVID cohorts associated with systemic inflammation and B-cell phenotype.