Novel genetic variants in tuberculosis-associated immune reconstitution inflammatory syndrome

To the Editor: Patients with HIV-associated tuberculosis (TB) are at risk of developing immune reconstitution inflammatory syndrome (IRIS), a self-limiting yet severe hyperinflammatory condition occurring shortly after the initiation of antiretroviral therapy (ART).1,2 The pathogenesis is mediated by dysregulated innate and adaptive immune responses. Specifically, the rapid restoration of CD4+ T-cell function following ART might amplify myeloid cell activation, triggering exaggerated inflammatory responses against mycobacterial antigens.3,4 Although the clinical manifestations and immunopathology are well-characterized, the genetic determinants underlying TB-IRIS susceptibility remain poorly defined. Initial genetic insights into TB-IRIS came from candidate gene studies identifying associations with variants in inflammatory cytokines like IL6 and TNFA and the immune-related gene SLC11A1.5,6 Complementary work highlighted associations with specific combinations of KIR and HLA alleles.7 More recently, targeted sequencing suggested a role for rare, protein-altering variants in genes linked to primary hemophagocytic lymphohistiocytosis in mycobacterial-IRIS.8 However, conflicting results regarding LTA4H promoter polymorphisms underscore potential ethnic variation in genetic susceptibility and the need for further investigation across diverse populations.9,10