Abstract
Cytomegalovirus (CMV) causes clinical issues primarily in immune-suppressed conditions. CMV-associated anterior uveitis (CMV-AU) is a notable new disease entity manifesting recurrent ocular inflammation in immunocompetent individuals. As patient demographics indicated contributions from genetic background and immunosenescence as possible underlying pathological mechanisms, we analyzed the immunogenetics of the cohort in conjunction with cell phenotypes to identify molecular signatures of CMV-AU. Among the immune cell types, natural killer (NK) cells are main responders against CMV. Therefore, we first characterized variants of polymorphic genes that encode differences in CMV-related human NK cell responses (Killer cell Immunoglobulin-like Receptors (KIR) and HLA class I) in 122 CMV-AU patients. The cases were then stratified according to their genetic features and NK cells were analyzed for human CMV-related markers (CD57, KLRG1, NKG2C) by flow cytometry. KIR3DL1 and HLA class I combinations encoding strong receptor–ligand interactions were present at substantially higher frequencies in CMV-AU. In these cases, NK cell profiling revealed expansion of the subset co-expressing CD57 and KLRG1, and together with KIR3DL1 and the CMV-recognizing NKG2C receptor. The findings imply that a mechanism of CMV-AU pathogenesis likely involves CMV-responding NK cells co-expressing CD57/KLRG1/NKG2C that develop on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor–ligand interactions.
Highlights
Human cytomegalovirus (HCMV) causes latent infection in 50–90% of global populations and is prevalent especially in Asian populations [1]
Our findings suggest a role for natural killer (NK) cells co-expressing CD57, KLRG1, and NKG2C that have developed on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor–ligand interactions, in CMV-anterior uveitis (CMV-AU) pathogenesis
Polymorphisms of Killer cell Immunoglobulinlike Receptors (KIRs) and Their Ligands Associated with CMV-AU
Summary
Human cytomegalovirus (HCMV) causes latent infection in 50–90% of global populations and is prevalent especially in Asian populations [1]. The recent, newly established entity of CMV-anterior uveitis (CMV-AU) is noteworthy in that recurrent, intraocular inflammation is induced by CMV in individuals without apparent immunodeficiency or immune suppression [5,6]. Newly developed, high-sensitivity, PCR-based detection methods have revealed that CMV is likely the most frequent cause of virus-induced anterior uveitis in Chinese and Japanese populations [7,8]. In terms of treatments for CMV-AU, topical combination therapy with the anti-viral drug ganciclovir and corticosteroids is effective; the inflammation recurs if treatment is discontinued [9]. This observation implies that the pathogenesis of CMV-AU likely involves dysregulation of the host immunity that controls CMV reactivation
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