THE ROLE OF THREE-LOCUS HLA HAPLOTYPES (HLA-DRB1-DQA1-DQB1) IN THE PATHOGENESIS OF ALLOIMMUNIZATION, ATOPY, AND VIRAL INFECTION

HLA alloimmunization, allergic rhinitis/atopic dermatitis, and tick-borne encephalitis serve as relevant models for investigating genetically determined immune responses to three types of antigens: alloantigens, allergens, and viral antigens. Previous research has primarily focused on individual HLA alleles, without considering haplotype-level interactions and potential synergistic effects among HLA genes. This study aimed to identify associations between three-locus HLA haplotypes (HLA-DRB1-DQA1-DQB1) and the risk of developing HLA alloimmunization, allergic rhinitis, atopic dermatitis, and tick-borne encephalitis. Twelve common European haplotypes were analyzed in 215 patients and 317 healthy controls. Alloimmunization risk was assessed in 61 recipients of blood components, atopic conditions were evaluated in 50 patients with persistent allergic rhinitis and atopic dermatitis, and the clinical course of tick-borne encephalitis was examined in 104 patients. Genotyping was performed using real-time PCR (DNA Technology, Russia) at the Laboratory of Immunohematology, Kirov Scientific Research Institute of Hematology and Blood Transfusion. Statistical analyses included chi-square. The haplotypes HLA-DRB104-DQA103:01-DQB1*03:02 and HLA-DRB103-DQA105:01-DQB1*02:01 were significantly associated with the development of HLA alloimmunization. Their complete overlap with genetic markers of autoimmune diseases suggests a shared mechanism by which HLA molecules mediate the presentation of both autoantigens and alloantigens. It has been shown that distinct HLA haplotypes are associated with specific clinical phenotypes of atopy. Specifically, HLA-DRB112-DQA105:01-DQB1*03:01 and HLA-DRB115-DQA101:02-DQB1*06:02 are linked to a selective predisposition toward respiratory sensitization, whereas HLA-DRB101-DQA101:01-DQB1*05:01 is associated with systemic atopy that includes a cutaneous component. These findings support the immunogenetic heterogeneity of atopic disorders, indicating that allergic rhinitis and atopic dermatitis are distinct endotypes within the broader “atopic continuum.” The analysis revealed that a prognostically favorable form of tick-borne encephalitis—the fever form, characterized by an intact humoral antiviral immune response—was found to be associated with the HLA-DRB109-DQA103:01-DQB1*03:03 haplotype. More severe forms involving central nervous system damage and dysfunction in both humoral and cellular immunity were linked to distinct haplotypes: the meningeal form was associated with HLA-DRB108-DQA104:01-DQB1*04:01/04:02, while the focal form correlated with HLA-DRB116-DQA101:02-DQB1*05:02/05:04. These findings have important implications for clinical practice, particularly in guiding patient stratification, forecasting disease progression, and informing the selection of targeted preventive and therapeutic strategies.

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