The role of three-locus HLA haplotypes (HLA-DRB1-DQA1-DQB1) in pathogenesis of alloimmunization, atopy, and viral Infection

HLA alloimmunization, allergic rhinitis / atopic dermatitis, and tick-borne encephalitis are relevant clinical models for investigating genetically determined immune responses induced by 3 types of antigens: alloantigens, allergens, and viral antigens. The earlier studies had 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 studied 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. HLA genotyping was performed using real-time PCR (DNA Technology, Moscow, Russia) at the Laboratory of Immunohematology, Kirov Scientific Research Institute of Hematology and Blood Transfusion. Statistical analyses included chi-square test. The haplotypes HLA-DRB1*04-DQA1*03:01DQB1*03:02 and HLA-DRB1*03-DQA1*05:01-DQB1*02:01 were significantly associated with 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. Distinct HLA haplotypes proved to be associated with specific clinical phenotypes of atopic disorders. Specifically, HLADRB1*12-DQA1*05:01-DQB1*03:01 and HLA-DRB1*15-DQA1*01:02-DQB1*06:02 are linked to a selective predisposal for respiratory sensitization, whereas HLA-DRB1*01-DQA1*01:01-DQB1*05:01 is associated with systemic atopy involving skin affection. These findings suggest the immunogenetic heterogeneity of atopic disorders, indicating that allergic rhinitis and atopic dermatitis are distinct endotypes within the broader “atopic continuum”. Moreover, a prognostically favorable form of tick-borne encephalitis (a febrile form, with intact humoral antiviral immune response) was found to be associated with the HLA-DRB1*09-DQA1*03:01DQB1*03:03 haplotype. More severe forms involving central nervous system damage and dysfunction in both humoral and cellular immunity were linked to the distinct haplotypes: the meningeal clinical form was associated with HLA-DRB1*08-DQA1*04:01-DQB1*04:01/*0402 , while the focal form correlated with HLA-DRB1*16DQA1*01:02-DQB1*05:02/*0504 . These findings have important implications for clinical practice, particularly in guiding patient stratification, forecasting disease progression, and choosing the targeted preventive and therapeutic strategies.