Immunogenetics and clinical phenotype of sympathetic ophthalmia in British and Irish patients

Abstract

Background/aims-Sympathetic ophthalmia (SO) is a classic example of autoimmune disease where human leucocyte antigen (HLA) genomic associations could provide further understanding of mechanisms of disease. This study sought to assess HLA genetic polymorphism in British and Irish patients with SO, and to assess whether HLA gene variants are associated with clinical phenotype or disease severity. Methods-High resolution DNA based HLA typing using polymerase chain reaction sequence specific primers was performed in 27 patients with SO and 51 matched healthy controls. Clinical phenotype and markers of disease severity were determined prospectively in 17 newly diagnosed patients and from medical record review and repeat clinical examination in 10 previously diagnosed patients. Results-HLA-Cw*03 (p=0.008), DRB1*04 (p=0.017), and DQA1*03 (p=0.014) were significantly associated with SO. For class II alleles at higher resolution, only HLA-DRB1*0404 (relative risk (RR) = 5.6, p = 0.045) was significantly associated with SO. The highest relative risk for any of the associated haplotypes was with HLA-DRB1*0404-DQA1*0301 (RR=10.9, p=0.019). Patients with the DRB1*04-DQA1*03 associated haplotype were significantly more likely to develop SO earlier, with fewer inciting ocular trauma events, and to require more systemic steroid therapy to control inflammatory activity. Conclusions-Sympathetic ophthalmia is associated with HLA-DRB1*04 and DQA1*03 genotypes in white patients, similar to Japanese patients. DiVerences in DRB1*04 gene variant associations (−0404 in Britain and Ireland and −0405 in Japan) may have implications for HLA peptide binding in disease initiation. The DRB1*04-DQA1*03 haplotype is a marker of increased SO susceptibility and severity, as in Vogt-Koyanagi-Harada disease, which also has similar clinicopathological and HLA associations. (Br J Ophthalmol 2001;85:281-286)

Posterior sympathetic ophthalmia: a single centre long-term study of 40 patients from North India

“…[12][13][14] The severity of the disease has been reported to be associated with HLA-DRB1*04. 12 Jaini et al 15 reported unusually high heterogeneity in DR4-DQB1 haplotype in North Indian population. They reported HLA DRB1*0405 to comprise only 11% of all DR4-positive patients in our population.…”

Doyne lecture 2016: intraocular health and the many faces of inflammation

“…7,8,36,37 The currently held notion is that of a CD4 + T helper cell-driven process and supported in man by the association of sympathetic ophthalmia and Vogt-Koyanagi-Harada disease with specific HLA class II alleles as well as the identification of ocular antigen-responsive T cells in both the peripheral blood and eyes of patients. [38][39][40] When T cells are activated, they assume different functional phenotypes directed through canonical transcription factors 41,42 and characterised by the secretion of signature cytokines. 43,44 In EAU, both Th1 and Th17 T helper cells are important inducers of autoimmune disease.…”

Common Genetic Determinants of Uveitis Shared with Other Autoimmune Disorders

“…3) Locus D7Rat26 on chromosome 7 interacts with multiple regions to modify EAU susceptibility (models 16 -20, Table IV), one of which is Eau1 (D4Arb7 and D4Arb8) that was originally identified. 4) The chromosome 1 locus D1Rat90 interacts with multiple regions (models [13][14][15][16] , Table IV), and 5) the chromosome 5 locus D5Mit10, which is the peak marker for Eae16 (supplementary table Ia), which interacts with the regions on chromosomes 2, 7, and 10. These models show that heterozygous genotypes at these interacting loci modulate the EAU susceptibility that is associated with EAU QTLs on the same or different chromosomes.…”

“…The inheritance pattern is complex and is influenced by multiple genetic factors (4). Because of the inflammatory nature of the disease and the allelic variations in the MHC genes that influence the immune response, susceptibility to uveitis has been associated with the major genes that are located within the MHC (HLA in human) class I (5-10) or class II (11)(12)(13)(14)(15)(16) loci. In addition to the MHC class I and class II genes, genetic associations have also been reported for several non-MHC genes like TNF-␣ (17,18), MCP-1/CCL2 promoter region (19), CCL2, CCL5 (20), CCR5 (21), the IL-1 gene cluster (22), ICAM-1 (23), eNOS (24), and CyP4501A1 (25).…”