- D1.536 - Immunological basis of coexisting slowly progressive insulin-dependent diabetes mellitus (SPIDDM) and Vogt–Koyanagi–Harada disease (VKH)

Background: Vogt–Koyanagi–Harada disease (VKH) and slowly progressive insulin-dependent diabetes mellitus (SPIDDM) share immunogenetic susceptibility, suggesting partially overlapping autoimmune mechanisms 1,2). Both conditions are characterized by T cell–mediated, organ-specific autoimmunity and are reported to occur preferentially in individuals carrying specific HLA class II alleles.

Methods: We describe a 32-year-old obese Japanese male with VKH who gradually developed SPIDDM, characterized by positivity for anti–glutamic acid decarboxylase (GAD) antibodies (138 U/mL) and insulinoma-associated antigen-2 (IA-2) antibodies, followed by progressive insulin dependency. Clinical findings, immunogenetic features, and experimental evidence from prior studies were reviewed to explore shared disease susceptibility and effector immune pathways.

Results: Both VKH and SPIDDM are strongly associated with HLA-DR4 alleles, particularly DRB10405 and 0401, which preferentially present tissue-specific autoantigen-derived peptides to CD4⁺ T cells 1,2). These alleles predispose to Th1- and Th17-dominant immune responses targeting melanocyte-associated antigens in VKH and pancreatic β-cell antigens in SPIDDM. Experimental animal models demonstrate that either Th1- or Th17-skewed effector polarization is sufficient to induce autoimmune tissue injury, whereas combined disruption of these pathways confers resistance to both autoimmune diabetes and uveitis 3,4). HLA-restricted antigen presentation further facilitates cross-reactive T-cell responses against autoantigens expressed in the eye, meninges, inner ear, hair follicle, synovium, and pancreas 1,2).

Conclusion: These observations support the concept that VKH and SPIDDM represent organ-specific clinical expressions of a shared Th1/Th17-mediated autoimmune diathesis under HLA-DR4 restriction.

References: 1)Hemidan AA, et al. Eur J Ophthalmol 2006;16(1):173–177. 2)Suzuki H, et al. Intern Med 2008;47(13):1241–1244. 3)Esensten JH, et al. J Immunol 2009;183(1):75–82. 4)Luger D, et al. J Exp Med 2008;205(4):799–810.