Abstract
Purpose: :
To investigate the relative contribution of B and T lymphocytes in the pathogenesis of lacrimal gland targeted autoimmunity and ocular surface inflammation in the Aire-deficient model of Sjögren’s syndrome.
Methods: :
in vivo analysis of autoimmunity, adoptive transfer of sorted lymphocyte populations, genetic crosses with B and T deficient mice, and intracellular cytokine staining by flow cytometry were investigated.
Results: :
Aire-deficient mice, which represent a new spontaneous model of Sjögren’s syndrome, generate B and T lymphocyte and high titer autoantibody responses against a novel set of self-antigens expressed in the lacrimal resulting in exocrinopathy and ocular surface pathology consistent with keratoconjunctivitis sicca in SS patients. We examined the pathogenicity of autoantibodies by sera transfers and by crossing the aire mutation on to the IgH / B cell deficient background. Ocular surface disease and exocrinopathy was not significantly different between controls and mice devoid of B cells and autoantibodies. In contrast, mice with the aire mutation in a TCRα deficient background, which results in the absence of T cells, failed to show any signs of disease. Furthermore, adoptive transfer experiments with aire-deficient lymphocytes in immunodeficient hosts, and genetic crosses that resulted in mice deficient for T lymphocyte subsets show that T cells are indispensable to the disease process. In particular, Th1 polarized CD4+ T cells play a major role in the pathogenesis of our mouse model of SS.
Conclusions: :
The Aire-deficient mouse represents a novel and clinically relevant model to study the immunopathogenesis of SS. Our results indicate that lacrimal gland autoimmunity and consequent ocular surface pathology is mediated specifically by cellular immune responses and suggests that autoantibodies, while present, do not play a major role in disease pathogenesis. These findings may facilitate the development of target-specific immunoregulatory therapeutics in SS patients.
Keywords: autoimmune disease • cornea: tears/tear film/dry eye • cornea: basic science