Abstract
In genetically prone individuals, chronic immune activation may lead to expansion of autoreactive lymphocyte clones that can induce organ damage developing autoimmune disorders. Sjögren’s Syndrome (SjS) is a systemic chronic autoimmune disease that primarily affects exocrine glands. Despite the accumulated evidences of profound B-cell alterations of humoral immunity, the repertoire and development of B-cell autoreactivity in SjS remains to be determined. We hypothesize that SjS mice will have an increased frequency of self-reactive B cells with a progressive evolution to antigen-driven oligoclonality. Here, we study the B cell repertoire of NOD.H-2h4 mice, a mouse model of spontaneous autoimmunity mimicking SjS without developing diabetes. A library of 168 hybridomas from NOD.H-2h4 mice and 186 C57BL/6J splenocytes at different ages was created. The presence of mono or polyreactive autoantibodies to several antigens was evaluated by ELISA, and their staining patterns and cellular reactivity were tested by IFA and FACS. We observed a higher frequency of autoreactivity among B-cell clones from NOD.H-2h4 mice as compared to wild-type mice. The presence of polyreactive and autoreactive IgG clones increased with mice age. Strikingly, all anti-Ro52 autoantibodies were polyreactive. No loss of polyreactivity was observed upon antibody class switching to IgG. There was a progression to oligoclonality in IgG B cells with mice aging. Our results indicate that in the NOD.H-2h4 mouse model of SjS, IgG+ B cells are mainly polyreactive and might expand following an unknown antigen-driven positive selection process.
Highlights
Sjögren’s syndrome (SjS) is a chronic autoimmune disease, of unknown etiology, that primarily affects the salivary and lacrimal glands with progressive dryness of mouth and eyes [1, 2]
To determine the B cell repertoire of Sjögren’s Syndrome (SjS)-like mice, we generated a library of 168 hybridomas from 28, 47 and 66 weeks old female NOD.H-2h4 mice
It has been described that all 28-week old female NOD.H-2h4 mice shows evidence of salivary gland lymphocyte infiltration and the presence of anti-Ro52 and anti-double strand DNA (dsDNA) autoantibodies [26]
Summary
Sjögren’s syndrome (SjS) is a chronic autoimmune disease, of unknown etiology, that primarily affects the salivary and lacrimal glands with progressive dryness of mouth and eyes [1, 2]. One of the hallmarks of SjS is inflammation of the exocrine tissue, termed focal lymphocytic sialadenitis, and the presence of anti-nuclear antibodies such as anti-dsDNA and anti-Ro52 that are useful diagnostic markers [4,5,6] These autoantibodies have been shown to play a pathogenic role [4, 7]. Besides the Autoimmune B Cell Repertoire occurrence of these autoantibodies, SjS patients are characterized by deep alterations in the frequency of several B lymphocyte populations, both in the blood and in the infiltrated exocrine glands [8,9,10] Another hallmark of the disease is the B cell hyperreactivity due to chronic antigenic stimulation, which is initially polyclonal but can progress to monoclonal B cell lymphoproliferation. Leading to B cell lymphoma development, being the most common marginal zone B-cell lymphoma [11, 12]
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