Background/Purpose . Autoantibodies reactive with Ro52 are present in almost 70% of Sjögren’s syndrome (SS) patients. This study was undertaken to investigate the role of Ro52 induced immune responses in the pathogenesis of SS in an experimental mouse model system.
Methods . New Zealand Mixed (NZM) 2758 mice were immunized with mouse Ro52, adsorbed on to alum adjuvant. Control mice were injected either with Maltose binding protein (MBP) or only with alum. Mice were monitored for anti-Ro52 antibody production, sialoadenitis, serum cytokine levels, and pilocarpine induced salivation. Antibody binding to salivary gland cells was analyzed in vivo and in vitro by immunofluorescence. Sera from immunized mice were passively transferred into untreated or alum injected NZM2758 mice. Internalization of antibodies by live cells was investigated by using the salivary gland cell line SCA9-15. Clinical data from the Oklahoma pSS patient cohort that met the AECG classification criteria for SS was analyzed for anti-Ro reactivity, minor labial salivary gland biopsy focus scores, and xerostomia.
Results . By day 30 post-immunization, Ro52 immunized mice generated immunoprecipitating anti-Ro52 antibodies and they had the maximum drop in saliva production. The glandular dysfunction in these mice was significantly associated with the level of anti-Ro52 antibody. Both Ro52 immunized and control mice showed evidence for very mild sialoadenitis. However, only Ro52 immunized mice had antibody deposition in their salivary glands. Passive transfer of Ro52 immune sera induced salivary gland dysfunction in the recipient mice, only if the recipients were pre primed with alum. The levels of IL-1α and CXCL1 were significantly upregulated in alum injected mice, indicative of the inflammasome pathway activation. In vitro, antibodies from Ro52 immune sera were internalized by SCA9-15 cells and the antibodies recognized cytoplasmic Ro52. The antibody internalization was inhibited by Cytochalasin D treatment, indicating it to be an active uptake process. Amongst the 298 pSS patients in Oklahoma cohort, 28 patients (9.3%) were anti-Ro positive and had a focus score of 0; and 37 anti-Ro positive patients (12%) had a focus score of >0 but <1. Several of these patients have dry mouth and dry eyes
Conclusion . Our data show for the first time that antibodies induced by Ro52 are capable of inducing salivary gland dysfunction and this phenomenon is dependent on the activation of innate immunity. The mouse model presented in this study mimics a subset (22%) of pSS patients in our cohort, who are biopsy negative (or have low focus scores) and are anti-Ro antibody positive. In this group of patients, in the absence of sialoadenitis, it is possible that salivary gland dysfunction is caused by autoantibodies. Our data also suggests that antibody deposition within the salivary glands might be an important step for the induction of glandular dysfunction. Overall this study suggests that down modulation of autoantibody responses should constitute a major therapeutic strategy for the treatment of SS.
Disclosure:
P. Kaplonek,
None;
B. Szczerba,
None;
N. Wolska,
None;
P. Rybakowska,
None;
A. Klopocki,
None;
P. Dey,
None;
A. Rasmussen,
None;
K. Hefner,
None;
S. Young,
None;
D. U. Stone,
None;
D. M. Lewis,
None;
L. Radfar,
None;
R. H. Scofield,
None;
K. Moser Sivils,
None;
H. Bagavant,
None;
U. Deshmukh,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interaction-between-innate-immunity-and-anti-ro52-antibodies-is-critical-for-the-induction-of-sjogrens-syndrome-like-disease-in-mice/