Background/Purpose: The presence of autoantibodies reactive against the Ro52/TRIM21 protein is a hallmark of Sjögren’s syndrome. We have reported that Ro52-immunized mice develop IgG deposits in their submandibular glands (SMG) and salivary gland dysfunction, which is facilitated by innate immune activation. This study was undertaken to investigate the mechanisms involved in anti-Ro52 mediated salivary gland hypofunction.

Methods: Female NZM2758 mice (12-14 wk old) were injected with alum on days 0 and 10, followed by passive transfer of immune sera from rabbits immunized either with Ro52 or the control protein, Maltose binding protein (MBP). Pilocarpine-induced saliva was measured to evaluate salivary gland function. Gene expression in SMG was analyzed by using the nCounter mouse inflammation panel (Nanostring Technologies Inc). Localization of IgG deposits in the SMG was investigated by immunofluorescence staining for anti-rabbit IgG and neuronal, and endothelial cell markers.  Antibody penetration in the brain was studied by fMRI and immunostaining.  To investigate the role of innate immunity, serum cytokines levels were measured by BioPlex mouse 23-plex assay in alum injected mice. Effects of cytokines on salivary epithelial cell tight junctions were evaluated by measuring trans-epithelial electrical resistance (TEER) in vitro.

Results: NZM2758 mice, pre-treated with alum, and injected with anti-Ro52 rabbit immune sera had significantly lower saliva production than mice receiving anti-MBP sera.  The IgG deposits in SMG of anti-Ro52 recipient mice, co-localized with the endothelial cell marker CD31 in small blood vessels and were present in close proximity of the neurons. Compared to anti-MBP treated mice, the SMG from anti-Ro52 recipients showed significantly higher expression of Ptgs2 that encodes for prostaglandin synthase (p=0.0043). Further, anti-Ro52 recipients showed IgG deposits along the cortical blood vessels in the brain and significant penetration of IgG into the brain parenchyma.  IL1α, one of the cytokines induced by alum, induced a drop in TEER indicating disruption of tight junctional complexes.

Conclusion: Our data suggest that in Sjögren’s syndrome, antibody deposition on endothelial cells in the vicinity of neurons in salivary glands induces localized inflammation that affects neuronal signaling and saliva production. The pathogenic effects of anti-Ro52 are further enhanced by inflammatory cytokines induced by innate immune activation.  In addition, antibody penetration into the brain might contribute to the glandular hypofunction and neurological issues such as brain fog and cognitive dysfunction, a feature often seen in Sjögren’s syndrome patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoantibody-mediated-salivary-gland-hypofunction-in-sjogrens-syndrome-involves-activation-of-innate-immunity-and-endothelial-cells/