a b s t r a c tMicroRNAs (miRNAs) are small conserved non-coding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3 0 untranslated region (UTR) of specific messenger RNAs (mRNAs) for degradation or translational repression. miRNA-mediated gene regulation is critical for normal cellular functions such as the cell cycle, differentiation, and apoptosis, and as much as one-third of human mRNAs may be miRNA targets. Emerging evidence has demonstrated that miRNAs play a vital role in the regulation of immunological functions and the prevention of autoimmunity. Here we review the many newly discovered roles of miRNA regulation in immune functions and in the development of autoimmunity and autoimmune disease. Specifically, we discuss the involvement of miRNA regulation in innate and adaptive immune responses, immune cell development, T regulatory cell stability and function, and differential miRNA expression in rheumatoid arthritis and systemic lupus erythematosus.

Sjögren's syndrome-like autoimmune exocrinopathy (AEC) in the nonobese diabetic (NOD) mouse progresses from a preimmune phase to an immune phase, resulting in dry mouth and/or dry eyes. In the present study, the impact of the prototypical T-helper type 1 cytokine, interferon-gamma (IFN-g), on the onset of AEC was investigated using both the IFN-g and the IFN-g receptor gene knockout mice, NOD.IFN-g -/-and NOD.IFN-gR -/-, respectively. Neither the NOD.IFN-g -/-nor the NOD.IFN-gR -/-mice exhibited increased acinar cell apoptosis and abnormal salivary protein expression, typically observed in parental NOD mice prior to disease. Without these preimmune phase abnormalities, NOD.IFN-g -/-and NOD.IFN-gR -/-mice showed no subsequent autoimmune responses against the salivary glands at 20 weeks. Interestingly, real-time polymerase chain reaction and electrophoretic gel mobility shift assays suggested that IFNg and STAT1, as well as the transcriptional activity of STAT1 in NOD glands, were increased at birth. Unlike the neonatal submandibular glands of NOD or NOD-scid mice that show abnormal glandular morphogenesis at birth, the submandibular glands of the newly constructed congenic strain, NOD-scid.IFN-g -/-, were found to be normal. Taken together, IFN-g appears to play a critical role not only during the later immune phase of AEC, but also the early preimmune phase, independent of effector functions of immune cells. How exactly IFN-g functions during this period remains speculative.

Objective. The NOD mouse is genetically predisposed to the development of at least 2 autoimmune diseases, autoimmune diabetes and autoimmune exocrinopathy (AEC). More than 19 chromosomal intervals (referred to as Idd regions) that contribute to diabetes susceptibility in the NOD mouse model have been identified, but only 2 chromosomal intervals (associated with Idd3 and Idd5) have been shown to control sialadenitis. In the present study, we bred the Idd3 and Idd5 chromosomal intervals from NOD mice into nonautoimmune C57BL/6 mice to determine if these intervals recreate a Sjögren's syndrome (SS)-like phenotype.Methods. C57BL/6.NODc3 mice carrying Idd3 and C57BL/6.NODc1t mice carrying Idd5 were crossed and intercrossed to generate a C57BL/6.NODc3.NODc1t mouse line homozygous for the Idd3 and Idd5 chromosomal intervals on an otherwise disease-resistant genetic background. C57BL/6.NODc3.NODc1t mice were evaluated for biochemical, pathophysiologic, and immunologic markers characteristic of the SS-like phenotype present in the NOD mouse.Results. C57BL/6.NODc3.NODc1t mice fully manifested the SS-like phenotype of the NOD mouse, including decreased salivary and lacrimal gland secretory flow rates, increased salivary protein content due in part to less fluid, aberrant proteolytic enzyme activity, decline in amylase activity, appearance of autoantibodies to exocrine gland proteins, and glandular lymphocytic focal infiltrates. Loss of secretory function occurred more rapidly in C57BL/6.NODc3.NODc1t mice (by 12 weeks of age) than in NOD mice (by 16 weeks of age). No signs of insulitis or autoimmune (type 1) diabetes were observed in the C57BL/6.NODc3.NODc1t mice.Conclusion. Genes located within the 2 chromosomal intervals Idd3 and Idd5 appear necessary and sufficient for manifestation of AEC. We propose that this murine model of SS-like disease be designated C57BL/6.NOD-Aec1Aec2. Identification of specific genes within the Aec1 and Aec2 genetic regions should help elucidate the mechanism(s) underlying SS-like disease.

Periodontal disease has been recently linked to a variety of systemic conditions such as diabetes, cardiovascular disease, preterm delivery, and oral cancer. The most common bacteria associated with periodontal disease, Porphyromonas gingivalis (P. gingivalis) has not yet been studied in the malignant gingival tissues. The objective of this study was to investigate the presence of P. gingivalis in specimens from squamous cell carcinoma patients. We have performed immunohistochemical staining to investigate the presence of P. gingivalis and Streptococcus gordonii (S. gordonii), a non invasive oral bacteria, in paraffin embedded samples of gingival squamous cell carcinoma (n=10) and normal gingiva (n=5). Staining for P. gingivalis revealed the presence of the bacteria in normal gingival tissues and gingival carcinoma, with higher levels (more than 33%, P<0.05) detected in the carcinoma samples. The staining intensity was also significantly enhanced in the malignant tissue by 2 folds (P<0.023) compared to specimens stained for the non-invasive S. gordonii. P. gingivalis is abundantly present in malignant oral epithelium suggesting a potential association of the bacteria with gingival squamous cell carcinoma.

Summary MicroRNAs (miRNAs), small non-coding RNA molecules that post-transcriptionally regulate gene expression, are known to play key roles in regulating immune responses and autoimmunity. We investigated miR-146a expression in Sjögren's syndrome (SjS) patients as well as in the SjS-prone C57BL/6.NOD-Aec1Aec2 mouse model, to elucidate its involvement in SjS pathogenesis. Expression of miR-146a was examined in the peripheral blood mononuclear cells (PBMCs) of 25 SjS patients and 10 healthy donors, as well as in PBMCs, salivary and lacrimal glands in SjS-prone mice and wild-type C57BL/6J mice. Functional assays using THP-1 human monocytes were conducted to determine the biological roles of miR-146a in innate immunity. miR-146a expression was significantly increased in SjS patients compared to healthy controls, and was upregulated in the salivary glands and PBMCs of the SjS-prone mouse at both 8 weeks (prior to disease onset) and 20 weeks (full blown disease) of age. More importantly, functional analysis revealed roles for miR-146a in increasing phagocytic activity and suppressing inflammatory cytokine production while migration, nitric oxide production, and expression of antigen presenting/costimulatory molecules are not affected. Taken together, our data suggest that abnormal expression/regulation of miRNA in innate immunity may contribute to or be indicative of the initiation and progression of SjS.

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These findings define a clear role for the humoral immune response and the targeting of the cell surface M3 signal transduction receptor as primary events in the development of clinical symptoms of autoimmune exocrinopathy. Furthermore, the anti-M3 receptor activity may negatively affect the secretory response through perturbation of normal signal transduction events, leading to translocation of the epithelial cell water channel.