IgA immunoglobulin isotype of rheumatoid factor in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune disease with autoantibodies overproduction, including rheumatoid factors (RF). RF-IgA, IgG immunoglobulin classes are suggested as potential biomarkers of pSS. We studied 76 patients with pSS (ACR/Eular 2017); laboratory tests included ESR, C-reactive protein, concentrations of gamma globulins, RF, Anti-SS-A/Ro, and anti-SS-B/La. Eye dryness and keratoconjunctivitis sicca were confirmed with Schirmer's test, the ocular staining score (OSS) using lissamine green, fluorescein staining and biopsy of minor salivary gland with the histopathological evaluation. Differences between groups were analyzed with U Mann-Whitney test. Correlations between quantitative variables were assessed with the Spearman correlation coefficient.. The best diagnostic values of immunoglobulin concentration for discriminating pSS patients and healthy individuals are for RF-IgA. With cut-off of 21.5 EU/mL, the sensitivity is 72% and specificity is 100%. Very high specificity (100%) is also obtained for RF-IgM concentration of 74.1 EU/mL. Sensitivity is, however, smaller than that for RF-IgA and amounted to 61%. The RF-IgG is the poorest indicator of pSS with 51% of sensitivity and 95% of specificity. To summarize RF-IgA strongly associate with anti-SS-A and anti-SS-B autoantibodies. Both RF-IgA and RF-IgM may be used as diagnostic tools for pSS. Conclusions: among the three studied rheumatoid factor subtypes, RF-IgA showed the best diagnostic accuracy for pSS. RF-IgA correlated with anti-SS-A/Ro and anti-SS-B antibodies even more closely than RF-IgM. The assessment of the RF-IgA serum concentration may be helpful in the process of establishing pSS diagnosis.

Autoantibodies, detection methods and panels for diagnosis of Sjögren's syndrome.

The presence of autoantibodies is one of several hallmarks of Sjögren's Syndrome, the detection of serum autoantibodies has a central role in the diagnosis and classification of Sjögren's syndrome. In this review, we will discuss autoantibodies that are helpful in the diagnosis of Sjögren's syndrome. This includes the traditional autoantibodies for disease classification (ANA, Anti-Ro/SSA, Anti-La/SSB, RF), autoantibodies identified from mouse models (Anti-SP1, Anti- PSP, Anti-CA6, and anti-alpha fodrin) and autoantibodies associated with other autoimmune disease (ACA, AMA, and Anti-CCP). We will also review the methods for the detection of autoantibodies and associated challenges for clinical results reporting. The significance of using an autoantibody panel for the diagnosis of SS will be also be reviewed.

Systemic manifestations of primary Sjögren's syndrome in the NOD.B10Sn-H2b/J mouse model.

Animal models that recapitulate human disease are crucial for the study of Sjögren's Syndrome (SS). While several SS mouse models exist, there are few primary SS (pSS) models that mimic systemic disease manifestations seen in humans. Similar to pSS patients, NOD.B10Sn-H2b/J (NOD.B10) mice develop exocrine gland disease and anti-nuclear autoantibodies. However, the disease kinetics and spectrum of extra-glandular disease remain poorly characterized in this model. Our objective was to characterize local and systemic SS manifestations in depth in NOD.B10 female mice at early and late disease time points. To this end, sera, exocrine tissue, lung, and kidney were analyzed. NOD.B10 mice have robust lymphocytic infiltration of salivary and lacrimal tissue. In addition, they exhibit significant renal and pulmonary inflammation. We identified numerous autoantibodies, including those directed against salivary proteins. In conclusion, the NOD.B10 model recapitulates both local and systemic pSS disease and represents an excellent model for translational studies.

Analysis of novel Sjogren's syndrome autoantibodies in patients with dry eyes.

BACKGROUND: Dry eye is a common problem in Ophthalmology and may occur for many reasons including Sjogren's syndrome (SS). Recent studies have identified autoantibodies, anti-salivary gland protein 1 (SP1), anti-carbonic anhydrase 6 (CA6) and anti-parotid secretory protein (PSP), which occur early in the course of SS. The current studies were designed to evaluate how many patients with idiopathic dry eye and no evidence of systemic diseases from a dry eye practice have these autoantibodies. METHODS: Patients from a dry eye clinic and normal controls were assessed by Schirmer's test for tear flow. Sera were assessed for autoantibodies using ELISA assays. Statistics was performed with Prism 7 software and student's unpaired t test. RESULTS: In this study 60% of the dry eye patients expressed one of these autoantibodies. Only 30% expressed one of the autoantibodies associated with long-standing SS, which are included in the diagnostic criteria for SS, anti-Ro and anti-La. Patients with disease for less than 2 years and mild dry eyes did not express anti-Ro or anti-La, while 25% expressed anti-SP1. Similar observations, with smaller numbers, were made when patients had not only dry eye but also dry mouth. CONCLUSIONS: Antibodies to SP1, CA6 and PSP occur in some patients with idiopathic dry eyes. Further studies will be needed to determine how many of these patients go on to develop systemic manifestations of SS. Testing for these autoantibodies may allow early recognition of patients with SS. This will lead to improved management of the patients and the development of new strategies to maintain normal lacrimal and salivary gland function in patients with SS.

Central role for marginal zone B cells in an animal model of Sjogren's syndrome.

Patients with Sjogren's syndrome (SS) have been shown to have abnormal B cell function and increased numbers of marginal zone B cells (MZB and MZB precursors. The current studies utilized the Interleukin 14 alpha transgenic mouse model (IL14aTG) for SS to investigate the roles of marginal zone B cells (MZB) of the innate immune system in the pathophysiology of the disease. Eliminating MZB from IL14aTG mice by B cell specific deletion of RBP-J resulted in complete elimination of all disease manifestations of SS. Mice had normal salivary gland secretions, negative autoantibodies and normal histology of the salivary and lacrimal glands compared to IL14aTG mice at the same time points. In contrast, eliminating B1 cells by deleting btk did not ameliorate the disease. Therefore, MZB are critical for the development of SS.

Different stages of primary Sjogren's syndrome involving lymphotoxin and type 1 IFN.

Primary Sjögren's syndrome (pSS) is a complex autoimmune disease starting in the salivary and lacrimal glands and continuing to involve the lungs and kidneys with the eventual development of lymphoma. Many studies have emphasized the role of type 1 IFN (IFN-α) and lymphotoxin α (LTα) in the pathogenesis of the disease. The present studies were designed to delineate the role of IFN-α in pSS using an animal model, the IL-14α (IL14αTG) transgenic mouse. IL14αTG mice lacking the type 1 IFNR (IL14αTG.IFNR(-/-)) had the same submandibular gland and lacrimal gland injury as did the IL14αTG mice, but they lacked the later parotid gland and lung injury. Development of lymphoma was delayed in IL14αTG.IFNR(-/-) mice. The switch from IgM to IgG autoantibodies as well as the increase in serum IgG2a seen is IL14αTG mice was inhibited in IL14αTG.IFNR(-/-) mice. Production of LTα was identified in both IL14αTG mice and IL14αTG.IFNR(-/-) mice at the time that salivary gland injury was occurring. These and previous studies suggest a model for pSS that separates the disease into several stages: 1) initial injury to the submandibular and lacrimal glands via an environmental insult and LTα; 2) amplification of local injury via the production of type 1 IFN; injury to the parotid glands, lungs, and kidneys is seen; 3) progression of systemic inflammation with the eventual development of large B cell lymphoma. Understanding these different stages will help to develop strategies for treatment of patients with pSS based on the status of their disease.

Investigation of novel autoantibodies in Sjogren's syndrome utilizing Sera from the Sjogren's international collaborative clinical alliance cohort.

BACKGROUND: Sjogren's syndrome (SS) is a chronic autoimmune disease mainly affecting salivary and lacrimal glands. Current diagnostic criteria for SS utilize anti-Ro and anti-La as serological markers. Animal models for SS have identified novel autoantibodies, anti-salivary gland protein 1 (SP1), anti-carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP). These novel antibodies are seen in the animals at an earlier stage of SS than anti-Ro and anti-La. The current studies were designed to evaluate these novel autoantibodies in the sera of well-characterized patients with dry eyes and dry mouth and lip biopsies from the Sjogren's International Collaborative Clinical Alliance (SICCA) to determine if they indeed identify SS with less severe disease than patients expressing anti-Ro and anti-La. METHODS: Sera were obtained from SICCA registry in patients for whom lymphocytic foci per 4 mm(2) on the lip biopsies was either 0 (F = 0), <1 (F <1) or > 3 (F >3). ELISA assays were utilized to evaluate these sera for anti-Ro, anti-La, anti-SP1, anti-CA6, and anti-PSP. RESULTS: In patients with dry eyes and dry mouth but F = 0, increased expression of anti- CA6 was noted compared to the F <1 group (p = .032) or the F > 3 group (p = .006). Neither anti-PSP nor anti-SP1 reached statistical significance because of the small numbers in the F0 group, although there was a trend for their expression to be higher in the F0 group. On the other hand, the expression of anti-Ro was significantly reduced in the F0 group compared to the F <1 (p = .0021) and F > 3 (p = .0003) groups. The reduced expression of anti-La in the F0 group compared to the F <1 and F > 3 groups did not quite reach statistical significance. CONCLUSIONS: Anti-Ro and anti-La identify patients with SS and more severe disease than anti-SP1, anti-CA6, and anti-PSP. More studies are needed to identify the timing in the course of SS when these different autoantibodies are expressed and/or whether they are expressed in patients with different clinical manifestations.

Evaluation of salivary gland protein 1 antibodies in patients with primary and secondary Sjogren's syndrome.

Sjogren's syndrome (SS) has been associated with the expression of anti-Ro and anti-La antibodies. Anti-salivary gland protein 1 (SP1) antibodies have recently been identified in patients with SS. The current work involved a cross sectional study to determine whether anti-SP1 antibodies were identified in particular subgroups of patients with SS. The results of this study revealed that anti-SP1 antibodies were present in the sera of 52% of SS patients while anti-Ro/anti-La was present in 63% of patients. 19% of patients had anti-SP1 without anti-Ro/anti-La. Patients with SS and lymphoma expressed anti-Ro, anti-La and anti-SP1 together. In SS associated with RA, 50% had antibodies anti-SP1 while 40% had anti-Ro/anti-La. In conclusion, anti-SP1 antibodies are commonly seen in both primary and secondary SS and rarely in normal controls. Future studies are needed to determine the roles and timing of expression of anti-SP1 antibodies in Sjogren's syndrome.

Temporal histological changes in lacrimal and major salivary glands in mouse models of Sjogren's syndrome.

BACKGROUND: Evidence in imaging studies suggests that there may be differences in glandular involvement in Sjogren's syndrome (SS) depending on the stage of the disease. No detailed histological studies are available to show if there are any such difference in glandular involvement at various time periods and stages of SS. This cross sectional study examines the inflammatory changes in mouse models of SS at various ages. METHODS: The histological changes in major salivary and lacrimal glands were studied at ages of 3, 6, 9, 12, 15 and 18 months in both sexes in well characterized mouse models of SS, non-obese diabetes mouse and Interleukin-14 alpha-transgenic mice. RESULTS: Our results indicate that early inflammation concurrently occur in submandibular and lacrimal glands around the age of 6 weeks. Parotid glands are involved much later in the course of SS with less severe inflammation. Sublingual glands are rarely involved. CONCLUSIONS: Our conclusions are that SS may be an organ specific disease with early inflammation occurring in submandibular and lacrimal glands, followed by the parotid. Non organ specific events occur in later courses of the disease. The understanding of the disease progression is important in tailoring early local therapeutic interventions before complete destruction of salivary and lacrimal glands.

Correlation of SARS-CoV-2 Neutralization with Antibody Levels in Vaccinated Individuals.

Neutralizing antibody titers are an important measurement of the effectiveness of vaccination against SARS-CoV-2. Our laboratory has set out to further verify the functionality of these antibodies by measuring the neutralization capacity of patient samples against infectious SARS-CoV-2. Samples from patients from Western New York who had been vaccinated with the original Moderna and Pfizer vaccines (two doses) were tested for neutralization of both Delta (B.1.617.2) and Omicron (BA.5). Strong correlations between antibody levels and neutralization of the delta variant were attained; however, antibodies from the first two doses of the vaccines did not have good neutralization coverage of the subvariant omicron BA.5. Further studies are ongoing with local patient samples to determine correlation following updated booster administration.

Novel autoantibodies in Sjogren's syndrome.

Sjogren's syndrome (SS) is defined by autoantibodies to Ro and La. The current studies identified additional autoantibodies in SS to salivary gland protein 1 (SP-1), carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP). These autoantibodies were present in two animal models for SS and occurred earlier in the course of the disease than antibodies to Ro or La. Patients with SS also produced antibodies to SP-1, CA6 and PSP. These antibodies were found in 45% of patients meeting the criteria for SS who lacked antibodies to Ro or La. Furthermore, in patients with idiopathic xerostomia and xerophthalmia for less than 2 years, 76% had antibodies to SP-1 and/or CA6 while only 31% had antibodies to Ro or La. Antibodies to SP-1, CA6 and PSP may be useful markers for identifying patients with SS at early stages of the disease or those that lack antibodies to either Ro or La.

A role for lymphotoxin in primary Sjogren's disease.

The etiology of salivary gland injury in primary Sjögren's disease is not well understood. We have previously described a mouse model of Sjögren's disease, IL-14α transgenic (IL14αTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin α (LTA) in the pathogenesis of Sjögren's disease in IL14αTG mice. IL14αTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14αTG mice were crossed with LTA(-/-) mice, the IL14αTG.LTA(-/-) mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14αTG and IL14αTG.LTA(-/-) mice produced similar amounts of IFN-α and had similar deposition of autoantibodies in their salivary glands. Both IL14α and IL14α/LTA(-/-) mice had similar B cell responses to T-dependent and T-independent Ags, L-selectin expression, and expression of RelA, RelB, and NF-κB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sjögren's disease. Furthermore, local production of soluble LTA in the salivary glands of IL14αTG mice is necessary for the development of overt Sjögren's disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sjögren's disease, further strengthening the biological relevance of the IL14αTG model to understanding the pathogenesis of human disease.

Prevalence of Myositis-Specific Autoantibodies and Myositis-Associated Autoantibodies in COVID-19 Patients: A Pilot Study and Literature Review.

Coronavirus disease 2019 (COVID-19) infection has been linked to numerous autoimmune manifestations. Neither the mechanism nor the etiology of this association has been fully explored or elucidated. Prior studies have detected myositis in patients with proven COVID-19 infection, suggesting a relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the development of myositis. Studies have reported elevated levels of autoimmune antibodies, including myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs), in patients with COVID-19 infection, however the prevalence is not well documented. Our objective was to assess the prevalence of MSAs and MAAs in COVID-19 patients compared with unaffected subjects. Serum samples from 74 unvaccinated, polymerase chain reaction (PCR)-positive COVID-19 infected patients were compared with serum samples from 41 healthy, unaffected individuals. All serum samples were tested for MSA and MAA reactivity. Within the COVID-19-positive group, six (8.1%) patients exhibited MSA/MAA positivity, compared with only one (2.4%) individual from the control group. Although a higher prevalence of MSA/MAA positivity was observed within the COVID-19 infected group, the difference did not reach statistical significance (p=0.223). The autoantibodies detected in this study have a unique association with dermatomyositis and other inflammatory myopathies, and may play a role in COVID-19-associated myopathy. This article was previously presented as an abstract at Jacobs School of Medicine and Biomedical Sciences Research Day on June 3rd, 2022.

IL-14 alpha, the nexus for primary Sjögren's disease in mice and humans.

To evaluate the role of interleukin 14 alpha (IL-14a) in Sjögren's syndrome (SS), we evaluated the expression of IL-14a in the peripheral blood lymphocytes (PBL) of patients with primary and secondary SS and normal controls by quantitative RT-PCR. In addition, transgenic IL-14a mice were analyzed from 6 weeks of age to death for both histological and immunological features of Sjögren's disease. Patients with both primary and secondary Sjögren's syndrome expressed IL-14a at statistically higher levels in their peripheral blood compared to normal controls matched for age, sex and ethnic group. Transgenic mice in which IL-14a expression was increased constitutively were previously demonstrated to develop hypergammaglobulinemia, autoantibodies, infiltration of the parotid glands with lymphocytes, mild immune-complex mediated renal disease and large B cell lymphoma. In this paper we expand these observations to demonstrate that these mice develop all the clinical and immunological features of primary Sjögren's disease in the same relative time frame as patients with primary Sjögren's disease: stage 1-early hypergammaglobulinemia and autoantibody production, stage 2-decreased salivary gland function with early lymphocytic infiltration of the submandibular glands only, but antibody deposition in the submandibular and parotid glands, stage 3-lymphocytic infiltration of the submandibular, parotid and lacrimal glands with B and T lymphocytes and plasma cells along with interstitial lung disease and mild renal disease, and stage 4-large B cell lymphoma. Thus IL-14a is important in the pathophysiology of Sjögren's disease. The IL-14a transgenic mouse is a novel animal model that can be utilized to understand the pathophysiology of Sjögren's disease.

Desmoplastic fibroma of the anterior mandible. Case report and review of literature.

Desmoplastic fibroma is a rare and locally aggressive lesion that affects the long bone and the jaw bones. Mandibular bone involvement has been mostly reported in the posterior segment; anterior region presentation is rare. This case report highlights the diagnosis, management and treatment of a midline mandibular involvement. It includes a literature review.

Prevalence and clinical significance of elongated calcified styloid processes in panoramic radiographs.

The styloid process refers to a mineralized styloid ligament of the temporal bone that usually appears (in different forms and lengths) on panoramic radiographs. This study sought to evaluate panoramic radiographs to determine the prevalence and clinical significance of elongated calcified styloid processes. For this study, panoramic radiographs from 1,000 dental patients were evaluated. Each styloid process length was measured and its pattern of calcification was assessed as elongated (that is, uninterrupted styloid calcification), pseudoarticulated (a single joint appearing as an articulated styloid process), or segmented (an interrupted calcified styloid process). Calcified styloid processes longer than 30 mm were considered to be elongated and were used for this study; 220 panoramic radiographs (22%) revealed such elongated processes. This retrospective study indicated that there is no clinical significance when elongated styloid processes are found coincidentally.

Simultaneous Distinction of Monospecific and Mixed DFS70 Patterns During ANA Screening with a Novel HEp-2 ELITE/DFS70 Knockout Substrate.

Systemic autoimmune connective tissue disorders are characterized by circulating antinuclear antibodies (ANA). Although there are several technologies available for ANA screening, indirect immunofluorescence (IIF) using Human epithelial cells-2 (HEp-2) substrate remains the primary and recommended method because of its superior sensitivity. HEp-2 substrates can detect a multitude of patterns resulting from autoantibody binding to various protein and nucleic acid autoantigens distributed throughout the nucleus and cytoplasm of the cells. The great diversity of monospecific and mixed patterns resulting from positive reactions on HEp-2 substrate also complicate the interpretation and accuracy of reporting. One specific example which received utmost attention recently is the dense fine speckled 70 (DFS70) pattern resulting from autoantibodies that specifically bind to a protein called lens epithelium derived growth factor (LEDGF). Lack of clear association with a specific systemic autoimmune disease and high prevalence in healthy populations have made accurate interpretation of DFS70 pattern important. Accurate distinction of DFS70 pattern from disease-associated patterns using conventional HEp-2 substrate is challenging. Moreover, frequent co-occurrence of DFS70 pattern along with disease-associated patterns such as homogeneous, speckled, and mixed homogeneous-speckled patterns complicate the IIF interpretation. The goal of this paper is to demonstrate the utility of a novel engineered HEp-2 IIF substrate that retains all advantages of conventional HEp-2 substrate while simultaneously providing the ability to distinguish DFS70 pattern with high confidence in both monospecific and mixed ANA positive examples. The new substrate is further able to unmask disease-associated ANA patterns previously concealed by DFS70 pattern.

Medical profile of a dental school patient population.

Advances in health care and pharmacotherapeutics have led to a growing aging population living with complex medical conditions. These changes are apparent in patients presenting for treatment at dental schools. This study assessed the medical profile of patients seeking treatment at the School of Dental Medicine, State University of New York at Buffalo. Medical records of 1,041 consecutive patients who presented for comprehensive dental care at the school were retrospectively reviewed. The demographic data, medical status, and use of medications from the charts were analyzed. The mean age of the patients was 52 (SD+/-18), and the female to male ratio was 1.2:1. More than half of the patients had one or more systemic illnesses or were taking medication. The results of this study reflect the medical complexity of the growing aging population. The dental school curriculum should address the needs for management of the growing number of medically complex patients.