Infiltration In Minor Salivary Glands Research Articles

Molecular B-cell clonality assay in minor salivary glands as a useful tool for the lymphoma risk assessment in Sjögren's syndrome

ObjectivesNon-Hodgkin's lymphoma (NHL) risk assessment is crucial in Sjögren's syndrome (SS). We studied the prevalence of clonal immunoglobulin gene rearrangements in minor salivary glands (MSG) and their correlations with lymphoma occurrence and with previously established NHL predictors. MethodsMolecular B-cell expansion was studied in fresh-frozen MSG of 207 patients with either suspected SS or with suspected lymphoma during SS, using a standardised multiplex PCR assay combined with heteroduplex analysis by microcapillary electrophoresis. The assignation of clonal cases was based on EuroClonality consortium guidelines. ResultsAmong 207 studied patients, 31 (15%) had MSG monoclonal B-cell infiltration. Monoclonality was significantly more frequent in patients with SS (28/123, 22.8%) compared with patients without SS (3/84, 3.6%, P<0.001). Monoclonal B-cell infiltration in MSG of SS patients correlated significantly with ongoing salivary gland NHL, salivary gland swelling, CD4+ T-cell lymphopenia, rheumatoid factor (RF) activity, low complement levels and type 2 mixed cryoglobulinemia. The accumulation of biological risk factors was associated with a higher rate of MSG B-cell monoclonality given that patients with only positive RF had no probability of MSG B-cell monoclonality, RF-positive patients with 1 or 2 other risk factors had a 25.0% and 85.7% probability of MSG B-cell monoclonality, respectively. ConclusionThe detection of MSG monoclonal B-cell expansion by this easy-to-perform molecular assay is useful, both at the time of diagnosis and during the course of SS. Monoclonal B-cell expansion is associated with a subset of SS patients presenting either ongoing lymphoma or other established lymphoma predictive factors.

Pathogenic Tissue-Resident Memory T Cells in Exocrine Gland Chronic Graft-Versus-Host Disease

Abstract Salivary glands are frequently affected in chronic graft-versus-host disease (cGVHD), an autoimmune-like disease that occurs after allogeneic hematopoietic stem cell transplant resulting in tissue sclerosis and gland dysfunction. Alloreactive T cells have been identified as disease drivers, yet the function/pathogenicity of tissue-resident memory cells (Trm) in target organs remain unclear. In this study, we examined glandular Trm populations and tissue-specific signals that regulate Trm differentiation and functionality. scRNAseq analysis of human labial minor salivary glands (MSG) revealed enrichment of immune cell clusters in MSG of oral cGVHD patients. Focusing on T CD8 cells, we identified 4 clusters, one of them unique to affected patients which had low expression of CD69, but expressed other markers of Trm, including CD103, BLIMP1 and PD1. Additionally, this cluster was enriched for genes associated with cytotoxicity (IFNG, PRF1 and GZMB) and exhaustion (TIM3, LAG3 and TIGIT). Interestingly, this population showed high expression of CXCR6 and ligand-receptor analysis predicted CXCL16 an important signaling ligand that targets T CD8 cells. Further analysis implicates macrophages as the main source of CXCL16, suggesting their role in local accumulation of CXCR6+ Trm in the gland. Flow cytometry confirmed increased number of CD69+CD103±CD8+ Trm cells in cGVHD patients. Lymphocytic infiltration in MSG using IHC, spatially related the elevated frequency of CD8+IFNg+ T cells within interacinar stroma and damaged acini. The importance of Trm in site-specific cGVHD still needs further investigation. Based on current data, site-specific Trm cells may represent a druggable target in the therapy of refractory local cGVHD. Supported by NIDCR (1ZIADE000747-05)

Clinical and laboratory characteristics of lymphoproliferative diseases in primary Sjogren's syndrome associated with anticentromere antibodies

Purpose of the study. To study the characteristics and frequency of lymphomas in patients with Sjogren's disease (SD) and anticentromere antibodies (ACA); to evaluate the predictors of the development of lymphoproliferative diseases (LPD) in this group of patients. Material and methods. Over the period from 1998 till 2019, 131 ACA-positive patients were under medical supervision at the Research Institute of Rheumatology named after Nasonova V.A. Isolated SD was diagnosed in 82 patients (62.6%), isolated limited form of SSc — in 12 patients (9.2%), combination of SD and limited form of SSc — in 37 patients (28.2%). Lymphoproliferative diseases (LPD) were diagnosed in 20 ACA-positive patients: in 15 — with SD, in 5 — with SD and SSc; no lymphomas were found in the group of patients with isolated SSc. All lymphomas were diagnosed on the basis of histological, immunohistochemical and PCR examination with of B-cell clonality determination in the tissue, and were classified on the base of haematopoietic and lymphoid tissue tumors classification by the World Health Organization. Further analysis included 15 ACA-positive patients with isolated SD and lymphomas. Results. In our study, 18.3% of patients with isolated ACA-positive SD were diagnosed with LPD, represented by MALT lymphomas of the salivary glands (subsequent transformation into aggressive diffuse large B-cell lymphoma (DLBCL) was noted in one patient) in most cases. The course of SD before the diagnosis of LPD was characterized by a gradual progression of dental manifestations of SD with the development of late stages of parenchymal parotitis, severe xerostomia, and significant enlargement of the salivary glands with a minimum number of systemic manifestations of the disease. Significant enlargement of salivary glands, severe infiltration of minor salivary glands, severe xerostomia, decreased level of C4-complement component, monoclonal secretion, low content of CD19+B-cells in peripheral blood, positive B-cell clonality in biopsy material were the main signs of LPD in this study. When diagnosing MALT lymphomas, a focal damage of the salivary glands with no signs of dissemination, no symptoms of B-cell intoxication, and minimal changes in laboratory assessment were found in patients with ACA-positive SD. Conclusion. The natural course of ACA-positive SD and the absence of pathogenetic therapy at an early stage contribute to the development of salivary gland lymphomas in the first 10 years of the disease. Persistent enlargement of the salivary glands in SD, especially in the presence of other predictors of lymphoproliferation, is a direct indication for biopsy followed by the research to exclude the presence of lymphoma.

Adipose tissue infiltration in minor salivary glands of patients with Sjögren’s syndrome: Lack of significant correlation with the disease. An image analysis of 174 cases

Fatty infiltration in minor salivary gland biopsies and its correlation to systemic autoimmune diseases are controversial in the literature. Presence and extent of fatty infiltration in minor salivary glands of 107 Sjögren’s syndrome patients and 67 age-matched sicca controls were compared with statistical analyses. No significant difference was found regarding the presence or the extent of fatty infiltration between the two groups. Fatty infiltration seems to be unrelated to Sjögren’s syndrome thus its examination in salivary gland biopsy samples cannot improve the diagnostic accuracy of the disease.

Low Protein A20 in Minor Salivary Glands is Associated with Lymphoma in Primary Sjögren's Syndrome.

Patients with primary Sjögren's syndrome (pSS) have an increased risk of developing lymphomas, particularly the subtype mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic antigen stimulation and increased activation of nuclear factor-κB (NF-κB) are important factors for the pathogenesis of MALT lymphomas. Protein A20 is an inhibitor of NF-κB. A recent study of pSS-associated MALT lymphomas identified potential functional abnormalities in the TNFAIP3 gene, which encodes protein A20. The present study aimed to assess protein A20 by immunohistochemistry (IHC) in minor salivary glands (MSGs) and lymphoma tissue sections of patients with pSS and investigate a potential association with lymphoma development. Protein A20 staining in lymphocytes was scored in four categories (0=negative, 1=weak, 2=moderate and 3=strong). For statistical purposes, these scores were simplified into negative (scores 0-1) and positive (scores 2-3). We investigated associations between protein A20-staining, focus scores, germinal centre (GC)-like structures and monoclonal B-cell infiltration in MSGs. MSG protein A20 staining was weaker in pSS patients with lymphomas than in those without lymphomas (P=0.01). Weak protein A20 staining was also highly associated with a lack of GC formation (P<0.01). Finally, weaker A20 staining was observed in the majority of pSS-associated MALT lymphoma tissues. In conclusion, we found absent or weak protein A20 immunoreactivity in MSGs of patients with pSS with lymphomas. This finding indicates that protein A20 downregulation in lymphocytes might be a mechanism underlying lymphoma genesis in patients with pSS.

Association of plasmacytoid dendritic cells with B cell infiltration in minor salivary glands in patients with Sjögren's syndrome

Objectives: Sjogren’s syndrome (SS) is an autoimmune disease with features of both over-production of specific autoantibodies and organ-specific disorders, mainly sialadenitis and dacryoadenitis. However, little is known about the factors that contribute to lymphocytic infiltration of SS.Methods: Minor salivary gland (MSG) tissue was obtained from 83 patients with primary SS (pSS) and 95 patients with secondary SS and examined pathologically, and correlation between infiltrated immune cells and histological features was evaluated.Results: Plasmacytoid dendritic cells (pDCs) were increased in MSG of SS compared to Sicca syndrome. The density of pDCs was characteristically correlated with the accumulation of CXCL13+CD68+ macrophages and CXCR5+CD19+ B in the MSG of pSS. In vitro analysis indicated that Type I interferon (IFN) enhanced CXCL13 production by macrophages. Type I IFN was mainly expressed in pDCs and its expression was correlated with the accumulation of CXCL13+ macrophages in the MSG of pSS.Conclusions: Our histological findings suggest the possible mechanism of type I IFN-CXCL13 axis during the pathological processes of acute/chronic salivary inflammation in SS; local production of type I IFN by pDCs, induction of CXCL13 production in macrophages by type I IFN, induction of accumulation of CXCR5+CD19+ B cells by CXCL13 in the MSG.

Immunoprofile of focal lymphocytic infiltration in minor salivary glands of healthy individuals

To characterize the immunohistochemical profile of the inflammatory cells included in the focal lymphocytic infiltration in the minor salivary glands of healthy individuals. Tissue samples of the labial and palatal salivary glands from 46 postmortem subjects, demonstrating the presence of focal lymphocytic infiltration were quantitatively evaluated for the presence of T- and B-cell lymphocytes, plasma cells and macrophages by immunohistochemical and morphometric methods. B-cell lymphocytes, the predominant cell population in labial (67.5%) and palatal salivary glands (60.8%), were more frequent than T-cell lymphocytes in both glands (P < 0.001). Among the T-cell lymphocytes, CD(4)-positive cells were significantly more prevalent than the CD(8)-positive cells (P < 0.001). Plasma cells were almost absent, comprising only 0.01% of the focal lymphocytic infiltration cells of the labial and palatal salivary glands. Focal lymphocytic infiltration in the samples of the salivary glands obtained from healthy individuals is devoid of plasma cells. This can serve as an additional means to differentiate between focal lymphocytic infiltration in patients with Sjögren's syndrome, in which plasma cells are abundant, and focal lymphocytic infiltration in individuals with other causes of focal sialadenitis.

Clinical and immunological profile of primary Sjogren's syndrome in Kuwait: First report from Middle East

AbstractAim: To describe the clinical and serological findings in primary Sjogren's syndrome (SS) patients seen in a teaching hospital in Kuwait.Methods: Using the European and San Diego criteria for the diagnosis of SS, we studied 10 consecutive (nine female and one male) SS patients seen in our rheumatology clinic. All these patients fulfilled four or more of the diagnostic criteria for SS proposed by the European Community Study Group in 1993 as well as the more stringent San Diego criteria.Results: The mean age of the patients at presentation was 32.9 years (SE 4.4 years), ranging from 15 to 56 years. The mean disease duration was 3.5 years (SE 1.4 years). The most frequently observed clinical manifestations were: xerostomia (80%); xerophthalmia (70%); and parotidomegaly (30%). The main extraglandular manifestation was arthritis (50%). The Schirmer test was positive in 90% and the rose Bengal test in 90%. The immunologic study showed antinuclear antibodies in 80% of patients, rheumatoid factor in 90%, anti‐Ro/SS‐A in 90% and anti‐La/SS‐B in 90%. Lip biopsy could be done in only six patients and showed characteristic focal lymphocytic infiltration of minor salivary glands in 67%. There was no statistically significant difference in the occurrence of parotidomegaly or arthritis in patients with disease onset before or after the age of 40 years. Likewise, there was no difference in the positivity of ANA, RF, ant‐Ro/SS‐A or anti‐La/SS‐B in the two age groups.Conclusions: Although primary SS is typically said to be a disease of middle‐aged women, this does not seem to be the case in Kuwait, where 60% had disease onset below the age of 40 years. We could not find any notable differences in clinical and immunological characteristics between patients with primary SS from Kuwait and those reported from elsewhere, except for higher rates of serological abnormalities (RF, anti‐Ro/SS‐A, anti‐La‐SS‐B), probably due to genetic differences and the use of the strict San Diego criteria.

Prevalence and clinical significance of lymphocytic foci in minor salivary glands of healthy volunteers.

To determine the prevalence and severity of focal lymphocytic sialadenitis in minor salivary glands of healthy, asymptomatic individuals, in whom Sjögren's syndrome (SS) has been excluded. Charts of 54 healthy volunteers who had salivary gland biopsies at the National Institutes of Health from January 1992 to August 1998 were reviewed. The healthy volunteers served as control subjects in various studies of salivary dysfunction. Significant medical conditions including SS were excluded. A biopsy with a focus score (FS) >1 was regarded as positive. Descriptive statistics were used to summarize the population's characteristics. The frequency of focal lymphocytic infiltration in the healthy volunteers was about 15% (8 of 54). None of these individuals had subjective xerostomia or dry eyes. The positive FS ranged from 2 to 6. FS did not correlate with age, smoking, serologic findings, or salivary flow in these patients. Lymphocytic infiltration in minor salivary glands is not uncommon among individuals without a history of salivary gland dysfunction. This finding is in agreement with the result of a previous autopsy survey study, indicating that focal sialadenitis may occur in the absence of SS.

Association of Sjögren's Syndrome with Hereditary Angioneurotic Edema: Report of a Case

A case of hereditary angioneurotic edema (HANE) associated with Sjögren's syndrome is presented. One of the members of a pedigree of HANE due to deficiency of C1 inhibitor (C1INH) had a positive titer for anti-SS-A and anti-SS-B antibodies in the serum, complaining of symptome of dry eyes and dry mouth. A lip biopsy revealed lymphocytic infiltration of minor salivary glands. The patient had renal tubular acidosis (RTA). Thus the patient was diagnosed as suffering from Sjögren's syndrome with RTA.

Progression of sialadenitis in Sjögren's syndrome.

An analysis of progression of sialadenitis in patients with primary and secondary SS has been performed. For this purpose patients were prospectively followed and evaluated with respect to stimulated whole salivary secretion and morphology of labial salivary gland biopsies. Twenty-one patients with primary SS and 18 with secondary SS were followed for a mean of 39 +/- 20 months (range 11-112 months). During this observation period the lymphocytic infiltration in minor salivary glands, measured as focus score, increased in 14/21 (67%) patients with primary SS and in 14/18 (78%) patients with secondary SS. Altogether there was a statistically significant increase in focus score in both primary and secondary SS, but no reduction in salivary production. Consequently, no correlation between changes in focus score and stimulated salivary secretion was found in either primary or secondary SS.

Focal lymphocytic infiltration in the human labial salivary glands: a postmortem study

Focal lymphocytic infiltration in the human labial salivary glands was examined in a series of 190 postmortem subjects after suitable exclusion had been made. Focal lymphocytic infiltration, with or without a slight degree of parenchymal atrophic change, was found in 22.4% of the males and in 35.7% of the females. Of these, 9.0% (12 subjects) of the males and 10.7% (6 subjects) of the females with focal lymphocytic infiltration did not show any atrophic changes of the parenchyma. In the series reported here, the prevalence of focal lymphocytic infiltration apparently differs from the results of earlier investigators who had reported that none of the postmortem subjects without autoimmune diseases or connective tissue diseases showed focal lymphocytic infiltration in minor salivary glands. Although the pathological significance of focal lymphocytic infiltration in the minor salivary glands remains obscure, its diagnostic value for Sjögren's syndrome is discussed.

Histologic and sialochemical findings indicating sicca syndrome in patients with systemic lupus erythematosus.

Twenty unselected patients with systemic lupus erythematosus (SLE) were investigated with respect to symptoms and signs of salivary gland involvement. Eight of them complained of xerostomia. Whole salivary flow was measured, parotid saliva was analyzed chemically, and palatal biopsy was performed to assess the degree of inflammatory infiltration in minor salivary glands. All but one of the patients showed signs of involvement on at least one of the tests and, as a group, the patients with SLE had significantly reduced values for salivary flow and increased concentrations of sodium, protein, and carbohydrates as compared to matched healthy controls.

Sjögren's syndrome in progressive systemic sclerosis.

Thirty-five consecutive patients with progressive systemic sclerosis were prospectively evaluated for evidence of Sjögren's syndrome. Six of the 35 (17%) were judged to have the disorder. This is a higher prevalence than in most reports, but much lower than that recently reportedly by Alarcón-Segovia and associates (7). An additional 17 of the 35 patients (48%) had significant fibrosis in the absence of sufficient mononuclear cell infiltrates to confirm the diagnosis of Sjögren's syndrome. This group had particularly aggressive scleroderma with serious visceral features, and five died after a short duration of illness. No significant abnormalities were found in biopsies from six patients with the mixed connective tissue disease syndrome, five with Raynaud's phenomenon alone, or in 29 autopsy control subjects who had no evidence of connective tissue disease. Fibrosis in the absence of mononuclear infiltration in minor salivary glands of patients with progressive systemic sclerosis indicates a poor prognosis.