Characteristics of the minor salivary gland infiltrates in Sjögren's syndrome☆
Introduction
Sjögren's syndrome (SS) is a rather common, chronic autoimmune disease with a broad clinical spectrum that extends from organ-specific exocrinopathy (predominantly of the salivary and lacrimal glands) to systemic manifestations, and in approximately 5% of patients development of lymphoma [1]. The destruction of the glandular tissue is associated with lymphocytic infiltrates that tend to develop around ducts, whereas the degree of glandular infiltration varies. In minor salivary glands (MSG), lymphocytic lesions extend from mild, focal to massive, diffuse infiltrates that are accompanied by loss of tissue architecture [1], [2]. The mechanisms underlying the variable degree of glandular infiltration in distinct patients have not been delineated. Nevertheless, intense salivary gland infiltration has been associated with the presence of extraglandular systemic manifestations, suggesting that these patients constitute a distinct SS subgroup with more severe disease and autoimmune responses [3], [4].
The MSG lymphocytic infiltrates mainly consist of activated T (predominantly primed CD4+-T cells) and B cells, whereas classical antigen-presenting cells (macrophages and dendritic cells) have been primarily reported in heavy infiltrates [5], [6], [7], [8], [9], [10]. Recently, we have shown that regulatory T cells (Tregs) are also present in the inflammatory lesions of SS and their frequency associates with lesion severity, with the higher to be observed in the intermediate lesions (compared to the mild or severe ones) [11]. Furthermore, in line with previous reports, we have found that T cells predominate in mild, but decrease in severe lesions [5], [9], [10], [11], [12]. The differential distribution of Tregs and T cells in infiltrates of distinct severity suggests that similar phenomena might apply for the other types of infiltrating cells. However, the evaluation of the literature revealed that, despite extensive studies, the incidence and differential distribution of infiltrating cells in MSG lesions of variable severity are not well-defined. MSG lesions of variable severity were not systematically studied, whereas inferences are further hindered by focusing the study of MSG inflammatory lesions on usually one infiltrating mononuclear cell-type, the method applied for the estimation of cell occurrence and the low number of samples evaluated.
Generally, local autoimmune responses are thought to be key regulators of the organ-specific SS-exocrinopathy. Furthermore, recent studies imply that they may also participate in the development and perpetuation of the SS systemic manifestations [13], [14], [15], [16], [17], [18], [19]. Thus, in SS patients, altered local B-cell responses are presumably linked to peripheral B-cell hyperactivity and abnormalities, including hypergammaglobulinemia, autoantibody production, oligoclonal B-cell proliferation and increased risk for lymphoma development [13]. Moreover, MSG infiltration by certain inflammatory cell-types, such as Tregs, macrophages and dendritic cells, has been associated with the presence of adverse prognostic factors for lymphoma development [4], [7], [8], [11], [15], [17], [18].
Herein, we sought to investigate the incidence and distribution of the major types of infiltrating cells in SS-MSG lesions of distinct severity (mild, intermediate and severe), as well as their relationship to the grade of infiltration. The infiltrating-cell-types studied included T cells and their subpopulations CD4+-T, CD8+-T and Treg cells, B cells, macrophages, dendritic cells (interdigitating and follicular) and natural-killer cells. Furthermore, since some of these infiltrating-cell-types have been previously correlated to certain clinical adverse prognostic factors, we also examined potential associations between the incidence of each infiltrating-cell-type and SS manifestations.
Section snippets
Patients and minor salivary gland (MSG) biopsies
The study was approved by the Ethic Committee of the School of Medicine, National University of Athens, Greece. MSG biopsies from 39 patients with primary SS (all women), as diagnosed by the revised American–European classification criteria [20], were included in the study. Based on Tarpley et al. biopsy score [2], MSG-biopsy samples were categorized in three groups according to the grade of infiltration. Thus, the first group (SS-I: mild lesions; n = 11) included specimens with 1 + biopsy
The distribution of infiltrating-cell-types varies according to the grade of MSG autoimmune lesions
CD3+-T cells (and their subpopulations CD4+-T, CD8+-T and Foxp3+-Tregs), CD20+-B cells, CD68+-MΦs, S100+-iDCs, fascin+-fDCs, and CD56+-NK cells were evident in the SS inflammatory lesions of all the MSG-biopsy samples studied (Fig. 1, Table 2). T and B lymphocytes comprised the vast majority of inflammatory cells (more than 90% of infiltrating MNC) and presented variable frequency (percentage of infiltrating MNC), ranging from 24.37% to 75.25% (median 47.08%) and 20.30% to 61.58% (median
Discussion
Previous studies of the SS inflammatory lesions have shown that they mainly consist of T and B lymphocytes, whereas MΦ and DC presence has been primarily linked to advanced lesions or infiltrates organized into GCs [5], [6], [7], [8], [9], [10], [17], [18]. Evidence implies a differential composition and/or distribution of inflammatory cells in SS-lesions depending on the grade of MSG infiltration [5], [6], [7], [9], [10], [11], [14], [17], [18], [21], [22], [23]. However, these differences are
Acknowledgements
The authors thank Niki M. Moutsopoulos, DDS/PhD for constructive suggestions and critical reviewing of the manuscript, Spyros Paikos, DDS for obtaining MSG biopsies and Issa Dehabreh, MD for statistical assistance.
References (39)
- et al.
Minor salivary gland involvement in Sjogren's syndrome
Oral Surg Oral Med Oral Pathol
(1974) - et al.
Foxp3+ T-regulatory cells in Sjogren's syndrome: correlation with the grade of the autoimmune lesion and certain adverse prognostic factors
Am J Pathol
(2008) - et al.
Distinct profiles of Sjogren's syndrome patients with ectopic salivary gland germinal centers revealed by serum cytokines and BAFF
Clin Immunol
(2005) - et al.
Professional antigen presenting cells in minor salivary glands in Sjogren's syndrome: potential contribution to the histopathological diagnosis?
Lab Invest
(2000) - et al.
Clinical evolution, and morbidity and mortality of primary Sjogren's syndrome
Semin Arthritis Rheum
(2000) - et al.
Predictors of lymphoma development in primary Sjogren's syndrome
Semin Arthritis Rheum
(1998) - et al.
Gene expression and chromosomal location for susceptibility to Sjogren's syndrome
J Autoimmun
(2009) - et al.
B cell apotopes of the 60-kDa Ro/SSA and La/SSB autoantigens
J Autoimmun
(2008) - et al.
Novel animal models for Sjogren's syndrome: expression and transfer of salivary gland dysfunction from regulatory T cell-deficient mice
J Autoimmun
(2006) - et al.
Autoimmune dacryoadenitis and keratoconjunctivitis induced in rabbits by subcutaneous injection of autologous lymphocytes activated ex vivo against lacrimal antigens
J Autoimmun
(2008)
Desiccating environmental stress exacerbates autoimmune lacrimal keratoconjunctivitis in non-obese diabetic mice
J Autoimmun
The weight of interleukin-6 in B cell-related autoimmune disorders
J Autoimmun
Sjogren's syndrome
Quantitative assessment of salivary gland inflammatory infiltration in primary Sjogren's syndrome: its relationship to different demographic, clinical and serological features of the disorder
Br J Rheumatol
An association between salivary gland disease and serological abnormalities in Sjogren's syndrome
J Oral Pathol Med
Immunohistologic analysis of lymphoid infiltrates in primary Sjogren's syndrome using monoclonal antibodies
J Immunol
Follicular dendritic cells confirm lymphoid organization in the minor salivary glands of primary Sjogren's syndrome
J Oral Pathol Med
Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjogren's syndrome: correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development
Arthritis Rheum
HLA-DR expression by labial minor salivary gland tissues in Sjogren's syndrome
Ann Rheum Dis
Cited by (348)
SLAMF3 promotes Th17 differentiation and is reversed by iguratimod through JAK1/STAT3 pathway in primary Sjögren's syndrome
2024, International ImmunopharmacologyThe Role of Viruses and Viral-Like Sequences in Sjogren’s Syndrome
2024, Infection and AutoimmunityMetformin-induced activation of Ca<sup>2+</sup> signaling prevents immune infiltration/pathology in Sjogren's syndrome-prone mouse models
2023, Journal of Translational Autoimmunity
- ☆
This work was supported by grants from the Hellenic Secretariat for Research and Technology.
- 1
Authors contributed equally to the study.