Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjögren's syndrome
TL;DR: The acquisition of lymphoid features byinflammatory foci in SS is critically associated with the enlargement of the inflammatory foci and with the expression of CXCL13 and CCL21 within the infiltrate, but is not associated with their expression by epithelial cells.
Abstract: Objective
Ectopic lymphoneogenesis can occur in the salivary glands of Sjogren's syndrome (SS) patients and is associated with local antigen-driven B cell responses, autoantibody formation, and potential lymphomatous transformation. CXCL13 and CCL21 have been identified in salivary glands, but their role in ectopic lymphoneogenesis in SS remains unclear. This study aimed to evaluate the microanatomic association between CXCL13 and CCL21 expression and the acquisition of lymphoid features in periductal foci.
Methods
Salivary glands from 37 SS patients and 9 chronic sialadenitis patients were analyzed by immunohistochemistry for T cell/B cell segregation, CD21+ follicular dendritic cell networks, and peripheral lymph node addressin (PNAd)–positive high endothelial venules (HEVs) in relationship to the size of the aggregates and the expression of CXCL13 and CCL21 within infiltrating cells, epithelium, and endothelium.
Results
Grade 1 aggregates (10–50 lymphocytes) demonstrated predominance of nonorganized CD3+ cells, while grade 2 (>50 lymphocytes) and grade 3 (>50 with germinal centers) showed a progressive increase in CD20+ B cells and T cell/B cell segregation. This higher degree of lymphoid organization was significantly related to an increased expression of CXCL13 within infiltrating cells and PNAd+ HEV–associated CCL21-producing cells. Conversely, no association between lymphoid organization and lymphoid chemokine expression by epithelial cells was observed.
Conclusion
The acquisition of lymphoid features by inflammatory foci in SS is critically associated with the enlargement of the inflammatory foci and with the expression of CXCL13 and CCL21 within the infiltrate, but is not associated with their expression by epithelial cells. These data strongly support an active participation of CXCL13 and CCL21 in regulating the progressive organization and maintenance of periductal foci.
Citations
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TL;DR: Recent progress in several aspects of lymphoid neogenesis are discussed, focusing on the similarities with lymphoid tissue development, the mechanisms of induction, functional competence and pathophysiological significance, and how these issues might eventually lead to new strategies to target immunopathological processes.
Abstract: The frequent observation of organized lymphoid structures that resemble secondary lymphoid organs in tissues that are targeted by chronic inflammatory processes, such as autoimmunity and infection, has indicated that lymphoid neogenesis might have a role in maintaining immune responses against persistent antigens. In this Review, we discuss recent progress in several aspects of lymphoid neogenesis, focusing on the similarities with lymphoid tissue development, the mechanisms of induction, functional competence and pathophysiological significance. As more information on these issues becomes available, a better understanding of the role of lymphoid neogenesis in promoting chronic inflammation might eventually lead to new strategies to target immunopathological processes.
852 citations
Cites background from "Association of CXCL13 and CCL21 exp..."
..., HEV-associated molecules (MADCAM1, PNAD and/or the sulphotransferase high endothelial cell N -acetylglucosamine 6- O -sulphotransferase ( HEC-GlcNAc6ST ), which is the enzyme involved in PNAD synthesis...
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TL;DR: The development of lymphoid organs can be viewed as a continuum, including lymph nodes and spleen, which are genetically 'preprogrammed' and 'prepatterned' during ontogeny, whereas tertiary lymphoids organs arise under environmental influences and are not restricted to specific developmental 'windows' or anatomic locations.
Abstract: The development of lymphoid organs can be viewed as a continuum. At one end are the 'canonical' secondary lymphoid organs, including lymph nodes and spleen; at the other end are 'ectopic' or tertiary lymphoid organs, which are cellular accumulations arising during chronic inflammation by the process of lymphoid neogenesis. Secondary lymphoid organs are genetically 'preprogrammed' and 'prepatterned' during ontogeny, whereas tertiary lymphoid organs arise under environmental influences and are not restricted to specific developmental 'windows' or anatomic locations. Between these two boundaries are other types of lymphoid tissues that are less developmentally but more environmentally regulated, such as Peyer's patches, nasal-associated lymphoid tissue, bronchial-associated lymphoid tissue and inducible bronchial-associated lymphoid tissue. Their regulation, functions and potential effects are discussed here.
647 citations
TL;DR: It is demonstrated that FDC+ follicular units invariably express AID and are surrounded by ACPA-producing plasma cells, providing strong evidence that ectopic lymphoid structures in the RA synovium are functional and support autoantibody production.
Abstract: Background
Follicular structures resembling germinal centres (GCs) that are characterized by follicular dendritic cell (FDC) networks have long been recognized in chronically inflamed tissues in autoimmune diseases, including the synovium of rheumatoid arthritis (RA). However, it is debated whether these ectopic structures promote autoimmunity and chronic inflammation driving the production of pathogenic autoantibodies. Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific markers of RA, predict a poor prognosis, and have been suggested to be pathogenic. Therefore, the main study objectives were to determine whether ectopic lymphoid structures in RA synovium: (i) express activation-induced cytidine deaminase (AID), the enzyme required for somatic hypermutation and class-switch recombination (CSR) of Ig genes; (ii) support ongoing CSR and ACPA production; and (iii) remain functional in a RA/severe combined immunodeficiency (SCID) chimera model devoid of new immune cell influx into the synovium.
463 citations
Additional excerpts
...networks characterising GC-like structures [41]....
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...cell segregation as previously reported [41]....
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TL;DR: Evidence for the roles of TLS in chronic infection, autoimmunity, and cancer, and the question of whether TLS present beneficial or deleterious effects in these contexts are discussed.
378 citations
TL;DR: In this review, some of these recent findings that provide insights into both murine models of autoimmunity and human autoimmune diseases are highlighted.
Abstract: The pathogenic roles of B cells in autoimmune diseases occur through several mechanistic pathways that include autoantibodies, immune complexes, dendritic and T cell activation, cytokine synthesis, chemokine-mediated functions, and ectopic neolymphogenesis. Each of these pathways participate to different degrees in autoimmune diseases. The use of B cell–targeted and B cell subset–targeted therapies in humans is illuminating the mechanisms at work in a variety of human autoimmune diseases. In this review, we highlight some of these recent findings that provide insights into both murine models of autoimmunity and human autoimmune diseases.
346 citations
References
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TL;DR: These classification criteria for Sjögren's syndrome have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.
Abstract: Classification criteria for Sjogren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.
4,914 citations
University of Pisa1, Autonomous University of Barcelona2, University of Manchester3, University of Erlangen-Nuremberg4, Royal National Hospital for Rheumatic Diseases5, University of Copenhagen6, University of Bristol7, Sheba Medical Center8, University of Ioannina9, University of Padua10, Sapienza University of Rome11
TL;DR: Using the findings of this prospective multicenter European study, general agreement can be reached on the diagnostic procedures to be used for patients with SS.
Abstract: Objective. Different sets of diagnostic criteria have been proposed for Sjogren's syndrome (SS), but none have been validated with a large series of patients or in a multicenter study. We conducted the present study involving 26 centers from 12 countries (11 in Europe, plus Israel), with the goals of reaching a consensus on the diagnostic procedures for SS and defining classification criteria to be used in epidemiologic surveys and adopted by the scientific community.
Methods. The study protocol was subdivided into two parts. For part I, questionnaires regarding both ocular and oral involvement were developed; they included 13 questions and 7 questions, respectively. For part II a limited set of diagnostic tests was selected, and the exact procedure to be followed in performing these tests was defined. Part I of the study ipcluded 240 patients with primary SS and 240 age- and sex-matched controls. Two hundred forty-six patients with primary SS, 201 with secondary SS, 113 with connective tissue diseases but without associated SS, and 133 control patients were studied in part II.
Results. The study resulted in (a) the validation of a simple 6-item questionnaire for determination of dry eyes and dry mouth, which showed good discriminant power between patients and controls, to be used in the initial screening for sicca syndrome; and (b) the definition of a new set of criteria for the classification of SS. The sensitivity and specificity of the criteria in correctly identifying patients with either the primary or the secondary variant of SS were also determined.
Conclusion. Using the findings of this prospective multicenter European study, general agreement can be reached on the diagnostic procedures to be used for patients with SS. Final validation of the preliminary classification criteria for SS is underway.
1,487 citations
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TL;DR: It is suggested that the term Sjögren's syndrome be used to describe one subset of patients with sicca symptoms who exhibit particular major histocompatibility complex antigens, the presence of T cell lymphoid infiltrates on glandular biopsy, and specific autoantibodies in their sera.
1,436 citations
TL;DR: It is established that B-lymphocyte chemoattractant (BLC/BCA1) and its receptor, CXCR5, are needed for B-cell homing to follicles in lymph nodes as well as in spleen, and that BLC is required for the development of most lymph nodes and Peyer's patches.
Abstract: Lymphoid follicles are B-cell-rich compartments of lymphoid organs that function as sites of B-cell antigen encounter and differentiation. CXC chemokine receptor-5 (CXCR5) is required for B-cell migration to splenic follicles, but the requirements for homing to B-cell areas in lymph nodes remain to be defined. Here we show that lymph nodes contain two types of B-cell-rich compartment: follicles containing follicular dendritic cells, and areas lacking such cells. Using gene-targeted mice, we establish that B-lymphocyte chemoattractant (BLC/BCA1) and its receptor, CXCR5, are needed for B-cell homing to follicles in lymph nodes as well as in spleen. We also find that BLC is required for the development of most lymph nodes and Peyer's patches. In addition to mediating chemoattraction, BLC induces B cells to up-regulate membrane lymphotoxin alpha1beta2, a cytokine that promotes follicular dendritic cell development and BLC expression, establishing a positive feedback loop that is likely to be important in follicle development and homeostasis. In germinal centres the feedback loop is overridden, with B-cell lymphotoxin alpha1beta2 expression being induced by a mechanism independent of BLC.
1,243 citations
TL;DR: SLC is the first chemokine demonstrated to have the characteristics required to mediate homing of lymphocytes to secondary lymphoid organs and the expression of SLC in lymphatic endothelium suggests that the migration of lymphocyte from tissues into efferent lymphatics may be an active process mediated by this molecule.
Abstract: Preferential homing of naive lymphocytes to secondary lymphoid organs is thought to involve the action of chemokines, yet no chemokine has been shown to have either the expression pattern or the activities required to mediate this process. Here we show that a chemokine represented in the EST database, secondary lymphoid-tissue chemokine (SLC), is expressed in the high endothelial venules of lymph nodes and Peyer’s patches, in the T cell areas of spleen, lymph nodes, and Peyer’s patches, and in the lymphatic endothelium of multiple organs. SLC is a highly efficacious chemoattractant for lymphocytes with preferential activity toward naive T cells. Moreover, SLC induces firm adhesion of naive T lymphocytes via β2 integrin binding to the counter receptor, intercellular adhesion molecule-1, a necessary step for lymphocyte recruitment. SLC is the first chemokine demonstrated to have the characteristics required to mediate homing of lymphocytes to secondary lymphoid organs. In addition, the expression of SLC in lymphatic endothelium suggests that the migration of lymphocytes from tissues into efferent lymphatics may be an active process mediated by this molecule.
1,028 citations