Ectopic Lymphoneogenesis Research Articles

Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren’s syndrome

BackgroundThe phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies....

Spoiling for a Fight: B Lymphocytes As Initiator and Effector Populations within Tertiary Lymphoid Organs in Autoimmunity and Transplantation.

Tertiary lymphoid organs (TLOs) develop at ectopic sites within chronically inflamed tissues, such as in autoimmunity and rejecting organ allografts. TLOs differ structurally from canonical secondary lymphoid organs (SLOs), in that they lack a mantle zone and are not encapsulated, suggesting that they may provide unique immune function. A notable feature of TLOs is the frequent presence of structures typical of germinal centers (GCs). However, little is known about the role of such GCs, and in particular, it is not clear if the B cell response within is autonomous, or whether it synergizes with concurrent responses in SLOs. This review will discuss ectopic lymphoneogenesis and the role of the B cell in TLO formation and subsequent effector output in the context of autoimmunity and transplantation, with particular focus on the contribution of ectopic GCs to affinity maturation in humoral immune responses and to the potential breakdown of self-tolerance and development of humoral autoimmunity.

KIR4.1 Antibodies as Biomarkers in Multiple Sclerosis.

KIR4.1 Antibodies as Biomarkers in Multiple Sclerosis.

101. Synovial Ectopic Lymphoneogenesis Predicts Primary Clinical Response to Certolizumab Pegol in Patients with Rheumatoid Arthritis

101. Synovial Ectopic Lymphoneogenesis Predicts Primary Clinical Response to Certolizumab Pegol in Patients with Rheumatoid Arthritis

A3.1 Pathogenic role of IL-17 producing double negative (DN) T cells in primary sjögren’s syndrome

Background and ObjectivesWe recently demonstrated that a CD3+ T cell population, that lacks both CD4 and CD8 molecules, defined as double negative (DN), is expanded in the peripheral blood of...

CD4−CD8− T-cells in primary Sjögren's syndrome: Association with the extent of glandular involvement

ObjectivesGrowing evidence suggests that IL-17-producing T cells, lacking both CD4 and CD8 molecules and defined as double negative (DN) cells, play a pivotal role in the pathogenesis of a number of systemic autoimmune disorders. We recently demonstrated that this T-cell subset is expanded in the peripheral blood (PB) of patients with primary Sjögren's syndrome (pSS), produces IL-17 and accumulates in minor salivary glands (MSGs). We aimed to investigate glandular and PB DN T cells in early pSS in order to verify a possible correlation with MSGs histological patterns and clinical parameters. MethodsPaired samples of PB mononuclear cells and MSGs from pSS patients were evaluated at the diagnosis by flow cytometry and immunofluorescence staining respectively. Histological analysis to identify histological scores, B/T cell segregation and the presence of germinal center (GC)-like structures was also performed. ResultsIn early stages of pSS, circulating DN T cells appear to be not yet expanded and inversely correlated with circulating CD4+Th17 cells. The number of infiltrating DN T cells were associated with extent of glandular involvement, presence of GC-like structures and dryness symptoms and were inversely correlated with circulating DN T cells. ConclusionsOur findings suggest that DN T cells are actively involved in the pathogenic mechanisms leading to glandular dysfunction and damage in pSS and may play a role in ectopic lymphoneogenesis development occurring during the disease.

IgG4-related epididymo-orchitis associated with bladder cancer: possible involvement of BAFF/BAFF-R interaction in IgG4-related urogenital disease

We describe herein a patient who presented with immunoglobulin G4-related disease (IgG4-RD) involving the testis and prostate as well as the submandibular glands. Massive infiltration of IgG4-expressing plasma cells was observed in testis and prostate tissues. Serum concentrations of B cell activating factor belonging to the tumor necrosis factor family (BAFF) were elevated in parallel with serum IgG4 concentrations, and infiltration of BAFF-receptor (BAFF-R)-expressing B cells and BAFF-expressing lymphoid cells was observed around the ectopic lymphoid foci in the affected urogenital tissues. To date, testicular involvement in a patient diagnosed with IgG4-RD had not been reported, making this the first reported case of IgG4-related epididymo-orchitis. These findings suggest that the immune mechanism underlying ectopic lymphoneogenesis in IgG4-RD may involve enhanced BAFF/BAFF-R interactions among lymphoid cells.

134: Interleukin-27 as a novel antagonist of ectopic lymphoid-like structure development in early inflammatory arthritis

Evaluation of joint tissue from early inflammatory arthritis patients through ultrasound-guided synovial biopsy has enabled disease classification based on local pathology. For example, the disease can be classed as fibroblast-, myeloid- or lymphoid-driven. Lymphoid histopathology can be further divided into patients displaying either diffuse infiltrates, or ectopic lymphoid-like structures (ELS) reminiscent of the follicular compartments in secondary lymphoid organs. Approximately 25% of rheumatoid arthritis (RA) patients develop ELS and display severe symptoms associated with local immune cell priming and autoantibody production. However, cytokine control of ELS development in inflammatory arthritis is poorly defined. Interleukin (IL)-27 is a negative regulator of adaptive immune responses. To investigate the role of IL-27 in inflammatory arthritis, wild type (WT) and IL-27 receptor (IL-27R)-deficient mice were exposed to antigen-induced arthritis. IL-27R-deficient mice developed exacerbated inflammatory arthritis, displaying increased synovial infiltrate, hypertrophy and bone erosions. Heightened peripheral T H 17- and B-cell responses in IL-27R-deficiency were reflected in increased serum IL-17 levels and antigen-specific IgG titers. Strikingly, IL-27R-deficient mice developed synovial histopathology reminiscent of RA patients with ELS, comprising synovial lymphoid aggregates with distinct T-cell (CD3 + ), B-cell (B220 + ) and DC (F/480 + , CD21 + ) areas that were absent in WT mice. Development of lymphoid aggregates was associated with elevated synovial expression of homeostatic chemokines that promote ectopic lymphoneogenesis (e.g. Cxcl13, Ccl21 ) and the transcriptional regulator Bcl-6 , which is involved in germinal center organization and functional regulation. Ectopic lymphoneogenesis in IL-27R-deficient mice was not associated with an increase in synovial IL-6 or IL-21 expression. Studies in clinical RA patients reflect our experimental outcomes and reveal reduced synovial IL-27 expression in patients with joint histopathology comprising ELS compared to patients with diffuse lymphocytic infiltrates. Thus, IL-27 may negatively regulate the formation of ELS in human pathologies such as RA and represents a potential biomarker of synovial histopathology in early RA.

THU0035 Lymphotoxin Beta Regulates Lymphatic Vessel Expansion in Ectopic Lymphoneogenesis

BackgroundSecondary lymphoid organs are characterized by concordance in time, function and response to stimuli between the lymphatic and vascular system that allows tight regulation of cellular recruitment and exit from...

SAT0191 Aberrant cytokine expression and severity of the infiltrates are reverted by rituximab therapy in salivary glands of patients with sjogren’s syndrome

BackgroundB lymphocytes are key players in the development of chronic autoimmune sialoadenitis and ectopic lymphoneogenesis is a milestone in the natural history of Sjögren’s syndrome (SS) (1). Much effort has...

OP0258 IL-22 Regulates Lymphoid Stromal Cell Expansion, Development of Germinal Centers and Humoral Response in Mucosal Ectopic Lymphoneogenesis

BackgroundFailure to treat autoimmune diseases with leukocyte-targeted therapies, candidates locally residing stromal cells as possible therapeutic intervention in chronic disease management. Phenotypical changes associated with the acquisition of lymphoid-like features...

Cooperation of innate and acquired immune system derived signals induces stromal cell activation in chronic inflammation and ectopic lymphoneogenesis

BackgroundAcquisition of lymphoid-like features is a hallmark of ectopic lymphoneogenesis. In lymph nodes, gp8+ fibroblastic reticular cells (FRC) are responsible for lymphoid chemokines/cytokine production and lymphocyte compartmentalisation. gp38 up-regulation on...

Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid‐like structures in Sjögren's syndrome

Ectopic lymphoneogenesis can occur in the salivary glands of Sjögren'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. 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. 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. 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.

Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis

CXCL13 and CCL21 have been functionally implicated in lymphoid tissue organization both in the upstream phases of lymphoid tissue embryogenesis and in ectopic lymphoid neogenesis in transgenic mice. Here, we analyzed the relationship between CXCL13 and CCL21 production and lymphoid tissue organization in rheumatoid synovitis as a model of a naturally occurring ectopic lymphoneogenesis. Through systematic analysis of mRNA and protein expression, we defined the microanatomical relationship between CXCL13 and CCL21 in progressive aggregational and structural phases of synovial inflammatory infiltrate. We provide the first direct in situ evidence that production of CXCL13 and CCL21 (rather than simply protein binding) is associated with inflammatory lymphoid tissue formation and development with the demonstration, in organized aggregates, of a secondary lymphoid organ-like compartmentalization and vascular association. Notably, the presence of CXCL13 and CCL21 (protein and mRNA) was also demonstrated in non-organized clusters and minor aggregational stages, providing evidence that their induction can take place independently and possibly upstream of T-B compartmentalization, CD21(+) follicular dendritic cell network differentiation and germinal center formation. Our data support the concept that, under inflammatory conditions, CXCL13 and CCL21 participate in lymphoid tissue microanatomical organization, attempting to recapitulate, in an aberrant lymphoid neogenetic process, their homeostatic and morphogenetic physiologic functions.

CXCL13 and CCL21 play a key role in ectopic lymphoneogenesis in Sjögren's syndrome

CXCL13 and CCL21 play a key role in ectopic lymphoneogenesis in Sjögren's syndrome