Objective. To examine whether the B cell tropic ␥-herpesvirus Epstein-Barr virus (EBV) is aberrantly expressed in its latent and lytic forms within ectopic lymphoid structures (ELS) in the salivary glands of patients with Sjögren's syndrome (SS), and to investigate the relationship between EBV dysregulation, B cell activation, in situ differentiation of autoreactive plasma cells, disease-specific autoantibody production, and cytotoxicity.Methods. Latent and lytic EBV infection in the salivary glands of 28 patients with SS and 38 patients with nonspecific chronic sialadenitis (NSCS), characterized for the presence or absence of ELS, was investigated by reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemical/ immunofluorescence staining. Glandular versus synovial production of anti؊Ro 52, anti-citrullinated protein antibodies (ACPAs), and anti-EBV peptide antibodies was analyzed in situ or in vivo in human SS/SCID and human rheumatoid arthritis/SCID mouse chimeras. Conclusion. Active EBV infection is selectively associated with ELS in the salivary glands of patients with SS and appears to contribute to local growth and differentiation of disease-specific autoreactive B cells. Results. EBV dysregulation within inflammatory infiltrates was observed exclusively in ELS؉ SS salivary gland tissue, as revealed by latent EBV infection and lytic EBV infection in B cells
ObjectivesTo explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren’s syndrome (SS) patients.MethodsSalivary gland (SG) biopsies with matched peripheral blood were collected from four centres across the European Union. Transcriptomic (microarray and quantitative PCR) analysis, FACS T-cell immunophenotyping with intracellular cytokine detection, multicolor immune-fluorescence microscopy and in situ hybridisation were performed to characterise lesional and circulating Tfh and Tph-cells. SG-organ cultures were used to investigate functionally the blockade of T-cell costimulatory pathways on key proinflammatory cytokine production.ResultsTranscriptomic analysis in SG identified Tfh-signature, interleukin-21 (IL-21) and the inducible T-cell co-stimulator (ICOS) costimulatory pathway as the most upregulated genes in ELS+SS patients, with parotid MALT-L displaying a 400-folds increase in IL-21 mRNA. Peripheral CD4+CXC-motif chemokine receptor 5 (CXCR5)+programmed cell death protein 1 (PD1)+ICOS+ Tfh-like cells were significantly expanded in ELS+SS patients, were the main producers of IL-21, and closely correlated with circulating IgG and reduced complement C4. In the SG, lesional CD4+CD45RO+ICOS+PD1+ cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L. In ELS+SG and MALT-L parotids, conventional CXCR5+CD4+PD1+ICOS+Foxp3- Tfh-cells and a uniquely expanded population of CXCR5-CD4+PD1hiICOS+Foxp3- Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression. Finally, ICOS blockade in ex vivo SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α).ConclusionsOverall, these findings highlight Tfh and Tph-cells, IL-21 and the ICOS costimulatory pathway as key pathogenic players in SS immunopathology and exploitable therapeutic targets in SS.
Ferritin has a key role in Adult-onset Still's disease (AOSD). Its production seems related to macrophage activation of which sCD163 is a major serum marker. Thus, we aimed at evaluating the role of sCD163 in AOSD and its relationship with ferritin. Furthermore, we determined the expression of CD163 and ferritin in a lymph-node from an AOSD patient. sCD163 and serum ferritin were measured in 34 patients with AOSD (21 active, 13 non-active), 18 sepsis and 22 healthy controls (HC). Immunohistology was performed on a lymph-node from an AOSD patient in order to detect CD163 and ferritin. A tonsil from an HC was used as control. Mean sCD163 (8.6 ± 5.4 mg/L) was higher in active AOSD than "non-active" patients (4.6 ± 2.7 mg/L, p = 0.02). The mean sCD163 in AOSD (6.9 ± 4.9 mg/L) and sepsis (7.1 ± 5.6 mg/L) were higher than in HC (2.56 ± 1.17 mg/L, p < 0.001), but no difference between AOSD and sepsis was detected. sCD163 positively correlated with ferritin (p = 0.0045; r = 0.4755) only in AOSD. Serum ferritin (mean 3,640.1 ± 6,896.9 µg/L) was higher in active AOSD than in sepsis (1,720.2 ± 3,882.1 µg/L, p < 0.007). CD163 was equally distributed in the B and T areas of both lymph-node and tonsil. Differently from the tonsil, ferritin was expressed only in the lymph-node B area. sCD163 is a marker of disease activity in AOSD. The correlation with ferritin may lead to hypothesize a macrophage activation related to hyperferritinemia. Ferritin was found expressed only in the B area of the AOSD lymph-node, suggesting a role for this molecule as an antigen in the disease pathogenesis.
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