Davide Lucchesi

Sanofi (United Kingdom)

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Stefano Bombardieri

University of Pisa

Elena Pontarini

William Harvey Research Institute

Costantino Pitzalis

Queen Mary University of London

Rachel Coleby

Queen Mary University of London

Liliane Fossati‐Jimack

William Harvey Research Institute

Felice Rivellese

RIKEN Center for Integrative Medical Sciences

Anwar R. Tappuni

Queen Mary University of London

Myles Lewis

Queen Mary University of London

Nurhan Sutcliffe

Barts Health NHS Trust

Domenico Mavilio

University of Milan

Cooperative Institutions

Queen Mary University of London

William Harvey Research Institute

Inserm

Istituti di Ricovero e Cura a Carattere Scientifico

University College London

Universidade de São Paulo

University of Milan

Assistance Publique – Hôpitaux de Paris

Academic Medical Center

University of Birmingham

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The role of viruses in autoreactive B cell activation within tertiary lymphoid structures in autoimmune diseases

Journal of Leukocyte Biology (2013)

Davide Lucchesi Stefano Bombardieri

ABSTRACT TLS, characterized by the formation of ectopic B/T cell follicles with FDCs supporting an ectopic GC response, have been described in the target organs of several autoimmune diseases, including MS, RA, SS, and autoimmune thyroiditis. These structures represent functional niches, whereby autoreactive B cells undergo in situ affinity maturation and differentiation to autoantibody-producing cells, thus contributing to the progression and persistence of autoimmunity. Increasing evidence demonstrates that TLS can also develop in the context of cancer, as well as chronic infections. In this review, we collect recent evidences that highlights the relationship between persistent viral infection and the development of ectopic lymphoid structures in animal models and patients. Furthermore, we shall discuss the concept that whereas in physiological conditions, inducible TLS are critical for viral clearance and the establishment of protective immunity, but in the context of susceptible individuals, persistent viral infections may contribute, directly or indirectly, to the development of breach of tolerance against self-antigens and the development of autoimmunity through the formation of TLS.

Self Tolerance

10.1189/jlb.0413240

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Citations (37)

EBV and other viruses as triggers of tertiary lymphoid structures in primary Sjögren’s syndrome

Expert Review of Clinical Immunology (2014)

Davide Lucchesi Costantino Pitzalis Stefano Bombardieri

Sjögren's syndrome (SS) is an autoimmune disease that targets salivary (SG) and lachrymal glands, leading to exocrine dysfunction. Several viruses have been associated with SS, although the role of persistent viral infections in triggering and/or perpetuating the disease is still a matter of controversy. Together with exocrine dysfunction, SS is characterised by the production of autoantibodies and the presence of lymphomonocytic periductal aggregates in the SG, which in 30/40% of the patients display features of tertiary lymphoid structures (TLS) supporting an ectopic germinal centre response. Here we first review i) the relevance of TLS in SS and ii) the evidence in support of a role for viruses in SS insurgence and/or persistence; next, iii) we review recent data which links viral infection with TLS formation in the SG and suggests that viral-host interactions within TLS favour breach of tolerance and development of autoimmunity in SS.

Exocrine gland

10.1586/1744666x.2014.892417

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Galectin-3 bindsNeisseria meningitidisand increases interaction with phagocytic cells

Cellular Microbiology (2012)

Paola Quattroni Yan-Wen Li Davide Lucchesi Sebastian Lucas Derek W. Hood

Galectin-3 is expressed and secreted by immune cells and has been implicated in multiple aspects of the inflammatory response. It is a glycan binding protein which can exert its functions within cells or exogenously by binding cell surface ligands, acting as a molecular bridge or activating signalling pathways. In addition, this lectin has been shown to bind to microorganisms. In this study we investigated the interaction between galectin-3 and Neisseria meningitidis, an important extracellular human pathogen, which is a leading cause of septicaemia and meningitis. Immunohistochemical analysis indicated that galectin-3 is expressed during meningococcal disease and colocalizes with bacterial colonies in infected tissues from patients. We show that galectin-3 binds to N. meningitidis and we demonstrate that this interaction requiresfull-length, intact lipopolysaccharide molecules. We found that neither exogenous nor endogenous galectin-3 contributes to phagocytosis of N. meningitidis; instead exogenous galectin-3 increases adhesion to monocytes and macrophages but not epithelial cells. Finally we used galectin-3 deficient (Gal-3(-/-) ) mice to evaluate the contribution of galectin-3 to meningococcal bacteraemia. We found that Gal-3(-/-) mice had significantly lower levels of bacteraemia compared with wild-type mice after challenge with live bacteria, indicating that galectin-3 confers an advantage to N. meningitidis during systemic infection.

Galectin-1

Galectin

Galectin-3

10.1111/j.1462-5822.2012.01838.x

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Citations (76)

IL-37: a new anti-inflammatory cytokine of the IL-1 family

European Cytokine Network (2011)

Diana Boraschi Davide Lucchesi Stefan Hainzl Maria Leitner Elisabeth Maier

The IL-1 family of cytokines encompasses eleven proteins that each share a similar β-barrel structure and bind to Ig-like receptors. Some of the IL-1-like cytokines have been well characterised, and play key roles in the development and regulation of inflammation. Indeed, IL-1α (IL-1F1), IL-1β (IL-1F2), and IL-18 (IL-1F4) are well-known inflammatory cytokines active in the initiation of the inflammatory reaction and in driving Th1 and Th17 inflammatory responses. In contrast, IL-1 receptor antagonist (IL-1Ra, IL-1F3) and the receptor antagonist binding to IL-1Rrp2 (IL-36Ra, IL-1F5) reduce inflammation by blocking the binding of the agonist receptor ligands. In the case of IL-37 (IL-1F7), of which five different splice variants have been described, less is known of its function, and identification of the components of a heterodimeric receptor complex remains unclear. Some studies suggest that IL-37 binds to the α chain of the IL-18 receptor in a non-competitive fashion, and this may explain some of the disparate biological effects that have been reported for mice deficient in the IL-18R. The biological properties of IL-37 are mainly those of down-regulating inflammation, as assessed in models where human IL-37 is expressed in mice. In this review, an overview of the role of IL-37 in the regulation of inflammation is presented. The finding that IL-37 also locates to the nucleus, as do IL-1α and IL-33, for receptor-independent organ/tissue-specific regulation of inflammation is also reviewed.

10.1684/ecn.2011.0288

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Citations (333)

Problems and challenges in the development and validation of human cell-based assays to determine nanoparticle-induced immunomodulatory effects

Particle and Fibre Toxicology (2011)

Gertie J. Oostingh Eudald Casals Paola Italiani Renato Colognato René Stritzinger

With the increasing use of nanomaterials, the need for methods and assays to examine their immunosafety is becoming urgent, in particular for nanomaterials that are deliberately administered to human subjects (as in the case of nanomedicines). To obtain reliable results, standardised in vitro immunotoxicological tests should be used to determine the effects of engineered nanoparticles on human immune responses. However, before assays can be standardised, it is important that suitable methods are established and validated. In a collaborative work between European laboratories, existing immunological and toxicological in vitro assays were tested and compared for their suitability to test effects of nanoparticles on immune responses. The prototypical nanoparticles used were metal (oxide) particles, either custom-generated by wet synthesis or commercially available as powders. Several problems and challenges were encountered during assay validation, ranging from particle agglomeration in biological media and optical interference with assay systems, to chemical immunotoxicity of solvents and contamination with endotoxin. The problems that were encountered in the immunological assay systems used in this study, such as chemical or endotoxin contamination and optical interference caused by the dense material, significantly affected the data obtained. These problems have to be solved to enable the development of reliable assays for the assessment of nano-immunosafety.

In vitro toxicology

Nanomaterials

Nanotoxicology

10.1186/1743-8977-8-8

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Citations (190)

Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction

Communications Biology (2022)

Saba Nayar Elena Pontarini Joana Campos Onorina Berardicurti Charlotte G. Smith

Abstract Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans.

Expression (computer science)

10.1038/s42003-022-03344-6

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Citations (15)

A6.2 Inducible Tertiary Lymphoid Structures and Autoimmunity in a Novel model of Sialoadenitis in Wild-Type Mice

Annals of the Rheumatic Diseases (2013)

Davide Lucchesi Stefano Bombardieri Francesca Barone Saba Nayar Gordon Proctor

Introduction

Salivary glands of patients with Sjögren's syndrome (SS) develop ectopic lymphoid structures (ELS) characterised by B/T cell compartmentalisation, the formation of high endothelial venules (HEV), follicular dendritic cell networks (FDCs), functional B cell activation with expression of activation-induced cytidine deaminase (AID) as well as local differentiation of autoreactive plasma cells. The mechanisms triggering ELS formation, autoimmunity and exocrine dysfunction in SS are largely unknown. Here we present a novel model of inducible ectopic lymphoid tissue formation, breach of humoral self-tolerance and salivary hypofunction following delivery of a replication-deficient adenovirus-5 (AdV5) in submandibular glands of C57BL/6 mice through retrograde excretory duct cannulation.

Materials and Methods

Luciferase- or LacZ-encoding Ad5 were delivered in C57BL/6 mice salivary glands (SG) through retrograde cannulation. SGs were collected at various time-points 1, 2 and 3 weeks post-cannulation (pc) and frozen sections were graded for infiltration and stained for T/B cell segregation, FDCs and HEV markers. Submandibular salivary flow was induced by pilocarpine stimulation and the amount of saliva measured. Expression of TLS-related genes was investigated by TaqMan-PCR. Anti-viral antibodies and autoantibodies were detected by IF and western blot.

Results

In this model, inflammation rapidly and consistently evolves from diffuse infiltration towards the development of SS-like periductal lymphoid aggregates within 2 weeks from AdV delivery. These infiltrates progressively acquire ELS features and support functional GL7+/AID+ germinal centres. Formation of ELS is preceded by ectopic expression of lymphoid chemokines CXCL13, CCL21 and CCL19 as well as lymphotoxin-β and is associated with development of anti-nuclear antibodies in 75% of the mice. Finally, reduction in salivary flow was observed over 3 weeks post AdV infection consistent with exocrine gland dysfunction as a consequence of the inflammatory response.

Conclusions

This novel model has the potential to unravel the cellular and molecular mechanisms regulating ELS formation and their role in exocrine dysfunction and autoimmunity in SS.

CXCL13

High endothelial venules

Activation-induced (cytidine) deaminase

10.1136/annrheumdis-2013-203220.2

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Zenodo (CERN European Organization for Nuclear Research) (2020)

Elena Pontarini Davide Lucchesi Liliane Fossati‐Jimack Rachel Coleby Paolo Tentorio

Salivary glands (SGs) represent a permissive site for several sialotropic viruses whose persistence is linked to the development of autoimmunity. Natural Killer (NK) cells play a key role in viral clearance but their involvement in viral infection control and in tertiary lymphoid structures (TLS) development within SGs is unknown. By using an inducible model of TLS in the SGs of wild-type C57BL/6 mice, induced by the local delivery of a replication-defective adenovirus (AdV), we demonstrated that circulating NK cells are rapidly recruited to SGs and highly enrich the early inflammatory infiltrate prior to TLS development. NK cells migrating to SGs in response to AdV infection up-regulate NKp46, undergo proliferation, acquire cytotoxic potential, produce Granzyme-B and IFN-γ, and reduce viral load in the acute phase of the infection. Nonetheless, the selective depletion of both circulating and infiltrating NK cells in AdV-infected mice neither affect the development and frequency of TLS nor the onset of autoimmunity. These data demonstrate that, upon local viral delivery of AdV, peripheral NK cells homing to SGs can exert an early control of the viral infection but are dispensable for the formation of TLS and breach of immunologic tolerance. This research used pzf and ets file form extensions, we attach pdfs information about

10.5281/zenodo.3712240

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B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure

Arthritis & Rheumatology (2019)

Felice Rivellese Frances Humby Serena Bugatti Liliane Fossati‐Jimack Hasan Rizvi

Objective To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis ( RA ). Methods Synovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors ( TNF i‐ IR ; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0–9) and of CD 20+ B cell infiltrate (on a scale of 0–4). B cell scores were validated by digital image analysis and B cell lineage–specific transcript analysis ( RNA ‐Seq) in the early RA (n = 91) and TNF i‐ IR (n = 127) cohorts. Semiquantitative CD 20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2). Results Semiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage–specific transcripts. B cell–rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNF i‐ IR cohort ( P = 0.025). B cell–rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti–citrullinated protein antibody in early RA but not in established RA , while significantly higher histologic synovitis scores in B cell–rich patients were demonstrated in both cohorts. Conclusion We describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell–rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA .

Rheumatoid factor

10.1002/art.41184

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Citations (44)

Stepwise changes in the murine salivary gland immune response during virally-induced ectopic lymphoid structure formation

Clinical and Experimental Rheumatology (2021)

Rachel Coleby Davide Lucchesi Elena Pontarini Costantino Pitzalis Stefano Bombardieri

CXCL13

Follicular dendritic cells

Infiltration (HVAC)

10.55563/clinexprheumatol/gb7pfc

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Citations (1)