For a long time after its discovery at the beginning of the 20th century, lactate was considered a waste product of cellular metabolism. Starting in the early ‘90s, however, lactate has begun to be ...recognized as an active molecule capable of modulating the immune response. Inflammatory sites, including in rheumatoid arthritis (RA) synovitis, are characterized by the accumulation of lactate, which is partly responsible for the establishment of an acidic environment. We have recently reported that T cells sense lactate via the expression of specific transporters, leading to inhibition of their motility. Importantly, this “stop migration signal” is dependent upon lactate's interference with intracellular metabolic pathways, specifically glycolysis. Furthermore, lactate promotes the switch of CD4+ T cells to an IL‐17+ subset, and reduces the cytolytic capacity of CD8+ T cells. These phenomena might be responsible for the formation of ectopic lymphoid structures and autoantibody production in inflammatory sites such as in RA synovitis, Sjogren syndrome salivary glands, and multiple sclerosis plaques. Here, we review the roles of lactate in the modulation of the inflammatory immune response.
Lactate accumulates in the synovial joints during inflammation, and inhibits T‐cell motility by interfering with the glycolytic pathway. Loss of motility might be the cause of T‐cell entrapment in the synovial joint. Increased T‐cell retention and high local IL‐17 might in turn be responsible of the formation of ELSs.
Ectopic lymphoid neogenesis often occurs in the target tissues of patients with chronic rheumatic autoimmune diseases such as rheumatoid arthritis, Sjögren syndrome and other connective tissue ...disorders, including systemic lupus erythematosus and myositis. However, the mechanisms of ectopic lymphoid-like structure (ELS) formation and function are not entirely understood. For example, it is unclear whether ELSs indicate distinct disease phenotypes or whether they are evolutionary manifestations of chronic inflammation. Also unclear is why ELSs form in some patients but not in others. Nonetheless, ELSs frequently display functional features of ectopic germinal centres and can actively contribute to the maintenance of autoimmunity through the production of disease-specific autoantibodies; furthermore, they seem to influence disease severity and response to both synthetic and biologic DMARDs. In this Review, we discuss current knowledge and gaps in understanding of ELS formation and function including their prevalence in the above rheumatic autoimmune diseases; the mechanisms underlying their formation, maintenance and function, including positive and negative regulatory pathways; their functional relevance in the perpetuation of autoimmunity; their relationship with disease phenotypes, clinical outcomes and response to treatment; and the potential for specific targeting of ELSs through novel therapeutic modalities.
Lymphoma development is the most serious complication of SS and the main factor impacting on mortality rate in patients with this condition. Lymphomas in SS are most commonly extranodal non-Hodgkin ...B-cell lymphomas of the mucosa-associated lymphoid tissue and frequently arise in salivary glands that are the target of a chronic inflammatory autoimmune process. Extensive work on lymphomagenesis in SS has established that the progression towards B-cell lymphoma is a multistep process related to local chronic antigenic stimulation of B cells. These neoplastic B cells in SS frequently derived from autoreactive clones, most commonly RF-producing B cells, which undergo uncontrolled proliferation and malignant escape. In this review, we highlight the most important recent findings that have enhanced our understanding of lymphoma development in SS, with particular reference to the close link between autoimmunity and lymphomagenesis. We also discuss how the identification of key factors involved in B-cell malignancies may impact on our ability to identify at early stages patients at increased risk of lymphoma with potential significant repercussions for the clinical management of SS patients. Finally, we identified the most promising areas of current and further research with the potential to provide novel basic and translational discoveries in the field. The questions of finding new biomarkers, developing a validated score for predicting lymphoma occurrence and assessing if a better control of disease activity will decrease the risk of lymphoma in primary SS will be the enthralling questions of the next few years.
Ectopic lymphoid-like structures often develop at sites of inflammation where they influence the course of infection, autoimmune disease, cancer and transplant rejection. These lymphoid aggregates ...range from tight clusters of B cells and T cells to highly organized structures that comprise functional germinal centres. Although the mechanisms governing ectopic lymphoid neogenesis in human pathology remain poorly defined, the presence of ectopic lymphoid-like structures within inflamed tissues has been linked to both protective and deleterious outcomes in patients. In this Review, we discuss investigations in both experimental model systems and patient cohorts to provide a perspective on the formation and functions of ectopic lymphoid-like structures in human pathology, with particular reference to the clinical implications and the potential for therapeutic targeting.
Rheumatoid arthritis (RA) is characterised by breach of self-tolerance towards citrullinated antigens with generation of anti-citrullinated peptide/proteins antibodies (ACPA). Currently, the nature ...and source of citrullinated antigens driving the humoral autoimmune response within synovial ectopic lymphoid structures (ELS) is a crucial unknown aspect of RA pathogenesis. Here we characterised the autoreactive B-cell response of lesional B cells isolated from ELS+RA synovium.
Single synovial tissue CD19+cells were Fluorescence Activated Cell Sorting (FACS)-sorted and VH/VL Ig genes cloned to generate recombinant monoclonal antibodies (rmAbs) from patients with ELS+/ACPA+RA.
RA-rmAbs immunoreactivity analysis provided the following key findings: (1) in a chIP-based array containing 300 autoantigens and in a 'citrullinome' multiplex assay, a strong reactivity against citrullinated histones H2A/H2B (citH2A/H2B) was observed in ∼40% of RA-rmAbs, followed by cit-fibrinogen and cit-vimentin; (2) anti-citH2A/H2B-reactive RA-rmAbs (but not anti-citH2A/H2B negative) selectively recognised neutrophil extracellular traps (NETs) from peripheral blood and/or RA joint neutrophils; (3) anti-citH2A/citH2B and anti-NET immunobinding was dependent on affinity maturation and was completely abrogated following reversion of hypermutated IgVH/VL genes to germline sequences; (4) ELS+ (not ELS-) RA synovial tissues engrafted into Severe Combined ImmunoDeficiency (SCID) mice released human anti-citH2A/citH2B and anti-NET antibodies in association with the intra-graft expression of CXCL13 and lymphotoxin (LT)-β, two master regulators of ELS.
We provided novel evidence that B cells differentiated within synovial ELS in the RA joints frequent target deiminated proteins which could be generated during NETosis of RA synovial neutrophils including histones. Thus, NETs could represent a source of citrullinated antigens fuelling the ACPA autoimmune response within the RA synovium.
Ectopic lymphoid structures (ELS) often develop at sites of inflammation in target tissues of autoimmune diseases, such as rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, myasthenia ...gravis, and systemic lupus erythematosus. ELS are characterized by the formation of organized T/B cells aggregates, which can acquire follicular dendritic cells network supporting an ectopic germinal center response. In this review, we shall summarize the mechanisms that regulate the formation of ELS in tertiary lymphoid organs, with particular emphasis on the role of lymphoid chemokines in both formation and maintenance of ELS, the role of emerging positive and negative regulators of ELS development and function, including T follicular helper cells and IL-27, respectively. Finally, we shall discuss the main functions of ELS in supporting the affinity maturation, clonal selection, and differentiation of autoreactive B cells contributing to the maintenance and perpetuation of humoral autoimmunity.
In neutrophils (but also in eosinophils and in mast cells), different inflammatory stimuli induce histone deimination, chromatin decondensation, and NET formation. These web-like structures that trap ...and kill microbes contain DNA, cationic granule proteins, and antimicrobial peptides, but the most abundant proteins are core histones. Histones contained in NETs have been deiminated, and arginines are converted in citrullines. While deimination is a physiological process amplified in inflammatory conditions, only individuals carrying genetic predisposition to develop rheumatoid arthritis (RA) make antibodies to deiminated proteins. These antibodies, collectively identified as anti-citrullinated proteins/peptides antibodies (ACPA), react with different deiminated proteins and display partially overlapping specificities. In this paper, we will summarize current evidence supporting the role of NETosis as critical mechanism in the breach of tolerance to self-antigens and in supporting expansion and differentiation of autoreactive cells. In fact, several lines of evidence connect NETosis with RA: RA unstimulated synovial fluid neutrophils display enhanced NETosis; sera from RA patients with Felty's syndrome bind deiminated H3 and NETs; a high number of RA sera bind deiminated H4 contained in NETs; human monoclonal antibodies generated from RA synovial B cells decorate NETs and bind deiminated histones. In RA, NETs represent on one side an important source of autoantigens bearing posttranslational modifications and fueling the production of ACPA. On the other side, NETs deliver signals that maintain an inflammatory milieu and contribute to the expansion and differentiation of ACPA-producing B cells.
Primary Sjögren’s syndrome (pSS) is a highly heterogeneous disease in terms of clinical presentation ranging from a mild disease localised to the salivary and lacrimal glands, to multiorgan ...complications of various degrees of severity, finishing with the evolution, in around 5% of pSS patients, to B cell lymphomas most commonly arising in the inflamed salivary glands. Currently, there are poor positive or negative predictors of disease evolution able to guide patient management and treatment at early stages of the diseases. Recent understanding of the pathogenic mechanisms driving immunopathology in pSS, particularly through histological and transcriptomic analysis of minor and parotid salivary gland (SG) biopsies, has highlighted a high degree of cellular and molecular heterogeneity of the inflammatory lesions but also allowed the identification of clusters of patients with similar underlying SG immunopathology. In particular, patients presenting with high degrees of B/T cell infiltration and the formation of ectopic lymphoid structures (ELS) in the SG have been associated, albeit with conflicting results, with higher degree of disease severity and enhanced risk of lymphoma evolution, suggesting that a dysregulated adaptive immune response plays a key role in driving disease manifestations in pSS. Recent data from randomised clinical trials with novel biological therapies in pSS have also highlighted the potential role of SG immunopathology and molecular pathology in stratifying patients for trial inclusion as well as assessing proof of mechanisms in longitudinal SG biopsies before and after treatment. Although significant progress has been made in the understanding of disease pathogenesis and heterogeneity through cellular and molecular SG pathology, further work is needed to validate their clinical utility in routine clinical settings and in randomised clinical trials.
•TLS develop in target organs of autoimmune diseases, transplantation and cancer.•TLS can function as germinal centres supporting B-cell selection/differentiation.•TLS can be destructive or have ...beneficial effects at the site of inflammation/disease.•Therapeutic targeting of TLS results in beneficial effects in patients, though inhibition may lead to immune suppression while stimulation may lead to autoimmunity.
Tertiary lymphoid organs named also tertiary lymphoid structures (TLS) often occur at sites of autoimmune inflammation, organ transplantation and cancer. Although the mechanisms for their formation/function are not entirely understood, it is known that TLS can display features of active germinal centres supporting the proliferation and differentiation of (auto)-reactive B cells. In this Review, we discuss current knowledge on TLS-associated B cells with particular reference on how within diseased tissues these structures are linked to either deleterious or protective outcomes in patients and the potential for therapeutic targeting of TLS through novel drugs.
Rheumatoid arthritis is a chronic systemic inflammatory disease primarily affecting the synovium of diarthrodial joints. Despite the currently unknown etiology, overwhelming evidence indicates that ...both innate and adaptive immunity play a central role in disease pathogenesis. In this review, we consider recent evidence examining the mechanisms of lymphoid tissue reactivity in rheumatoid arthritis with a focus on the dynamics controlling secondary and ectopic lymphoid tissue response. We then examine the cellular and molecular mechanisms regulating the biopathology of these processes with specific emphasis on cell trafficking, contribution to autoimmunity, and joint damage‐repair. We finally provide a brief overview of the most recent studies addressing the clinical relevance of synovial lymphoid tissue analysis as a diagnostic and prognostic tool as well as its response to current biological therapies.
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