Academic literature on the topic 'Lymphocyte precursors, chronic inflammation, autoimmune diseases'

BackgroundThe pathogenesis of systemic lupus erythematosus and systemic sclerosis is characterized by derangements of the innate and adaptive immune systems, and inflammatory pathways leading to autoimmunity, chronic cytokine production, and chronic inflammation. Diagnosis is rooted in meeting established criteria. However, in pre-clinical states criteria is not fulfilled but biochemical and autoimmune derangements are present. Understanding the underlying processes responsible for disease pathogenesis in pre-clinical states, which place patients at increased risk for the development of established connective tissue diseases, presents a prognostic opportunity, and could enable timely treatment leading to limiting disease progression.ObjectivesWe aim to describe the role of the innate and adaptive immune system in the pre-clinical states of UCTD-risk-SSc and prescleroderma, the underlying immune dysregulation in these pre-clinical states, and the evolution of antibodies from nonspecific antinuclear antibodies to specific prior to SLE development.MethodsOur search strategy was developed alongside an experienced information specialist. We searched the databases EMBASE and MEDLINE with restrictions for the English language. Reference lists of all primary studies and review articles were searched for additional references. Studies reported in full-text and abstract formats were included.ResultsMultiple cytokines are observed to increase along a disease spectrum from UCTD-risk-SSc to classified SSc and include sICAM-1, CCL2, CXCL8, ang-2, CXCL16, e-selectin, and IL-13. The mechanism of action of these cytokines includes transmigration of lymphocytes endothelium, innate immune cell activation and signal propagation, and extracellular matrix deposition. The progressive nature of cytokine increase through a spectrum from pre-clinical to clinical emphasizes disease evolution and enables the discernment of patients who may warrant early intervention. Furthermore, there are disease markers which are observed to be predictive of established SSc and include sIL-2Rα, PIIINP, CXCL4, CXCL10, and CXCL11. Pre-clinical SLE is characterized by an evolving IFN signature and progressive SLE-specific antibody formation prior to disease classification.ConclusionThe coordinated dysregulation of the innate and adaptive immune systems, and inflammatory signalling pathways leads to the pathogenesis of connective tissue disease. Our improved understanding of these underlying aberrations in pre-clinical stages of disease will serve to better identify patients at increased risk.References[1]Valentini G, Pope JE. Undifferentiated connective tissue disease at risk for systemic sclerosis: Which patients might be labeled prescleroderma? Autoimmunity reviews. 2020 Nov;19(11):102659.[2]Lambers WM, Westra J, Bootsma H, de Leeuw K. From incomplete to complete systemic lupus erythematosus; A review of the predictive serological immune markers. Seminars in arthritis and rheumatism. 2021;51(1):43–8.Disclosure of InterestsNone declared

Dendritic cells (DCs) are the sentinels of the immune system able to recognize pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), promoting a bridge between the innate and adaptive immune systems. They form a heterogeneous group of cells with different development, phenotype and functions, and they are mainly classified in conventional DCs 1 (cDC1) and 2 (cDC2), plasmacytoid DCs (pDC) and inflammatory DCs. Changes in the development of DCs, in the ratio of the subsets or in the maturation and activation can impair immunity or tolerance, inducing susceptibility to infections, as well as the development of inflammatory and autoimmune diseases. Sickle cell disease (SCD), one of the most common hemoglobinophaties throughout the world, can be considered as a chronic inflammatory disease, with systemic release of TNF-α, IL-6, IL-1β and IL-8. Despite presenting more inflammation, SCD patients have dysfunction of lymphocytes T and B responses, and are more susceptible to infections. Although DCs are the main responsible for the activation and polarization of lymphocytes function and are able to produce the pro-inflammatory cytokines present in the serum of SCD patients, very little attention has been giving to these cells so far. In the present study, we characterized the subpopulations of circulating DCs in SCD patients. Our data of flow cytometry show that SCD patients (SS) have higher percentage (AA: 0.6±0.09, n=20; SS: 1.25±0.2 n=22; p<0.05) and total number/μl (AA: 10.92±1.9, n=17; SS: 27.9±5.2, n=22; p=0.01) of circulating DCs than healthy individuals (AA) as shown by gating on linage- (CD19/CD56/CD3/CD14) and HLA-DR+ cells. The development of these cells from the bone marrow is likely to be, at least in part, responsible for this raise, since the percentage (AA: 1.7±0.45, n=17; SS: 10.85±1.53, n=11; p=0.0001) and total number/μl (AA: 0.25±0.05, n=12; SS 1.52±0.31, n=16; p=0.0004) of the DCs precursors are increased in the blood of the patients. The ratio of the different subpopulations of DCs is also altered, with a decrease in the percentage of circulating cDC1 (linage-HLA-DR+CD141high) (AA: 2.6±0.2, n=16; SS: 2.0±0.3, n=18; p=0.02), whereas no change was seen on cDC2 (linage-HLA-DR+CD1c+) and pDCs (linage-HLA-DR+CD123+) (AA: n=18; SS: n=22). Isolated circulating monocytes from patients are able to differentiate in vitro in DCs with the expression of the characteristic markers CD1c and CD209, however, unlike healthy individuals, a great percentage of these cells also express CD14 (AA: 5.5±2.2, n=16; SS: 17.6±6.1, n=14; p=0.02), indicating the presence of inflammatory DCs. These cells are more mature and activated in steady state as shown by CD83 (p=0.007), CD86 (p=0.0001) and HLA-DR (p<0.0001) expression (n=14 pairs of CD14- and CD14+ DCs). Since SCD patients have higher number of circulating monocytes as shown by previous studies, it is possible that part of the raise in circulating DCs comes from the differentiation of inflammatory monocytes in vivo. Monocyte-derived DCs (mo-DCs) from patients are able to induce more proliferation of CD4+ and CD8+ T lymphocytes than mo-DCs from healthy individuals (AA: n=4; SS: n=4), and CD14+ DCs induce higher proliferation of T lymphocytes than CD14- DCs from the same patient (n=2 pairs of CD14- and CD14+ DCs). We have also seen that SCD patients have reduced percentage of regulatory T cells, as shown by Foxp3+ in the gate of CD3+CD4+ cells (AA: 4.0±0.26, n=17; SS: 3.1±0.3, n=17; p=0.01), and increased IL-17-producing CD4+ (AA: 1.1±0.08, n=18; SS: 1.7±0.18, n=17; p=0.05) and CD8+ (AA: 0.24±0.02; SS: 0.68±0.1, n=17; p=0.0001) T lymphocytes in the blood. Whether DCs are responsible for this skewing of T lymphocyte phenotype in SCD is still to be determined. Our data so far show that there are differences in circulating DC populations in SCD patients and they could explain the changes observed on T cell responses and the susceptibility to infections. The present data add new knowledge about the chronic inflammation in SCD, which is one of the major events in the pathophysiology of the disease. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 286 Background: The cell of origin of CLL is unknown. Researchers have proposed various B cell subsets as the normal counterparts based on surface marker similarities or Ig gene utilization comparisons of normal and CLL cells. Regulatory B lymphocytes (“B10” cells), with the capacity to produce IL-10, negatively regulate T cell, B cell, and mononuclear phagocyte function. CLL patients are immunosuppressed with abnormalities in both humoral and cellular immunity. B10 cells have a phenotype similar to CLL cells (CD24hiCD27+CD5+CD19+). B10 cells are increased in autoimmune mice and in humans with autoimmune diseases—situations in which these cells negatively regulate immune-mediated inflammation. Since CLL cells and B10 cells may share common phenotypes and immunosuppressive mechanisms, we sought to determine if mouse and human CLL cells share common cellular origins and regulatory properties. Methods: Mouse spleen, lymph node, and bone marrow cell, and human blood B lymphocyte and CLL cell preparation and culture; IL-10, TNF, IGHV determinations; and flow cytometry were done as we have reported before (Blood 109:1559, 2007; Blood 117:530–541, 2010; Immunity 28:639–650, 2008). After culture for 5 hours with LPS and PMA+ionomycin+brefeldin A (PIB), or CpG+PIB, we assessed for intracellular IL-10 by flow cytometry. We term these IL-10 producing cells “B10” cells. Alternately, cells were cultured 48 hours with CD40 ligand+LPS or CD40L+CpG, and then PIB was added during the last 5 hours, after which cells were assessed for intracellular IL-10. We term these IL-10 positive cells “B10+B10pro” cells. Results: We examined CLL cells from 54 CLL patients. Most had low-risk disease: 90% were either Rai stage 0 or stage 1, 89% were CD38 negative, 46% were Zap70 negative, and 70% had a mutated IGHV. Twenty percent had normal cytogenetics, 48% del13q, 20% trisomy 12, 4% del17p, 4% del11q, and 4% with complex abnormalites. Patients with CLL as compared to healthy controls had higher numbers of B10pro cells compared to those of normal controls (7.7±0.9% and 3.2±0.3%, respectively; p<0.0001). CLL cells had a CD24hiCD27+ memory B cell phenotype similar to normal human B10 cells, and CLL cells secreted IL-10 when treated in vitro with CpG or CD40L/CpG, as do normal human B10 cells. CLL cell TCL-1 protein levels (immunoblot) correlated directly with CLL B10pro percentages (p=0.001) and absolute numbers (p=0.01). CLL patients' plasma IL-10 levels were 1.5 fold higher than those of age-matched healthy controls (p=0.008), and these levels correlated directly with the absolute numbers of CLL cells that were competent to produce IL-10 after 48 hours stimulation with CD40L/CpG. To validate the precursor/product relationship between B10 cells and CLL, we studied the TCL-1 transgenic mouse model of CLL. TCL-1 transgenic mice had an age-dependent expansion of splenic CD5+B220int cells, and these leukemic cells were IL-10-competent. Likewise, aged TCL-1 mice had increased numbers of B10 cells in the bone marrow, lymph nodes, and peritoneal cavity. The TCL-1 CLL cells were similar in phenotype (IgM+CD11BhiCD23lowCD43hiCD19+) to mouse regulatory B10 cells (CD1dhiIgMhiIgDlowCD19hiCD23lowCD24hiCD43±) that we have previously reported. TCL-1 CLL cells produced IL-10 in vitro and in vivo, and depressed mouse macrophage TNF production. This TCL-1 CLL cell-mediated inhibition of mouse TNF production was blocked by anti-IL-10 antibody. Plasma IL-10 increased with age and with development of overt leukemia in TCL-1 mice. Summary: We demonstrate for the first time that human CLL cells and CLL-like cells from TCL-1 mice share a common origin with regulatory B10 and B10pro cells. Both CLL cells and B10 cells can produce the immuno-inhibitory cytokine IL-10 in vitro and in vivo, and they can suppress mononuclear phagocyte activation in vitro through IL-10-dependent pathways. The immunophenotype of CLL cells matches that of human B10, and B10pro cells. It is likely that IL-10 competent CLL cells derive directly from either regulatory B10pro or B10 cells. B10 cell-derived IL-10 may contribute to the immunosuppression noted in mice and humans with CLL. Future studies may lead to new and better treatments that take advantage of links between B10 cells, IL-10, and CLL. Disclosures: Lanasa: GlaxoSmithKline: Consultancy, Speakers Bureau. Tedder:Angelica: Consultancy, Share holder; Takeda Therapeutics: Consultancy.

Abstract The adaptive arm of the immune system facilitates recognition of specific foreign pathogens and, via the action of T and B lymphocytes, induces a fine-tuned response to target the pathogen and develop immunological memory. The functionality of the adaptive immune system exhibits daily 24-h variation both in homeostatic processes (such as lymphocyte trafficking and development of T lymphocyte subsets) and in responses to challenge. Here, we discuss how the circadian clock exerts influence over the function of the adaptive immune system, considering the roles of cell intrinsic clockwork machinery and cell extrinsic rhythmic signals. Inappropriate or misguided actions of the adaptive immune system can lead to development of autoimmune diseases such as rheumatoid arthritis, ulcerative colitis and multiple sclerosis. Growing evidence indicates that disturbance of the circadian clock has negative impact on development and progression of these chronic inflammatory diseases and we examine current understanding of clock-immune interactions in the setting of these inflammatory conditions. A greater appreciation of circadian control of adaptive immunity will facilitate further understanding of mechanisms driving daily variation in disease states and drive improvements in the diagnosis and treatment of chronic inflammatory diseases.

Autoimmune thyroid diseases include several distinct clinical entities and mainly concern Graves` disease and Hashimoto's thyroiditis. An incompetent immune response directed against the body’s own tissues and the production of antibodies against specific cell antigens, accompanied by chronic inflammation occur in autoimmune thyroid diseases. The autoimmune process is induced by difficult to identify genetic and environmental factors, and generates the development of concomitant diseases of other systems. The inflammatory mediators, high level of thyroid hormones, lymphocyte activation and other immune cells play an important role in the chronic course of these diseases. Autoimmune thyroid diseases are caused by disruptions of T-cells and other cells functions. The autoantibodies react with target antigens in different kinds of cells, including blood platelets. The autoimmune processes can cause the increased activity different kinds of cells including blood platelets and lymphocytes. The activity of blood platelets and lymphocytes is reciprocally regulated. It is suggested that blood platelets can influence lymphocyte function by direct contact through the receptors and via soluble mediators. The platelet–immune cell interactions represent a hallmark of immunity, as they can potently enhance immune cell functions.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome is a rare inflammatory disease of an undetermined aetiology. The condition is characterised by a range of clinical manifestations generally associated with damage to brainstem structures, the cerebellum, with characteristic magnetic resonance imaging (MRI) findings. The main feature is a good clinical and radiological response to glucocorticosteroid (GCS)-based immunosuppressive treatment. The diagnosis of CLIPPERS is difficult and requires extensive differential diagnosis. A specific biomarker in serum or cerebrospinal fluid (CSF) for this disorder is currently unknown. The pathogenesis of CLIPPERS remains poorly understood and its nosological position has not yet been established. Whether CLIPPERS represents an independent, genuine new disorder or a syndrome in the course of diseases with heterogeneous aetiology and/or their precursor stages remains debatable and incompletely clarified. We present a case report of a patient who was diagnosed with CLIPPERS syndrome on the basis of her clinical and radiological features and by performing an extensive differential diagnosis. The patient has been under neurological follow-up for five years.