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Objective: The aim of this study was to assess whether circulating histone‐specific T cells represent tools for precision medicine in systemic lupus erythematosus (SLE). Methods: Seroprevalence of autoantibodies and HLA‐DR beta (DRB) 1 profile were assessed among 185 patients with SLE and combined with bioinformatics and literature evidence to identify HLA–peptide autoepitope couples for ex vivo detection of antigen‐specific T cells through flow cytometry. T cell differentiation and polarization was investigated in patients with SLE, patients with Takayasu arteritis, and healthy controls carrying HLA‐DRB1*03:01 and/or HLA‐DRB1*11:01. SLE Disease Activity Index 2000 and Lupus Low Disease Activity State were used to estimate disease activity and remission. Results: Histone‐specific CD4+ T cells were selectively detected in patients with SLE. Among patients with a history of anti‐DNA antibodies, 77% had detectable histone‐specific T cells, whereas 50% had lymphocytes releasing cytokines or upregulating activation markers after in vitro challenge with histone peptide antigens. Histone‐specific regulatory and effector T helper (Th) 1‐, Th2‐, and atypical Th1/Th17 (Th1*)‐polarized cells were significantly more abundant in patients with SLE with quiescent disease. In contrast, total Th1‐, Th2‐, and Th1*‐polarized and regulatory T cells were similarly represented between patients and controls or patients with SLE with active versus quiescent disease. Histone‐specific effector memory T cells accumulated in the blood of patients with quiescent SLE, whereas total effector memory T cell counts did not change. Immunosuppressants were associated with expanded CD4+ histone‐specific naive T (TN) and terminally differentiated T cells. Conclusion: Histone‐specific T cells are selectively detected in patients with SLE, and their concentration in the blood varies with disease activity, suggesting that they represent innovative tools for patient stratification and therapy. [ABSTRACT FROM AUTHOR]

Objective: It is unclear why activated platelets and platelet‐derived microparticles (MPs) accumulate in the blood of patients with systemic sclerosis (SSc). This study was undertaken to investigate whether defective phagocytosis might contribute to MP accumulation in the blood of patients with SSc. Methods: Blood samples were obtained from a total of 81 subjects, including 25 patients with SSc and 26 patients with stable coronary artery disease (CAD). Thirty sex‐ and age‐matched healthy volunteers served as controls. Studies were also conducted in NSG mice, in which the tail vein of the mice was injected with MPs, and samples of the lung parenchyma were obtained for analysis of the pulmonary microvasculature. Tissue samples from human subjects and from mice were assessed by flow cytometry and immunochemical analyses for determination of platelet–neutrophil interactions, phagocytosis, levels and distribution of P‐selectin, P‐selectin glycoprotein ligand 1 (PSGL‐1), and HMGB1 on platelets and MPs, and concentration of byproducts of neutrophil extracellular trap (NET) generation/catabolism. Results: Activated P‐selectin+ platelets and platelet‐derived HMGB1+ MPs accumulated in the blood of SSc patients but not in the blood of healthy controls. Patients with CAD, a vasculopathy independent of systemic inflammation, had fewer P‐selectin+ platelets and a negligible number of MPs. The expression of the receptor for P‐selectin, PSGL‐1, in neutrophils from SSc patients was significantly decreased, raising the possibility that phagocytes in SSc do not recognize activated platelets, leading to a failure of phagocytosis and continued neutrophil release of MPs. As evidence of this process, activated platelets were not detected in the neutrophils from SSc patients, whereas they were consistently present in the neutrophils from patients with CAD. HMGB1+ MPs elicited generation of NETs, which were only detected in the plasma of SSc patients. In mice, P‐selectin–PSGL‐1 interaction resulted in platelet phagocytosis in vitro and influenced the ability of MPs to elicit NETs, endothelial activation, and migration of leukocytes through the pulmonary microvasculature. Conclusion: The clearance of activated platelets via PSGL‐1 limits the undesirable effects of MP‐elicited neutrophil activation. This balance is disrupted in patients with SSc. Its reconstitution might curb vascular inflammation and prevent fibrosis. [ABSTRACT FROM AUTHOR]

Objective: Memory stem T (Tscm) cells are long‐lived, self‐renewing T cells that play a relevant role in immunologic memory. This study was undertaken to investigate whether Tscm cells accumulate in rheumatoid arthritis (RA). Methods: The polarization and differentiation profiles of circulating T cells were assessed by flow cytometry. Antigen‐specific T cells were characterized by staining with major histocompatibility complex class II tetramers. The T cell receptor (TCR) repertoire was analyzed by high‐throughput sequencing using an unbiased RNA‐based approach in CD4+ T cell subpopulations sorted by fluorescence‐activated cell sorting. Results: We analyzed the dynamics of circulating Tscm cells (identified as CD45RA+CD62L+CD95+ T cells) by flow cytometry in 27 RA patients, 16 of whom were also studied during treatment with the anti–tumor necrosis factor (anti‐TNF) agent etanercept. Age‐matched healthy donors were used as controls. CD4+ Tscm cells were selectively and significantly expanded in RA patients in terms of frequency and absolute numbers, and significantly contracted upon anti‐TNF treatment. Expanded CD4+ Tscm cells displayed a prevalent Th17 phenotype and a skewed TCR repertoire in RA patients, with the 10 most abundant clones representing up to 53.7% of the detected sequences. CD4+ lymphocytes specific for a citrullinated vimentin (Cit‐vimentin) epitope were expanded in RA patients with active disease. Tscm cells accounted for a large fraction of Cit‐vimentin–specific CD4+ cells. Conclusion: Our results indicate that Tscm cells, including expanded clones specific for relevant autoantigens, accumulate in RA patients not exposed to biologic agents, and might be involved in the natural history of the disease. Further analysis of Tscm cell dynamics in autoimmune disorders may have implications for the design and efficacy assessment of innovative therapies. [ABSTRACT FROM AUTHOR]

Objective: To prospectively assess the performance of the systemic lupus erythematosus (SLE) responder index (SRI) and the lupus low disease activity state (LLDAS) in a cohort‐based, "real‐life" clinical setting. Methods: One hundred and thirty‐one consecutive patients with SLE were subdivided into two groups based on the need or not to escalate their immune suppressive treatment. Clinimetrics including physician global assessment scale (PGA), SLE Disease Activity Index 2000 (SLEDAI‐2K), European Consensus Lupus Activity Measurement index (ECLAM) and British Isles Lupus Assessment Group index (BILAG) 2004 version were measured at baseline and at 6 and 12 months, together with laboratory data and treatment changes. LLDAS and SRI were calculated at each time point. Results: Lupus low disease activity state but not SRI‐4 correlated with treatment de‐escalation. Low disease activity attainment as estimated by LLDAS was more frequent in patients starting with lower SLEDAI‐2K, whereas a decrease in SLEDAI score ≥ 4 points with < 0.3 increased PGA and no new grade A or more than one new grade B BILAG domains (SRI‐4) was more frequent in patients with higher SLEDAI‐2K and/or severe renal activity at baseline. Anti‐DNA‐positive patients were less likely to be in LLDAS at any time point. Serositis was associated with lack of LLDAS at baseline, but did not affect LLDAS achievement at 12 months. Normalizing complement levels heralded the achievement of LLDAS and SRI‐4. Conclusion: Lupus low disease activity state is a valuable tool for assessing response to treatment in the daily rheumatology practice. SRI might be less informative, at least in patients with low basal SLEDAI. [ABSTRACT FROM AUTHOR]

Objective: Toll‐like receptor 7 (TLR‐7), TLR‐8, and interferon (IFN)–induced genes are expressed in patients with idiopathic inflammatory myositis. This study was undertaken to investigate whether their activation influences the natural history of the disease. Methods: Experimental autoimmune myositis was induced in mice by injection of the amino‐terminal portion of the murine histidyl–transfer RNA synthetase (HisRS). Disease was compared in the presence or the absence of the TLR‐7/8 agonist R‐848 in wild‐type mice and in mice that fail to express the IFNα/β receptor (IFNα/βR‐null mice). Results: Experimental autoimmune myositis induced by a single intramuscular immunization with HisRS spontaneously abated after 7–8 weeks. In contrast, levels of anti‐HisRS autoantibodies, endomysial/perimysial leukocyte infiltration, and myofiber regeneration persisted at the end of the follow‐up period (22 weeks after immunization) in mice immunized with HisRS in the presence of R‐848. Myofiber major histocompatibility complex (MHC) class I molecules were detectable only in mice immunized with both HisRS and R‐848. MHC up‐regulation occurred early and in muscles that were not directly injected with HisRS. Muscle MHC expression paralleled with leukocyte infiltration. MHC class I molecules were selectively up‐regulated in myotubes challenged with R‐848 in vitro. Type I IFN was necessary for the prolonged autoantibody response and for the spreading of the autoimmune response, as demonstrated using IFNα/βR‐null mice. Muscle infiltration was maintained in the injected muscle up to the end of the follow‐up period. Conclusion: TLR‐7/8 activation is necessary to induce and maintain a systemic autoimmune response targeting the skeletal muscle. This experimental autoimmune myositis model reproduces many characteristics of human idiopathic inflammatory myopathies and may represent a tool for preclinical studies. [ABSTRACT FROM AUTHOR]

Objective: An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7–positive (SLAMF7+) cytotoxic effector memory T (TEM) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4‐related disease (IgG4‐RD). Glucocorticoids represent the first‐line therapeutic approach in patients with IgG4‐RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+ CTLs in IgG4‐RD. Methods: Expression of CD8α, granzyme A, perforin, and SLAMF7 within the effector memory compartment of CD45RO+ (TEM) and CD45RA+ effector memory T (TEMRA) CD4+ cells was quantified by flow cytometry in 18 patients with active IgG4‐RD, both at baseline and after 6 months of glucocorticoid treatment. Eighteen healthy subjects were studied as controls. Next‐generation sequencing of the T cell receptor α‐ and β‐chain gene was performed on circulating CD4+ CTLs from patients with IgG4‐RD before and after treatment and in affected tissues. Results: Circulating CD4+ TEM and TEMRA cells were not expanded in IgG4‐RD patients compared to healthy controls. CD4+SLAMF7+ TEM cells (but not TEMRA cells) were significantly increased among IgG4‐RD patients. Within CD4+SLAMF7+ TEM cells, CD8α− cells but not CD8αlow cells were elevated in IgG4‐RD patients. The same dominant clones of CD8α−CD4+SLAMF7+ TEM cells found in peripheral blood were also identified in affected tissue. CD8α− and CD8αlowCD4+SLAMF7+ TEM cells both expressed cytolytic molecules. Clonally expanded CD8α− but not CD8αlowCD4+SLAMF7+ TEM cells decreased following glucocorticoid‐induced disease remission. Conclusion: A subset of CD8α−CD4+SLAMF7+ cytotoxic TEM cells is oligoclonally expanded in patients with active IgG4‐RD. This TEM cell population contracts following glucocorticoid‐induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Tissue damage frequently occurs. The immune system senses it and enforces homeostatic responses that lead to regeneration and repair. The synthesis of acute phase molecules is emerging as a crucial event in this program. The prototypic long pentraxin PTX3 orchestrates the recruitment of leukocytes, stabilizes the provisional matrix in order to facilitate leukocyte and stem progenitor cells trafficking, promotes swift and safe clearance of dying cells and of autoantigens, limiting autoimmunity and protecting the vasculature. These non-redundant actions of PTX3 are necessary for the resolution of inflammation. Recent studies have highlighted the mechanisms by which PTX3 adapts the functions of innate immune cells, orchestrates tissue repair and contributes to select the appropriate acquired immune response in various tissues. Conversely, PTX3 continues to be produced in diseases where the inflammatory response does not resolve. It is therefore a valuable biomarker for more precise and personalized stratification of patients, often independently predicting clinical evolution and outcome. There is strong promise for novel therapies based on understanding the mechanisms with which PTX3 plays its homeostatic role, especially in regulating leukocyte migration and the resolution of inflammatory processes. [ABSTRACT FROM AUTHOR]

A single protein, HMGB1, directs the triggering of inflammation, innate and adaptive immune responses, and tissue healing after damage. HMGB1 is the best characterized damage-associated molecular pattern ( DAMP), proteins that are normally inside the cell but are released after cell death, and allow the immune system to distinguish between antigens that are dangerous or not. Notably, cells undergoing severe stress actively secrete HMGB1 via a dedicated secretion pathway: HMGB1 is relocated from the nucleus to the cytoplasm and then to secretory lysosomes or directly to the extracellular space. Extracellular HMGB1 (either released or secreted) triggers inflammation and adaptive immunological responses by switching among multiple oxidation states, which direct the mutually exclusive choices of different binding partners and receptors. Immune cells are first recruited to the damaged tissue and then activated; thereafter, HMGB1 supports tissue repair and healing, by coordinating the switch of macrophages to a tissue-healing phenotype, activation and proliferation of stem cells, and neoangiogenesis. Inevitably, HMGB1 also orchestrates the support of stressed but illegitimate tissues: tumors. Concomitantly, HMGB1 enhances the immunogenicity of mutated proteins in the tumor (neoantigens), promoting anti-tumor responses and immunological memory. Tweaking the activities of HMGB1 in inflammation, immune responses and tissue repair could bring large rewards in the therapy of multiple medical conditions, including cancer. [ABSTRACT FROM AUTHOR]

The peritoneum defines a confined microenvironment, which is stable under normal conditions, but is exposed to the damaging effect of infections, surgical injuries, and other neoplastic and non-neoplastic events. Its response to damage includes the recruitment, proliferation, and activation of a variety of haematopoietic and stromal cells. In physiological conditions, effective responses to injuries are organized; inflammatory triggers are eliminated; inflammation quickly abates; and the normal tissue architecture is restored. However, if inflammatory triggers are not cleared, fibrosis or scarring occurs and impaired tissue function ultimately leads to organ failure. Autoimmune serositis is characterized by the persistence of self-antigens and a relapsing clinical pattern. Peritoneal carcinomatosis and endometriosis are characterized by the persistence of cancer cells or ectopic endometrial cells in the peritoneal cavity. Some of the molecular signals orchestrating the recruitment of inflammatory cells in the peritoneum have been identified in the last few years. Alternative activation of peritoneal macrophages was shown to guide angiogenesis and fibrosis, and could represent a novel target for molecular intervention. This review summarizes current knowledge of the alterations to the immune response in the peritoneal environment, highlighting the ambiguous role played by persistently activated reparative macrophages in the pathogenesis of common human diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Signals released by leukocytes contribute to tumor growth and influence the efficacy of antineoplastic treatments. The outcome of peritoneal carcinomatosis treatments is unsatisfactory, possibly because chemotherapy activates events that have in the long-term deleterious effects. In this study we offer evidence that 5-fluorouracile (5-FU), besides provoking apoptosis of MC38 colon carcinoma cells, induces a striking attraction of leukocytes both in an orthotopic model of colon carcinomatosis in vivo and in monocyte-migration assays in vitro. Leukocyte attraction depends on the presence of High Mobility Group Box 1 (HMGB1), an endogenous immune adjuvant and chemoattractant released by dying cells. Leukocyte recruitment is prevented in vivo and in vitro using blocking antibodies against HMGB1 and its competitive antagonist BoxA or by interfering with HMGB1 expression. Autophagy is required for leukocyte chemoattraction, since the latter abates upon pharmacological blockade of the autophagic flux while activation of autophagy per se, in the absence of death of colon carcinoma cells, is not sufficient to attract leukocytes. Our results identify autophagy induction and HMGB1 release in colon carcinoma cells as key events responsible for 5-FU elicited leukocyte attraction and define a novel rate-limiting target for combinatorial therapies. [ABSTRACT FROM AUTHOR]

Objective Muscle regeneration is a hallmark of the idiopathic inflammatory myopathies (IIMs), a group of autoimmune disorders that are characterized by leukocyte infiltration and dysfunction of the skeletal muscle. Despite detailed studies describing the clinical and histopathologic features of IIMs, the immunopathogenesis of these disorders remains undefined. The aim of this study was to investigate the immunopathologic processes of autoimmune myositis in experimental murine models. Methods Expression of the autoantigen histidyl-transfer RNA synthetase (HisRS) was analyzed in mice with acutely injured or dystrophic muscles, in inflammatory leukocytes, and in purified satellite cells. Anti-HisRS antibodies and myositis induction were assessed in mice after muscle injury and immunization with apoptotic satellite cells or C2C12 myoblasts, in the presence or absence of the Toll-like receptor 7 (TLR-7) agonist R848. Results Muscle necrosis, leukocyte infiltration, and myofiber regeneration induced by toxic agents (cardiotoxin or glycerol) or promoted by genetic disruption of the α-sarcoglycan/dystrophin complex in mice were uniformly associated with up-regulated expression of HisRS. Although regenerating myofibers and purified satellite cells are known to show increased expression of HisRS in these settings, anti-HisRS antibodies were not detectable. However, intramuscular immunization with ultraviolet B-irradiated, HisRS-expressing apoptotic myoblasts in the presence of R848 triggered the production of anti-HisRS IgG antibodies as well as persistent lymphocyte infiltration and prolonged/delayed muscle regeneration. Conversely, intramuscular administration of R848 alone or in combination with living or postapoptotic/necrotic myoblasts failed to generate this myositis phenotype. Conclusion In the presence of TLR/adjuvant signals and underlying muscle injury, apoptotic myogenic precursors expressing high levels of autoantigen can provoke autoantibody formation and lymphocytic infiltration of muscle tissue, effectively replicating the features of IIM. [ABSTRACT FROM AUTHOR]

Objective To assess local expression and plasma levels of pentraxin 3 (PTX3) in patients with giant cell arteritis (GCA). Methods Plasma and serum samples were obtained from 75 patients with GCA (20 of whom had experienced optic nerve ischemia in the previous 3 weeks and 24 of whom had experienced symptom onset in the previous 6 months and had no history of optic nerve ischemia) and 63 controls (35 age-matched healthy subjects, 15 patients with rheumatoid arthritis, and 13 patients with chronic stable angina). In 9 patients in whom GCA was recently diagnosed, circulating levels of interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12p70, CCL2/monocyte chemotactic protein 1, CCL3/macrophage inflammatory protein 1α (MIP-1α), CCL4/MIP-1β, CCL11/eotaxin, CXCL9/monokine induced by interferon-γ, CXCL10/interferon-γ-inducible 10-kd protein, tumor necrosis factor α (TNFα), interferon-γ, vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor, and FasL were measured via a multiplexed cytometric assay. PTX3 and VEGF concentrations were assessed by enzyme-linked immunosorbent assay. PTX3 and CD68 expression were determined by immunohistochemistry and immunofluorescence on temporal artery samples. Results GCA patients with very recent optic nerve ischemia had significantly higher PTX3 and VEGF levels compared to other GCA patients and controls. GCA patients with a disease duration of <6 months had significantly higher PTX3 levels compared to other GCA patients and controls. Immunohistochemistry revealed selective PTX3 expression in the wall of inflamed arteries. Conclusion Our findings indicate that local expression of PTX3 is a feature of vascular inflammation in GCA; elevated circulating levels of PTX3 identify patients with very recent optic nerve ischemia or a recent diagnosis. Optic nerve ischemia is also associated with increased circulating VEGF levels. [ABSTRACT FROM AUTHOR]

High-mobility group box-1 (HMGB1) is a prototypical endogenous signal that links tissue necrosis and wound healing. Extracellular HMGB1 has apparently contrasting biological actions: it sustains inflammation (with the possible establishment of autoimmunity or of self-maintaining tissue damage) while activating and recruiting stem cells, which foster tissue repair. However, little is known about the role environmental cues play in the extracellular functions of HMGB1. The skeletal muscle is an optimal tissue model to help us unravel these underlying molecular events. Here, sterile injury triggers a potent inflammatory response that includes infiltration by inflammatory leukocytes and the parallel activation, proliferation, and fusion of muscle-specific stem cells. Recent data suggest that the regulation of environmental redox is critical for the bioactivity of HMGB1, which is extremely sensitive to oxidation. Moreover, data suggest a potential role for infiltrating alternatively activated macrophages to influence the outcome of inflammatory responses to sterile skeletal muscle necrosis. [ABSTRACT FROM AUTHOR]

Tissue damage occurs often in the life of mammals and is usually repaired. Dying cells are swiftly phagocytosed, but before disappearing, they alert surrounding cells to activate homeostatic programs. They release signals that recruit inflammatory cells to the site of injury, promote cell migration and cell division to replace dead cells, and activate the immune system in anticipation of microbial invasion. Many of these events involve high-mobility group box 1 protein (HMGB1), a nuclear protein that is released passively when necrotic cells lose the integrity of their membranes. HMGB1 behaves as a trigger of inflammation, attracting inflammatory cells, and of tissue repair, recruiting stem cells and promoting their proliferation. Moreover, HMGB1 activates dendritic cells (DCs) and promotes their functional maturation and their response to lymph node chemokines. Activated leukocytes actively secrete HMGB1 in the microenvironment. Thus, HMGB1 acts in an autocrine/paracrine fashion and sustains long-term repair and defense programs. DCs secrete HMGB1 several hours after contact with the first maturation stimulus; HMGB1 secretion is critical for their ability to reach the lymph nodes, to sustain the proliferation of antigen-specific T cells, to prevent their activation-dependent apoptosis, and to promote their polarization towards a T-helper 1 phenotype. These immune responses will also be directed against self-antigens that DCs process at the time of injury and can lead to autoimmunity. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) and natural killer (NK) cells are key players at the interface between innate resistance and acquired immunity. NK cells can induce DC maturation, a differentiation process whereby DCs respond to a environmental stimulus and acquire the ability of eliciting adaptive immunity. Conversely, maturing DCs promote NK functions in vivo and in vitro. This interplay has important consequences on the immune response to pathogens and possibly to neoplastic cells. Here, we show that B16 melanoma cells actively modulate the interaction between DCs derived from bone marrow precursors and NK/LAK cells propagated from the spleen of C57BL/6 mice. DCs increased in a dose-dependent manner the ability of NK/LAK cells to kill melanoma cells and to produce cytokines. This activatory cross-talk entailed the production of IL-18 by DCs and of IFN-γ by NK/LAK cells. Melanoma cells were not a passive target of NK activity; they regulated the outcome of the interaction between DCs and NK/LAK cells, inhibiting the in vitro production of cytokines as effectively as the genetic deletion of IL-18 or IFN-γ. Interference with the NK/DC interaction possibly represents a mechanism used by growing tumors to evade the immune response. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α (TNFα) is a main actor in the pathogenesis of rheumatoid arthritis (RA), interacting with other molecules in complex mechanisms. The neuroendocrine system is known to be involved and Chromogranin A (CHGA) serum levels are elevated in patients with RA. We evaluated the effect of the selective blockade of TNF-α, induced by treatment with anti-TNF-α monoclonal antibodies (mAbs), on the serum levels of CHGA and on its correlation with TNF-α and TNF-α receptors (TNFRs) serum levels. Seven patients with RA have been treated with the anti-TNF-α mAb, infliximab. We measured the serum levels of TNF-α, its receptors (tumor necrosis factor receptor-I [TNFR-I] and tumor necrosis factor receptor-II [TNFR-II]), and CHGA before and during the treatment. We also measured, as a control, the serum levels of CHGA, TNF-α, and soluble TNFRs in 14 patients who were being treated with infliximab, adalimumab, or etanercept and in 20 matching negative controls. The serum levels of TNFR-I and TNFR-II, which are a sensitive marker for the TNF-α pathway, correlated with those of CHGA before treatment (Pearson's coefficient, respectively, 0.59 and 0.53). Treatment with anti-TNF-α mAb provided a significant clinical response in all patients and the correlation between CHGA and TNFR-I and TNFR-II was no more evident during treatment (respectively, −0.09 and −0.07). TNF-α blockade allows a clinical effect in patients with RA and modifies the correlation between CHGA and TNFRs, suggesting that TNF-α and CHGA reciprocally interfere in the pathogenesis of RA, through intermediate adaptors, whose identification warrants further studies. [ABSTRACT FROM AUTHOR]

A correction to the article "Selective up-regulation of the soluble pattern-recognition receptor pentraxin 3 and of vascular endothelial growth factor in giant cell arteritis: Relevance for recent optic nerve ischemia," by Baldini and colleagues in March 2012 issue, is presented.

BACKGROUND#ENTITYSTARTX02014;: Adaptive T-cell response is promoted during atherogenesis and results in the differentiation of naïve CD4(+)T cells to effector and/or memory cells of specialized T-cell subsets. Aim of this work was to investigate the relationship between circulating CD4(+)T-cell subsets and atherosclerosis. METHODS AND RESULTS#ENTITYSTARTX02014;: We analyzed 57 subsets of circulating CD4(+)T cells by 10-parameter/8-color polychromatic flow cytometry (markers: CD3/CD4/CD45RO/CD45RA/CCR7/CCR5/CXCR3/HLA-DR) in peripheral blood from 313 subjects derived from 2 independent cohorts. In the first cohort of subjects from a free-living population (n=183), effector memory T cells (T(EM): CD3(+)CD4(+)CD45RA(-)CD45RO(+)CCR7(-) cells) were strongly related with intima-media thickness of the common carotid artery, even after adjustment for age (r=0.27; P<0.001). Of note, a significant correlation between T(EM) and low-density lipoproteins was observed. In the second cohort (n=130), T(EM) levels were significantly increased in patients with chronic stable angina or acute myocardial infarction compared with controls. HLA-DR(+)T(EM) were the T(EM) subpopulation with the strongest association with the atherosclerotic process (r=0.37; P<0.01). Finally, in animal models of atherosclerosis, T(EM) (identified as CD4(+)CD44(+)CD62L(-)) were significantly increased in low-density lipoprotein receptor and apolipoprotein E deficient mice compared with controls and were correlated with the extent of atherosclerotic lesions in the aortic root (r=0.56; P<0.01). CONCLUSIONS#ENTITYSTARTX02014;: Circulating T(EM) cells are associated with increased atherosclerosis and coronary artery disease in humans and in animal models and could represent a key CD4(+)T-cell subset related to the atherosclerotic process. (J Am Heart Assoc. 2012;1:27-41.).

Objective: Phagocytosis of apoptotic cells can be facilitated by complement components and short pentraxins, such as serum amyloid P (SAP). In contrast, the long pentraxin PTX3 was shown to inhibit phagocytosis of apoptotic Jurkat cells by dendritic cells and to bind late apoptotic polymorphonuclear leukocytes (PMNs). Recently, levels of the pentraxin PTX3 were shown to parallel disease activity in small-vessel vasculitis, which is often characterized by leukocytoclasia, a persistence of leukocyte remnants in the vessel wall. We undertook this study to test our hypothesis that PTX3 inhibits phagocytosis of late apoptotic PMNs by macrophages, thereby leading to their accumulation in the vessel wall., Methods: Macrophages were allowed to phagocytose late apoptotic or secondary necrotic PMNs that were incubated with or without PTX3 for 30 minutes prior to phagocytosis. Phagocytosis was allowed to occur in the presence of 30% normal human serum with or without SAP and with or without depletion of complement. To discriminate between an inhibitory effect of PTX3 on binding and the internalization of apoptotic PMNs into macrophages, internalization was blocked by cytochalasin B., Results: SAP and complement were both necessary for effective in vitro phagocytosis. In contrast, PTX3 inhibited phagocytosis in a dose-dependent manner, from 11% inhibition at 6.25 microg/ml to almost complete inhibition at 100 microg/ml. Furthermore, PTX3 partly affected binding of apoptotic PMNs to macrophages., Conclusion: PTX3, in contrast to SAP and complement, inhibits phagocytosis of late apoptotic PMNs by monocyte-derived macrophages in a dose-dependent manner. Therefore, PTX3 can play a role in the development of leukocytoclasia by affecting the clearance of apoptotic PMNs, thereby inducing their accumulation in the vessel wall.

Objective: Cells commonly die without eliciting autoimmunity. However, dying cells are a potential initiating stimulus for systemic lupus erythematosus (SLE). Our goal was to verify whether immune adjuvants influence the autoimmunity induction that ensues following in vivo injection of dying cells., Methods: Mice were immunized with apoptotic thymocytes in the presence of artificial moieties, such as Freund's incomplete adjuvant (IFA), or natural adjuvants, such as dendritic cells (DCs). Renal involvement and the development of autoantibodies were monitored., Results: Apoptotic cells failed to induce clinical disease or to sustain production of autoantibodies in (NZB x NZW)F(1) mice. In contrast, autoimmunity developed in the presence of IFA or DCs. The characteristics of the adjuvant influenced the array of autoantibodies, the kinetics of their development, and the severity of the disease. DCs were required for induction of anti-beta(2)-glycoprotein I IgG. Adjuvants alone did not elicit disease., Conclusion: A "two-hit" signal composed of autoantigens and adjuvants initiates systemic autoimmunity. Moreover, environmental signals at the site of clearance of dead cells shape the features and the severity of the autoimmune disease. Strategies aimed at preventing the accumulation of dying cells and at modulating endogenous adjuvants may be beneficial for the treatment of SLE.