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The objective of this retrospective cohort study was to assess the relationship between Corona Disease 2019 (COVID-19) and Secukinumab treatment in patients with Spondylarthritis (SpA) in China during the omicron surge. Researchers retrieved 1018 medical records of Secukinumab-treated patients between January 2020 and January 2023 from the West China Hospital of Sichuan University. Out of these, 190 SpA patients from the rheumatology clinic were selected for the study. Guided phone questionnaires were administered by research staff to collect baseline characteristics, SpA disease status, and COVID-19 clinical outcomes. Cohabitants served as the control group and provided COVID-19 related data. Of the 190 potential SpA patients, 122 (66%) completed the questionnaire via phone, along with 259 cohabitants. 84.4% of SpA patients were diagnosed with Ankylosing Spondylitis (AS), and 15.6% were diagnosed with Psoriatic Arthritis (PsA). The rate of SARS-CoV-2 infection was 83.6% in the Secukinumab group and 88.8% in the cohabitants control group, with no significant difference (OR = 0.684, CI 0.366–1.275). One instance of severe COVID-19 was observed in the Secukinumab group, while two were identified in the cohabitants control group. Patients in the Secukinumab group had less time with fever caused by COVID-19 (p = 0.004). Discontinuing Secukinumab after SARS-CoV-2 infection did not significantly affect the course of COVID-19 or worsen SpA status according to our data. Our study suggests that administering Secukinumab to SpA patients does not increase their susceptibility to contracting SARS-CoV-2, and may have a positive effect on the course of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Anti-citrullinated protein autoantibodies (ACPA) precede the onset of clinical and subclinical rheumatoid arthritis (RA). ACPA are frequently generated in further chronic inflammatory diseases, e.g. chronic obstructive pulmonary disease, lupus, periodontitis (PD), characterized by citrullination and mucosal as well as systemic autoimmunity against citrullinated proteins. PD is of particular interest, as it exhibits two sources of citrullination, namely peptidylarginine deiminase 4 (PAD4) of periodontal neutrophils and neutrophil extracellular traps (NETs) as well as the PAD of Porphyromonas gingivalis (PPAD). Whereas the PAD4-citrullinated host peptides and/or proteins occur physiologically, PPAD-citrullinated ones appear under pathological conditions as neo-antigens. Frequently, the oral pathogens P. gingivalis and A. actinomycetemcomitans directly and indirectly participate in synovitis in RA, providing topical citrullination: P. gingivalis via PPAD and A. actinomycetemcomitans via leukotoxin A-mediated ROS-independent NET formation. In addition, transient bacteraemia due to tooth brushing indicates the possibility that citrullinated peptides and/or proteins from periodontium regularly enter the blood circulation. In this way, the mucosal firewall is evaded and the systemic immune response against citrullinated peptides and/or proteins is facilitated. However, the role of swallowed PD-derived sludge for the induction of oral tolerance remains to be established. We hypothesize (I) PD-driven endotoxemia may increase the host responsiveness to autoantigens via TLR4 activation and (II) this participates in development and propagation of RA (III) circulating PD-derived bacterial DNA is taken up by phagocytes, activates TLR9, and thus increases the responsiveness to autoantigens. [ABSTRACT FROM AUTHOR]

Rheumatic diseases are a group of inflammatory conditions that affect joints and connective tissues and are often accompanied by pain and restriction of motility. In many of these diseases, autoantibodies develop that react with molecules/structures commonly found hidden in neutrophils. Neutrophil extracellular trap (NET) formation and release is considered a defense mechanism against pathogens or endogenous danger signals and it has been associated with initial inflammatory responses. NETs are also endowed with an important resolution potential based on its intrinsic enzymatic activity, but in the case they are not timely removed from the crime scene they might modulate subsequent immune responses and contribute to the pathogenesis of chronic inflammatory diseases. In this review, we will summarize the actual knowledge about the multifaceted roles of NETs in the etiology and pathogenesis of rheumatic autoimmune diseases. [ABSTRACT FROM AUTHOR]

Overwhelming apoptosis combined with a deficiency in clearing apoptotic cells is thought to be an important etiopathogenic event in the autoimmune disease systemic lupus erythematosus (SLE). Lazy macrophages, complement or DNase I deficiency as well as insufficient natural IgM might be important factors leading to such a clearance deficiency. A defective clearance of apoptotic cells leads to the activation and maturation of plasmacytoid and myeloid dendritic cells (DCs) by material derived from secondary necrotic cells carrying modified autoantigens. This results in the presentation of autoantigens to autoreactive T and B cells in an immunogenic manner, thereby leading to autoantibody production, chronic inflammation and severe tissue damage. Since DC activation and IFN-α production by plasmacytoid dendritic cells play a critical role in the course of SLE pathogenesis, therapeutic intervention to end this vicious cycle might be a promising approach for treating the disease. [ABSTRACT FROM AUTHOR]

The response of the immune system against dying and dead cells strongly depends on the cell death phenotype. Beside other forms of cell death, two clearly distinct populations, early apoptotic and secondary necrotic cells, have been shown to induce anti-inflammation/tolerance and inflammation/immune priming, respectively. Cytofluorometry is a powerful technique to detect morphological and phenotypical changes occurring during cell death. Here, we describe a new technique using AnnexinA5, propidiumiodide, DiIC1(5) and Hoechst 33342 to sub-classify populations of apoptotic and/or necrotic cells. The method allows the fast and reliable identification of several different phases and pathways of cell death by analysing the following cell death associated changes in a single tube: cellular granularity and shrinkage, phosphatidylserine exposure, ion selectivity of the plasma membrane, mitochondrial membrane potential, and DNA content. The clear characterisation of cell death is of major importance for instance in immunization studies, in experimental therapeutic settings, and in the exploration of cell-death associated diseases. It also enables the analysis of immunological properties of distinct populations of dying cells and the pathways involved in this process. [ABSTRACT FROM AUTHOR]

'The enemy of my enemy is my friend.' According to this motto, the human protagonists in Paul W. S. Anderson's science-fiction movie 'Alien vs. Predator' (2004) solidarize with a predator in order to fight the aliens. Can this ancient and simple logic be transferred to the field of oncology and cancer immunotherapy? Can we utilize mechanisms known from the context of autoimmunity to fight cancer? Here, we summarize immune cell-mediated detection of danger and damage, central and peripheral tolerance, immunoregulation and immune privilege - processes known to be deregulated in the context of autoimmunity. We discuss them with special regard towards their misusage by tumors and pathogens and how they might be instrumentalized in the context of anti-cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The formation of antibodies against double-stranded (ds)DNA is considered to be the serologic hallmark of systemic lupus erythematosus (SLE) and anti-dsDNA antibodies play an important role in the pathogenesis of the disease. Anti-dsDNA antibodies from lupus mice and SLE patients arise by somatic mutation. Importantly, autoantibodies in which somatic mutations have been reverted to germ-line V regions did not show any measurable autoreactivity, suggesting that anti-dsDNA autoantibodies develop from non-autoreactive B-cells by somatic hypermutation, presumably during the germinal center reaction. As the random nature of somatic hypermutation will inevitably create autoreactive B cells, self-tolerance checkpoints at the postmutational stage of B cell differentiation have to exist that normally prevent the induction of pathogenic anti-dsDNA specificities. This review summarizes the proposed mechanisms for the generation of anti-dsDNA in murine lupus and in SLE patients. [ABSTRACT FROM AUTHOR]

Apoptotic cells and subcellular microparticles expose increased sialidase activity on their surfaces, which results from caspase-3 dependent activation of plasma membrane associated Neuraminidase-1 (Neu1). Desialylation of dying cells is also known to promote efferocytosis. The intriguing question remained whether sialidase on the surface of dying cell merely acts on self targets (cis-action), or whether it can also cleave glycoepitopes of neighboring cells (trans-action). Here, we co-incubated human viable and apoptotic Jurkat lymphocytes or neutrophils with human erythrocytes and evaluated their glycoprofile for terminal sialic acids by agglutination assay, flow cytometry, ELISA and dot-blot analyses. Data suggest that erythrocytes were desialylated as soon as 3 hours after co-incubation with apoptotic cells, but not with viable ones. After co-incubation of L929 murine fibroblasts with viable or apoptotic murine L1210 cells the L929 cells gained a desialylated glycoprofile, only after co-incubation with apoptotic cells. Our data suggests that activated sialidase(s) on the surfaces of apoptotic cells are capable to desialylate neighboring cells in trans. [ABSTRACT FROM AUTHOR]

Rapid clearance of apoptotic cells, frequently referred to as efferocytosis, is crucial for the maintenance of tissue homeostasis and the prevention of autoimmunity. The common model of apoptotic cell clearance involves a system of released 'Find me' and exposed 'Eat me' signals on apoptotic cells, detected and recognized by matching receptors on macrophages or dendritic cells (DC), referred to as the phagocytic synapse. Osteoclasts share the monocyte lineage with these professional mononuclear phagocytes, thus raising the question if, in addition to bone resorption, osteoclasts can act as scavengers for apoptotic cells. Our qPCR data clearly show that osteoclasts express most of the genes required for dying cell clearance at mRNA levels similar to or even higher than those observed in M1-macrophages, M2-macrophages or DC. Our microscopical analyses reveal that osteoclasts in fact can bind and/or engulf apoptotic cells in an essentially serum-independent fashion. Together with our data on the abundance of the respective mRNAs, these results identify the vitronectin receptor (integrin ανβ3)/milk fat globule-EGF factor 8 protein (MFG-E8) axis, the scavenger receptors (CD36, CD68 and class A macrophage scavenger receptor (SR-A)), the complement/complement receptor axis, the Mer/Tyro3/Protein S axis, and the phosphatidylserine (PS) receptor brain-specific angiogenesis inhibitor 1 (BAI1) as the most promising candidates to be involved in osteoclast-mediated efferocytosis. [ABSTRACT FROM AUTHOR]

Hydrocarbon oils such as pristane or hexadecane induce arthritis and lupus in rodents sharing clinical and pathological features with the human diseases rheumatoid arthritis and systemic lupus erythematosus, respectively. In pristane-induced lupus in the mouse induction of apoptosis and augmentation of type-I Interferon signalling by pristane have been suggested to contribute to pathology, whereas in pristane-induced arthritis (PIA) in the rat the pathological mechanisms are still elusive. Here we show that pristane induces cell death in rat and human cells. Increased numbers of apoptotic cells were found in draining lymph nodes of pristane-injected rats and increased percentages of apoptotic and necrotic cells were observed in peripheral blood. In addition, neutrophil extracellular trap formation was triggered by pristane and hexadecane in neutrophils. Because levels of interleukin (IL)-1β were elevated in sera of pristane-injected rats, with levels mirroring the course of PIA, we examined the effect of pristane at single cell level in vitro, using rat splenocytes and the human monocytic cell line THP-1. Pristane and other hydrocarbon oils induced IL-1β secretion in THP-1 cells as well as in rat splenocytes. The potassium channel inhibitor glibenclamide partly inhibited IL-1β induction, suggesting involvement of the inflammasome. Elevated levels of IL-1α were also found in supernatants of cells treated with pristane and hexadecane. In conclusion, autoimmunogenic hydrocarbon oils induce various forms of cell death in rat and human cells. The higher serum IL-1β levels in pristane-injected animals might be caused by both inflammasome-dependent and -independent mechanisms, such as passive release from dying-cells and probably extracellular maturation of pro-IL-1β. [ABSTRACT FROM AUTHOR]

Patients with Systemic Lupus Erythematosus (SLE) carry an increased risk for the development of coronary artery disease (CAD). The R131 allele of the Fc gamma receptor IIa (FcγRIIa) is associated with SLE incidence and disease severity but also with CAD. Compared to stable angina pectoris (SAP) the unstable angina (UAP), as a manifestation of destabilizing CAD, is associated with increased risk of persistent instability, myocardial infarction, and death. Identification of clinically relevant determinants for unstable angina promises reduction of UAP-associated mortality in patients with SLE. We conducted a clinical study among 553 consecutive patients with stable angina pectoris ( n = 330) and unstable angina pectoris ( n = 223). All patients were genotyped for a frequent functional variant at position 131 of the mature FcγRIIa. UAP, but not SAP was significantly associated with the R/R131 genotype ( P < 0.001). In troponin-negative patients with angina carrying the R/R131 genotype the odds ratio for suffering from UAP was 4.02 (95% confidence interval, 2.52-6.41) compared to those with non-R/R131 genotypes. In a multivariable analysis, the R/R131 genotype independently predicted the risk for development of UAP in a model adjusted for classical atherogenic risk factors. Our data imply that risk stratification of SLE- and other high risk patients with troponin-negative angina could be significantly improved by FcγRIIa genotyping. [ABSTRACT FROM AUTHOR]

Objectives. One of the neurobiological core features of schizophrenic illnesses is a hypo-functionality of the frontal cortex ('cerebral hypofrontality'). The two major classes of antipsychotic medication differ regarding their impact on frontal lobe function and metabolism, with a presumably more positive effect of 'atypical' compared to 'typical' agents. To date, neurobiological markers reliably predicting the treatment response to different antipsychotics are lacking. The present study, therefore, aimed at establishing a neurophysiological marker of frontal lobe function (NoGo-Anteriorization, NGA) as a predictor of the treatment response to first- and second-generation antipsychotics. Methods. Seventy-six schizophrenic patients were examined three times over a 6-week study period. Patients were treated with first- or second-generation antipsychotics, and NGA, neurocognitive performance, and symptomatology were assessed on admission as well as during two follow-up measurements. Results. Baseline NGA values significantly predicted the treatment response to typical and atypical antipsychotics; however, the direction of this prediction was dependent on the antipsychotic drug regimen. Moreover, atypical antipsychotics had a superior impact on neurocognitive performance and self-reported quality of life. Conclusions. The NGA might be a useful tool in developing individualized treatment strategies based on pathophysiological aspects of schizophrenic illnesses that can be easily determined in clinical routine settings. [ABSTRACT FROM AUTHOR]

In the 53 years since the discovery of anti-DNA autoantibodies in lupus [1, 2, 3], recalcitrant questions have been pondered and possible answers have been debated. The discovery of anti-DNA autoantibodies presented many puzzles: How is immunological tolerance to native B-form DNA broken? What elicits characteristic systemic lupus erythematosus (SLE) autoantibodies? Which of the diverse anti-nuclear reactivities are pathogenic? What is the role of autoantibodies in the clinical presentation of disease? How do genetic predisposition and environmental triggers contribute to SLE? These questions were brought into focus by Professor David Stollar in an introductory presentation to an intense, three-day meeting set among the rugged and inspiring scenery of the Norwegian arctic coastline (the Scientific Program is included as supplemental File 1). Other participants presented and discussed topics directed to understanding the origin and clinico-pathological impact of autoantibodies to chromatin and phospholipid antigens. In the following, several aspects of the workshop are discussed. [ABSTRACT FROM AUTHOR]

Deficiencies in the recognition and engulfment of apoptotic cells have been reported in patients with systemic lupus erythematosus (SLE). If dying cells are not promptly cleared, they undergo secondary necrosis and release nuclear autoantigens. Secondarily necrotic cell-derived material (SNEC) can be generated in vitro employing various methods. SNEC generated by either methods shows similar DNA content, light scatter characteristics, and binding pattern of dead and dying cell ligands and is readily recognized by autoantibodies (AAb) of many patients with SLE. In whole blood, AAb opsonize SNEC and foster its uptake by blood-borne non-professional phagocytes. We observed a significant secretion of the inflammatory cytokines IL-8 and TNF-α by phagocytes which had engulfed different types of opsonized SNEC. Phagocytosis of SNEC and the subsequent production of inflammatory cytokines were strongly influenced by the presence of DNA in this prey, since DNase I treatment reduced both the uptake of SNEC and the induction of IL-8 and TNF-α production. In conclusion, the proinflammatory phagocytosis by circulating phagocytes of IgG-opsonized cellular remnants fosters systemic inflammation in SLE. [ABSTRACT FROM AUTHOR]

Introduction. In this study, the neural correlates of error processing in adult patients with attention deficit hyperactivity disorder (ADHD) are to be investigated for the first time. Recent studies in children with ADHD suggested, with some inconsistencies, deficits in error processing. Based on an analogue study with students, we hypothesized that ADHD patients show reduced amplitudes in the event-related potential (ERP) of the Pe (error positivity) but normal amplitudes of the ERN (error-related negativity) after incorrect responses. Method. In this study we investigated 34 adult ADHD patients and 34 healthy controls with a modified version of the Eriksen flanker task while recording the neural activity with 26 scalp EEG electrodes. Patients discontinued all medication at least 3 days prior to investigation. Age was included as a control variable for the statistical analyses. Results and conclusion. As hypothesized, we found reduced Pe amplitudes, but also reduced ERN values, in ADHD patients. Importantly, theses differences as well as the deficits in behavioural performance were mainly detectable in the younger subsample, but not in the elderly subsample. Our results indicate that adult ADHD patients are characterized by deficits in error processing, which vanish with age. [ABSTRACT FROM AUTHOR]

Multimodal tumor therapies should aim not only to kill the tumor cells, but also to stimulate a specific immune response to keep residual tumor (stem) cells and metastases under control. Apoptotic cells are mostly noninflammatory or even anti-inflammatory while necrotic cells stimulate the immune system. Whether the immunogenicity of apoptotic tumor cells can be increased by interfering with their swift and phosphatidylserine (PS)-dependent clearance by macrophages was examined. AnnexinA5 (AnxA5) is a naturally occurring highly specific ligand for PS. Proteins of the annexin family are characterized by a selective affinity for phospholipids in the presence of Ca2+ ions. The phagocytosis by macrophages of irradiated, apoptotic tumor cells (ITC) was partially inhibited when the ITC were preincubated with AnxA5. Activated macrophages secreted higher amounts of TNFα and IL-1β after contact with ITC plus AnxA5 in comparison with ITC alone, while the amount of TGF-β was decreased. Macrophages of AnxA5-deficient mice showed an increased phagocytosis of dead cells. Wild-type mice, where endogenous AnxA5 is present, displayed a significantly faster decline in size of allogeneic tumors in comparison with AnxA5-deficient animals. The addition of AnxA5 to ITC vaccines increased the percentage of tumor-free mice in syngeneic tumor protection and tumor cure assays. AnxA5 alone led to a retard of syngeneic tumor growth that was, however, less pronounced in comparison to treatment of the tumor with ionizing irradiation. In conclusion, AnxA5 disturbs the PS-dependent clearance by macrophages of dying tumor cells, leading to the accumulation of the latter, to the occurrence of secondary necrotic cells, and to an increased uptake of the dead cells by dendritic cells. Tumor cure appendages with dead tumor cells should be performed with AnxA5 as an immune stimulator and could be combined with irradiation, chemotherapy, and hyperthermia to induce immunogenic cell death forms in vivo or ex vivo. [ABSTRACT FROM AUTHOR]

Apoptosis serves many functions in the homeostasis of multicellular organisms. Defects in apoptosis may lead to clonal expansion and accumulation of autoreactive lymphocytes, which may result in the rare human autoimmune lymphoproliferative syndrome, a mild autoimmune reaction against cells in the blood. Defects in the clearance of apoptotic cells lead to accumulation of dying cells, which may enter later stages of cell death and release their contents, thereby critically contributing to the etiopathogenesis of the autoimmune disease systemic lupus erythematosus. For an efficient therapy of systemic lupus erythematosus, it is necessary to analyze apoptosis and clearance defects and to unravel factors leading to its onset. [ABSTRACT FROM AUTHOR]

The generation of autoantibodies against chromatin is a hallmark of the multifactorial autoimmune disease systemic lupus erythematosous (SLE). Impaired clearance of apoptotic cells together with the release of nuclear autoantigens are supposed to contribute to the loss of self-tolerance in SLE. Phospholipids such as phosphatidylserine (PS) and phosphatidylethanolamine (PE) are exposed on the surfaces of apoptotic cells and on apoptotic blebs. Also histones/nucleosomes can be detected on apoptotic cells; however, their binding motifs are still unknown. Therefore, we investigated the interaction of PS, PE, phosphatidylcholine (PC), and cardiolipin (CL) with histones H1, H2A, H2B, H3, and H4 by surface plasmon resonance (SPR). Strong binding to phospholipids was found for all histones, with H2A displaying the highest binding affinity to all phospholipids investigated. Hence, phospholipids including PS and PE may contribute to the binding of histones to surfaces and blebs of apoptotic cells. Moreover, histones/nucleosomes complexed to uningested apoptotic membrane structures may foster autoimmunity towards nuclear compounds. [ABSTRACT FROM AUTHOR]

Apoptotic cells are readily recognized and engulfed by phagocytes and usually do not induce inflammation or tissue damage. Furthermore, they can actively suppress a pro-inflammatory response in phagocytes: In the presence of apoptotic cells, activated monocytes/macrophages produce more of the anti-inflammatory and immunoregulatory cytokines IL-10 and TGF-β, but less of the pro-inflammatory cytokines TNFα, IL-1β and IL-12. This immunoregulatory effect is most likely mediated by several receptors on monocytes/macrophages including the thrombospondin receptor (CD36). In addition to the modulation of cytokine secretion, apoptotic cell material inhibited the expression of MHC class II molecules on the surface of monocytes/macrophages. Decreased MHC II expression appeared to be mediated predominantly by increased IL-10 secretion in a para-/autocrine manner. Here, we show that the functional modulation of antigen-presenting monocytes/macrophages by apoptotic cells also influences T cell activation and function. When human peripheral blood mononuclear cells were stimulated with recall antigens in the presence of apoptotic cells, interferonγ (IFNγ) secretion was markedly suppressed, whereas secretion of the Th2 cytokine IL-4 was not significantly altered. Hence, apoptotic cells shift the T cell cytokine secretion pattern towards a Th2-like response. This Th2 shift can largely be prevented by neutralizing IL-10, indicating an important role of this cytokine for modulating T cell cytokine secretion patterns. [ABSTRACT FROM AUTHOR]

The authors comment on the concept of clearance of apoptotic cell and autoimmunity. They question whether apoptotic cells exist, even if they have seen necrotic cells in clinical conditions. The authors believe that apoptosis is important in the production of new tissues. Furthermore, they present an inflammatory outcome of the clearance process through infiltration of leukocytes in the areas of apoptotic cells.

Patients suffering from dementia show altered functional brain activation patterns especially in prefrontal brain regions, as research suggests. The present study follows three aims: to replicate these findings, to investigate treatment effects when administering galantamine, and to put gender differences in focus. We compared 12 patients with dementia to 12 age- and gender-matched healthy subjects regarding changes in haemoglobin concentration in brain tissue while performing a verbal fluency task (VFT). Concentration changes of oxygenated (O2Hb) and deoxygenated (HHb) haemoglobin were measured by multi-channel near-infrared spectroscopy (NIRS), an easily applicable and non-invasive method of optical topography. In the patient group, measurement was repeated 4 and 8 weeks after starting treatment with galantamine. The results showed a reduced increase in O2Hb during task performance for patients compared to healthy controls. Furthermore, female subjects showed more pronounced activation in O2Hb as well as HHb compared to male subjects. Regarding treatment effects, no clear results could be obtained. In HHb, evidence for an entrainment effect was found. In the light of existing literature, the present study suggests an interaction of gender and age regarding brain activation patterns which should be aimed at in future investigations. [ABSTRACT FROM AUTHOR]

Autoimmunopathies are chronic inflammatory diseases which can be subdivided into several specificities on the ground of the clinical picture as well as serological findings and involvement of organ systems like the kidney, central nervous system or the hematopoietic system. The pathogenesis of these diseases is incompletely understood. With the exception of rare diseases in which the autoantigens are known, in the most frequent autoimmunopathies like rheumatoid arthritis or Systemic Lupus Erythematosus (SLE) only some partial aspects of the pathogenetic scenario are understood and rather well substantiated by experimental data. In RA, there are controversies concerning the central involvement of T-lymphocytes and/or synovial fibroblasts in the initiation of the diseases. It is meanwhile well known that TNF-α and possibly other related cytokines are inviolved at least in the perpetuation of the inflammatory cascades. Specific blockade of TNF-α leads to rapid improvement of RA disease activity and can prevent tissue destruction. An intriguing hypothesis postulates a central role for a dysregulated apoptosis in the development of SLE. In this review we will concentrate on pathogenetic concepts of autoimmune diseases as exemplified by RA and SLE. [ABSTRACT FROM AUTHOR]

Apoptotic cells are recognized and cleared by the innate immune system. This process severely influences the outcome of several important functions of the latter. Apoptotic cells serve as sources for autoantigens employed by immature dendritic cells to maintain tolerance, excellent to prevent autoimmune diseases disastrous when this causes tumor tolerance. Apoptotic cells orchestrate healing and repopulation of the tissues, in which they died, again advantageous during wound healing and in the resolution phase of infections but a disaster after tumor reducing therapies. Many highly pathogenic microorganisms and viruses mimic changes of apoptotic cells like exposure of phosphatidyl serine and abuse their immune silencing signals to escape immune detection and eradication. If autologous chromatin is not properly cleared it is misinterpreted by the immune system as virus and causes the secretion by phagocytes of type-1 interferons. The continuous presence of these cytokines challenges tolerance and leads to SLE-like autoimmunity. [ABSTRACT FROM AUTHOR]

Accumulation in tissues of post-apoptotic cells is a feature frequently observed in patients with systemic lupus erythematosus and in murine models of systemic autoimmune diseases. One of the endogenous danger molecules released by secondarily necrotic cells is monosodium urate (MSU), which is already established to be the causative agent of gout. Here, we show that MSU is taken up by eosinophils, neutrophils and monocytes in a process involving (a) heat-labile serum factor(s) and divalent cations. The uptake induces the release of the pro-inflammatory cytokines IL-1β/IL-18/TNFα and IL-6/IL-8 by monocytes and PMN, respectively. [ABSTRACT FROM AUTHOR]

The architectural chromosomal protein high-mobility group box 1 protein (HMGB1) acts as an alarmin when released from cells. It is involved in the pathogenesis of inflammatory and autoimmune diseases. HMGB1 can undergo post-translational modifications including oxidation. However, the mechanisms and functional relevance of HMGB1 oxidation are not yet understood. Increased concentrations of reactive oxygen species (ROS) have been reported during apoptosis and necrosis. Hence, we investigated the oxidative status of HMGB1 in dead cells. Immunoblot analyses under reducing and non-reducing conditions revealed that HMGB1 is oxidized in dead cells. Moreover, tagging of oxidized cysteine residues by a maleimide moiety linked to polyethylene glycol showed that HMGB1 passively released from primary and secondary necrotic cells was predominantly oxidized. Also HMGB1 in plasma of patients with systemic lupus was reversibly oxidized. In conclusion, HMGB1 undergoes reversible oxidative modifications at cysteine residues during cell death, which may modulate its biological properties. [ABSTRACT FROM AUTHOR]

Uric acid (UA) is identified as a danger signal released from dying cells. It precipitates in sodium-rich extracellular fluid and in potassium-rich intracellular fluid as monosodium urate (MSU) and monopotassium urate (MPU), respectively. Here, we examined the structural and functional features of these crystals. In contrast to MPU MSU crystals induced reactive oxygen species production and release of pro-inflammatory cytokines in whole blood ex vivo assays. These results show that the cation of urate crystals determines the response of innate immune cells, indicating that the micromilieu at the site of crystal formation is important for their inflammatory potential. [ABSTRACT FROM AUTHOR]

Low dose radiotherapy (LD-RT) is known to exert an anti-inflammatory effect. The underlying molecular mechanisms, however, are still a matter of actual research. We have recently shown that LD-RT of stimulated EA.hy.926 endothelial cells (EC) resulted in a biphasic DNA-binding and transcriptional activity of NF-κB in parallel with a biphasic course of leukocyte adhesion. Here we report, that following low dose X-irradiation, an increased activator protein 1 (AP-1) DNA-binding activity was observed in EC with a first relative maximum at 0.3 Gy as analysed by electrophoretic mobility shift assay. AP-1 activity then decreased at doses between 0.5 and 1 Gy and subsequently increased again at 3 Gy. This biphasic profile was confirmed on the transcriptional level by an AP-1 specific chemoluminescence reporter assay. In conclusion, the discontinuous dose response of AP-1 activation may add a further facet to the plethora of mechanisms contributing to the anti-inflammatory efficacy of LD-RT. [ABSTRACT FROM AUTHOR]

The autoimmune lymphoproliferative syndrome (ALPS) is characterized by non-malignant lymphoproliferation and signs of autoimmunity. A hallmark of ALPS are high amounts of circulating CD3+/CD4 - /CD8 - double negative T-lymphocytes (DN T cells). The origin of these cells remains elusive. To investigate the relationships of DN T cells and the single positive T cell populations (CD4+ and CD8+), we analyzed by spectratyping the complementarity determining regions 3 (CDR3) of the T cell receptors in sorted "single positive" (CD4+, CD8+) and DN T cells in a patient with ALPS type 1a. We observed signs for clonal expansion in all three T cell subpopulations. Strong and weak clonal expansions were to be seen in 16 and 14 for DN, 6 and 12 for CD8+, and 1 and 5 for CD4 + T cells, respectively. Most importantly, 24 out of 30 aberrant peaks in the spectratype histograms of the DN T cells where unique for this population and were not to be detected in the histograms of the single positive T cells. In contrast to published data, we conclude that expanded DN T cell populations in ALPS are not generally derived from expanded CD3+/CD4+ or CD3+/CD8+ populations. [ABSTRACT FROM AUTHOR]

The article offers the author's views on the factors affecting the rheumatologic diseases. According to him, they display a multi causal etiology influenced by genetic and environmental factors. He suggests that even small amounts of cellular waste can cause devastating pathology of rheumatologic diseases if they persist permanently.