Autoimmune Activity Research Articles

Pembrolizumab Therapy Triggering an Exacerbation of Preexisting Autoimmune Disease: A Report of 2 Patient Cases.

Historically, metastatic melanoma was uniformly and rapidly lethal, and treatment options were limited. In recent years, however, checkpoint inhibitors have emerged as an accepted standard treatment for patients with advanced melanoma. In clinical trials, these agents have been largely well tolerated and have the potential to result in durable responses. Importantly though, one must recognize the unique side effect profile of these therapies, which can trigger or exacerbate underlying autoimmune disease. Whether this autoimmune activation is associated with a clinical response to therapy has been debated, and while not definitive, there is evidence in the literature of a possible association. The 2 cases presented describe this autoimmune phenomenon, along with a review of the existing literature on the relationship between response to immunotherapy and autoimmune side effects.

Gender-modulated risk of coronary heart disease, diabetes and coronary mortality among Turks for three major risk factors, and residual adiposity risk.

BackgroundWe determined the proportion of the effects of body mass index (BMI) or its categories on cardiometabolic outcomes mediated through systolic blood pressure (SBP), total cholesterol and fasting glucose.MethodsCox regression analyses were performed for incident outcomes among Turkish Adult Risk Factor study participants in whom the three mediators had been determined (n = 2158, age 48.5 ± 11 years). Over a mean 10.2-years’ follow-up, new coronary heart disease (CHD) developed in 406, diabetes in 284 individuals, and 149 CHD deaths occurred.ResultsHazard ratios (HR) of BMI for incident diabetes were no more than marginally attenuated by the 3 mediators including glucose, irrespective of gender. Compared to “normal-weight”, sex- and age-adjusted RRs for incident CHD of overweight and obesity were 1.40 and 2.24 (95 % CI 1.68; 2.99), respectively, in gender combined. Only three-tenths of the excess risk was retained by BMI in men, six-tenths in women. No mediation of glycemia was discerned in males, in contrast to greatest mediation in females. HR of age-adjusted continuous BMI was a significant but modest contributor to CHD mortality in each gender. While the BMI risk of CHD death was abolished by mediation of SBP in men, HR strengthened to over two-fold in women through mediation of fasting glucose.ConclusionsMediation of adiposity by 3 traditional factors exhibited among Turkish adults strong gender dependence regarding its magnitude for CHD risk and the mediation by individual risk factors. Retention of the large part of risk for diabetes in each sex and for CHD in women likely reflects underlying autoimmune activation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12902-016-0134-6) contains supplementary material, which is available to authorized users.

Interleukin-6 Detection with a Plasmonic Chip

Interleukin-6, a cytokine relating inflammatory and autoimmune activity, was detected with three fluorescence assays using a plasmonic chip. In their assays, the way of surface modification, sample volume, incubation time and mixing solution, were found to influence the detection sensitivity. When the assay was revised in the point of a rapid and easy process, the detection sensitivity was not compromised compared to assays with sufficient sample volume and assay time. To suit the purpose of immunosensing, the assay conditions should be determined.

Spondyloarthritis: Pathogenesis, Clinical Manifestations, Diagnosis and Management

The term spondyloarthritis (SpA) is used to describe a heterogeneous group of diseases sharing certain characteristics. Traditionally, patients with SpA have been classified in five subgroups: ankylosing spondylitis (AS), psoriatic arthritis, arthritis associated with inflammatory bowel disease (IBD), reactive arthritis, and undifferentiated SpA. The pathogenesis of SpA is still not entirely clear; it is considered to be multifactorial, the result of interaction between genetic risk factors and environmental triggers that lead to activation of autoinflammation and autoimmunity. This group of diseases is characterised by a chronic inflammation in entheses and other anatomical structures, leading to their main clinical features: sacroilitis, enthesitis, and peripheral arthritis. An association with extra-articular manifestations such as psoriasis, uveitis, and IBD is also a distinctive feature of SpA. Several diagnostic and classification criteria have been proposed over time. However, all of these criteria have a main limitation, which is the difficulty to identify patients at an early stage of the disease. The Assessment of Spondyloarthritis International Society (ASAS) proposed the ASAS classification criteria that introduced two major changes: first, the classification of patients with SpA based on the predominant symptoms (axial or peripheral); second, the introduction of magnetic resonance imaging, which allows detection of sacroiliitis at the early stages of the disease. Nowadays, the ASAS criteria classify SpA in two groups: axial SpA, including classical AS and non-radiographic axial SpA, and peripheral SpA. The therapy for SpA has evolved dramatically over time. The introduction of biological therapy in recent years, which has continuously progressed, has improved the functional and clinical prognosis of SpA patients.

Enhanced Signal and Quantitative Detection of Anti-Interferon-Gamma Antibody by Using a Nanometer Biolinker.

For rapid screening and quantification of an antisera antibody, a nanometer bithiophene-based conductive biolinker can enhanced signal performance and can be used to verify the interaction of an anti-IFN-γ antibody with an IFN-γ protein. The experimental measurements take a generic approach which takes advantage of the functionality of thiophene-based linkers for biosensors. Effects associated with using bithiophene as a biolinker for surface plasmon resonance (SPR) spectroscopy are examined in this paper. By using an atomic force microscope (AFM), it was observed that the morphology of the bithiophene modified gold sensor surface became smoother than the original gold surface. We compared the response and concentration of the anti-IFN-γ antibody on a bithiophene-coated and dextran-coated biochip as well as on different thickness-modified surfaces under SPR relevant conditions. The results indicate that a response to IFN-γ molecules immobilized on a sensor using a bithiophene biolinker improved more than 8-fold when compared to that of a sensor using a dextran biolinker. Furthermore, the regeneration ability of the sensor surface shows good repeatability as only less than a 1% decrease was found after repeating the experimental work over 6 cycles. The characteristics provided us with a good platform for rapid screening, real-time monitoring and quantitative concentration of the autoimmune antibody activities.

Improvement of Sclerodermatous Graft-Versus-Host Disease in Mice by Niclosamide

Sclerodermatous graft-versus-host disease, a frequent complication of allogeneic hematopoietic stem cell graft, shares many features with systemic sclerosis, such as production of autoantibodies and fibrosis of skin and inner organs. Recent reports on the implication of signal transducer and activator of transcription 3 and of Wnt/β-catenin in fibrosis have prompted us to investigate the effects of the inhibition of both signaling pathways in a mouse model of sclerodermatous graft-versus-host disease, using niclosamide, an anthelmintic drug, with a well-defined safety profile. Sclerodermatous graft-versus-host disease was induced in BALB/c mice by B10.D2 bone marrow and spleen cell transplantation. Mice were treated every other day, 5 days a week, for 5 weeks by niclosamide. Clinical and biological features were studied 42 days after transplantation. Niclosamide reversed clinical symptoms including alopecia, vasculitis, and diarrhea and prevented fibrosis of the skin and visceral organs. Beneficial immunological effects were also observed: niclosamide decreased the production of effector memory CD4 and CD8 T cells, T-cell infiltration of the skin and visceral organs, and decreased productions of IL-4 and IL-13, and autoimmune B-cell activation. The improvement provided by niclosamide in the mouse model of sclerodermatous graft-versus-host disease provides a rationale for the evaluation of niclosamide in the management of patients affected by systemic fibrotic disease.

Assessment of cardiovascular involvement in Connective Tissue Disease: Let’s open Pandora’s box

Connective Tissue Disease (CTD) is characterized by autoimmune activation and systemic inflammatory response, affecting several internal organs. Cardiac involvement represents one of the most severe complications associated with higher rates of death and reduced life expectancy in this population. Cardiovascular abnormalities occurring in CTD encompass different aspects of cardiac disease, such as pericarditis, myocarditis, coronary artery disease, heart failure due to systolic and diastolic dysfunction and valvular disease. Considering the increased risk of cardiovascular disease (CVD) in CTD, early assessment and diagnosis of cardiovascular involvement is of utmost importance. However, CVD in CTD has often an atypical clinical presentation, and traditional diagnostic approaches such as transthoracic echocardiography have low sensitivity in the early stages. Cardiac magnetic resonance imaging can identify subtle morphological changes of the myocardium and contribute to earlier diagnosis of CVD in patients with CTD.

Treatment of systemic sclerosis: is there any hope for the future?

Systemic sclerosis (SSc) is an orphan connective tissue disease characterised by skin and multiorgan involvement. The following original pathological processes distinguish SSc from other connective tissue diseases: (1) microvascular modifications,...

Взаимосвязь особенностей аутоиммунного статуса у пациентов с катарактой на фоне псевдоэксфолиативного синдрома с развитием у них нарушений гидродинамики глаза

Pseudoexfoliation syndrome (PEX) is the established trigger of glaucoma. The systemic character of PEX and the multifactor character of glaucoma can point to possible changes of the autoimmune profile of human body in the presence of this pathology and its possible link with hydrodynamic disturbances. Purpose. To study the peculiarities of the autoimmune serum profile in patients with cataract and PEX in the presence and absence of glaucoma. Material and methods. In the study there were examined 45 female patients aged 70-84 years with cataract and severe PEX. The patients were divided into 3 groups depending on the intensity of systemic cardio-vascular pathology and the presence or absence of glaucoma. Enzyme-linked immunosorbent assay was used to define the serum autoantibody level. Results. In examined groups it was detected the exceeding of the average statistical norm of the following serum autoantibodies: to the cytoplasm of neutrophilic granulocytes (ANCA), β1-adrenoreceptors and membrane antigen of trombocyte, which was the most pronounced one in the presence of systemic cardiovascular pathology and glaucoma process. Conclusions . The detected peculiarities of the autoimmune activity in patients with PEX can point to the significant role of the endothelial dysfunction in the development of glaucoma in such group of patients.

National Heart, Lung, and Blood Institute Working Group Report on Salt in Human Health and Sickness: Building on the Current Scientific Evidence.

Humans have had a long and complex relationship with salt. Although highly valued in many societies, dietary salt has long been associated with high blood pressure1–3 and, more recently, with other diseases.4–6 Some individuals with hypertension often display salt-sensitive blood pressure changes, which is a condition more prevalent among blacks, older people, and individuals with renal insufficiency or diabetes mellitus.7–9 In general, for those with salt-sensitive hypertension, excess sodium intake is associated with higher blood pressure, whereas a low-salt diet decreases blood pressure.3 In spite of this well-known association, the basic molecular and cellular mechanisms underlying the effects of salt on blood pressure regulation are still not well understood. Furthermore, individuals with high blood pressure are at increased risk for multiple diseases (ie, coronary artery disease, heart failure, stroke, and renal disease) although at present whether or not a high dietary salt intake can directly lead to these diseases (ie, in the absence of hypertension) is not known. Our understanding of the effect of salt on health has grown even more complex recently. Researchers have reported a new connection between salt and autoimmunity: a high-salt diet was shown to accelerate autoimmune activity in a mouse model of multiple sclerosis.10,11 In addition, a close connection between hypertension and the immune system has been revealed.12–16 However, the causal relationships between salt, immunity, and hypertension (eg, how salt could mediate interactions between the immune system and the vasculature, brain, or kidney to increase blood pressure) are not well understood. The National Heart, Lung, and Blood Institute convened a Working Group (WG) in 2014 to discuss this new emerging scientific area in hypertension research. The WG brought together experts from diverse backgrounds including hypertension, epidemiology, preeclampsia, cardiovascular disease, …

Action of methotrexate and tofacitinib on directly stimulated and bystander-activated lymphocytes.

Chronic inflammation associated with autoimmune activation is characteristic of rheumatic diseases from childhood to adulthood. In recent decades, significant improvements in the treatment of these types of disease have been achieved using disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) and, more recently, using biologic inhibitors. The recent introduction of kinase inhibitors (for example, tofacitinib; Tofa) further increases the available ARDs. However, there are patients that do not respond to any treatment strategies, for whom combination therapies are proposed. The data regarding the combined action of different drugs is lacking and the knowledge of the mechanisms of ARDs and their actions upon pathogenic lymphocytes, which are hypothesized to sustain disease, is poor. An invitro model of inflammation was developed in the current study, in which stimulated and unstimulated lymphocytes were cultured together, but tracked separately, to investigate the action of MTX and Tofa on the two populations. By analysing lymphocyte proliferation and activation, and cytokine secretion in the culture supernatants, it was established that, due to the presence of activated cells, unstimulated cells underwent a bystander activation that was modulated by the ARDs. Additionally, varying administration schedules were demonstrated to affect lymphocytes differently invitro, either directly or via bystander activation. Furthermore, MTX and Tofa exerted different effects; while MTX showed an antiproliferative effect, Tofa marginally effected activation, although only a slight antiproliferative action, which could be potentiated by sequential treatment with MTX. Thus, it was hypothesized that these differences may be exploited in sequential therapeutic strategies, to maximize the anti‑rheumatic effect. These findings are notable and must be accounted for, as bystander‑activated cells invivo could contribute to the spread of autoimmune activation and disease progression.

MOLECULAR APOPTOSIS MECHANISMS WITH UNDERLYING EXPERIMENTAL ACUTE LUNG INJURY

<p>Background. Current data suggest systemic autoimmune activation in the pathogenesis of bronchopulmonary<br />diseases. The imbalance in the system of pro- and anti-inflammatory cytokines is very important in<br />immunopathogenesis.<br />Objective. The aim of our research was to determine the caspase-3 rate in the dynamics of experimental<br />acute lung injury and to study the relationship between their level and the number of cells carrying membrane<br />binding TNF receptor type 1 to define the main mechanisms of cell death.<br />Results. The analysis of the results of caspase-3 rate in lung homogenate showed that this cysteine proteinase<br />was uniformly increasing in all experimental groups during simulating of ALI induced by administration of<br />hydrochloric acid (p<0.001). When comparing the results of caspase course of apoptosis it was defined that,<br />despite the progressive increase in caspase-3 rate in lung homogenate, cysteine proteinase rate in plasma did<br />not change.<br />The receptor mechanism of apoptosis was studied by establishing correlation relationships with the number<br />of cells carrying membrane binding TNF type 1 (TNF-R1) receptor. A strong positive correlation relationship<br />between the number of neutrophils with TNF-R1 and caspase-3 rate in lungs of all research groups was<br />determined.<br />Conclusions. The implementation of neutrophils death by apoptosis is caused by change of activity of<br />caspase cascade effector components, such as caspase-3, in cases of ALI induced by intratracheal administration<br />of hydrochloric acid. One of the potential mechanisms responsible for the activation of caspase course is excessive<br />generation of active forms of oxygen and increase in the number of neutrophils carrying membrane binding TNF<br />receptor type 1.<br />KEY WORDS: caspase-3, tumour necrosis factor alpha receptor 1, acute lung injury</p>

Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood-brain barrier, CD56(bright) NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4β1 integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4(+) T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4(+) T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor's ligand CD155 on CD4(+) T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4(+) T cells and the cytolytic activity of NK cells.

Th17/TfH cells in rheumatoid arthritis: correlations with disease activity and therapy response

Abstract Th17 and TfH cells are thought to promote tissue inflammation (Th17) and autoantibody production (TfH) in rheumatoid arthritis (RA) and other autoimmune diseases. TfH cells that co-express Th17 markers (Th17/TfH) correlate with disease activity in juvenile dermatomyositis. However, Th17/TfH cells have not been detailed in RA subjects in context of therapy response. Blood T cell and B cell subsets were analyzed by flow cytometry in 16 subjects with active RA, before and after TNF inhibitor therapy. Proportions of CXCR5+ TfH cells that co-expressed the Th17 marker CCR6 (Th17/TfH cells) directly correlated with disease activity at baseline. In contrast, there were no correlations between disease activity and other T cell subsets including total Th17 (CCR6+), TfH (CXCR5+) or Th1 (CXCR3+) cells, or with CXCR3-expressing TfH cells. Th17/TfH cell frequencies were unchanged by TNF inhibition, fitting with no effect of TNF on stimulation of IL-17 or IL-21 in vitro. In fact, Th17/TfH cell proportions showed remarkable stability within individuals over time despite changes in disease activity. Activated class-switched B cells were increased in subjects with high autoantibody, but B cell subsets did not correlate with disease activity or with Th17/TfH cells. Finally, baseline Th17/TfH cells correlated with numbers of swollen joints at baseline and following one year of stable therapy. These data demonstrate the stability of chemokine receptors as markers of blood T cell phenotypes within individuals, and point to differences in underlying T cell phenotypes as drivers of autoimmune joint disease activity and response to TNF inhibitor therapy.

059 HLA drives both autoimmune activation and protection in pemphigus

Pemphigus vulgaris (PV) is tightly correlated with HLA types DRB1*0402 and DQB1*0503, but their full functional importance remains to be determined. Prior work by our group evaluated genome-wide expression profiles in patients and healthy controls by microarray. A distinct separation was observed by unsupervised hierarchical clustering between PV patients (both matched and unmatched for the PV-associated HLA risk allele) and HLA-matched controls based upon the most variable genes in the dataset, and a PV-associated “disease signature” of differentially expressed genes was determined. In a new analysis presented here, we further include transcriptional profiles from HLA-unmatched controls that do not carry the PV associated HLA risk alleles as compared to PV patients and HLA matched controls. Surprisingly, when all 3 sample types are examined together the HLA-matched healthy individuals group more closely with PV patients carrying DRB1*0402 or DQB1*0503, while PV patients negative for these risk alleles group together with HLA-unmatched controls. These data highlight HLA as a key driver of gene expression, overriding even disease status, leading us to define a PV-associated “HLA signature”. Ontology enrichment analysis of the “HLA signature” reveals a large overlap with the PV “disease signature” in pathways and processes related to immune/inflammatory response, cytoskeletal reorganization, MAPK signaling, cell adhesion and apoptosis, indicating that even among healthy individuals the presence of PV HLA risk alleles results in (at least partial) autoimmune activation. There are additional upregulated pathways and processes in the “disease signature” that are absent in the “HLA signature”, i.e. lacking in “at risk”, but healthy, individuals. We have previously reported that healthy individuals carrying PV-associated HLA alleles may be “protected” from progression to disease by the down-regulation of several “disease signature” associated genes/pathways. We propose that HLA status is central to both autoimmune activation and protection in PV.

Interleukin-17-producing CD4+ T lymphocytes are increased in patients with primary immune thrombocytopenia.

The present study was performed to investigate the role of interleukin-17-producing CD4-positive T cells in the pathogenesis of primary immune thrombocytopenia (ITP). Peripheral blood was collected from ITP patients and healthy controls. The immunophenotyping of T lymphocytes and the detection of T helper 1/2/17 (Th1/Th2/Th17) cells were performed by flow cytometry, Th1/Th2/Th17-associated cytokines were determined by cytokines microarray and ELISA. The association between Th17 and T regulatory cells (Tregs) was also investigated. The percentage of Th17 and Th1 cells were markedly increased in ITP patients especially in those with severe ITP compared with normal controls. Th17 cytokines microarray revealed the upregulation of proinflammatory cytokines and downregulation of inflammatory inhibitory cytokines in ITP patients compared with that in the normal controls. Further ELISA analysis verified high levels of Th17-associated proinflammatory cytokines such as interleukin-17A/F, interleukin-6 and interleukin-23 and low levels of inflammatory inhibitory factors including interleukin-10 and transforming growth factor-β in ITP patients compared with normal controls. We also observed that the ratio of Th17/Treg was significantly higher in severe ITP than that in mild ITP and normal controls and inversely correlated with platelet count. In addition, Tregs from ITP patients could suppress the secretion of interferon-γ by effector CD4-positive T cells, but had no effect on interleukin-17 production in vitro. Th17 cells are increased in ITP patients, and the inversion of Th17/Treg may contribute to the activation of autoimmunity.

Autoimmunity Against the Heart and Cardiac Myosin in Children With Myocarditis

BackgroundHost autoimmune activity in myocarditis has been proposed to play a role in development of cardiac disease, but evidence of autoimmunity and relationship to outcomes have not been evaluated in pediatric myocarditis. MethodsWe performed a multi-institutional study of children with clinical myocarditis. Newly diagnosed patients were followed for up to 12 months and previously diagnosed patients at a single follow-up for serum levels of autoantibodies to human cardiac myosin, beta-adrenergic receptors 1 and 2, muscarinic-2 receptors, and antibody-mediated protein kinase A (PKA) activation in heart cells in culture. Results were compared with those of healthy control children. ResultsBoth previously diagnosed patient at follow-up (P = .0061) and newly diagnosed patients at presentation (P = .0127) had elevated cardiac myosin antibodies compared with control subjects. Antibody levels were not associated with recovery status at follow-up in either group. PKA activation was higher at presentation in the newly diagnosed patients who did not recovery normal function (P = .042). ConclusionsChildren with myocarditis have evidence of autoantibodies against human cardiac myosin at diagnosis and follow-up compared with control subjects. Differences in antibody-mediated cell signaling may contribute to differences in patient outcomes, as suggested by elevated antibody-mediated PKA activation in heart cells by the serum from nonrecovered patients.

Plasma cells as an innovative target in autoimmune disease with renal manifestations.

Autoantibodies are secreted by plasma cells and have an essential role in driving the renal manifestations of autoimmune diseases such as systemic lupus erythematosus and antineutrophil cytoplasmic autoantibody-associated vasculitis. Effective depletion of autoreactive plasma cells might be the key to curative treatment of these diseases. Two major plasma-cell compartments exist: short-lived plasmablasts or plasma cells, which result from differentiation of activated B cells, and long-lived plasma cells, which result from secondary immune responses. Long-lived plasma cells reside in survival niches in bone marrow and inflamed tissue and provide the basis of humoral memory and refractory autoimmune disease activity. Unlike short-lived plasmablasts, long-lived plasma cells do not respond to conventional immunosuppression or to therapies that target B cells. Existing therapies that target long-lived plasma cells, such as proteasome inhibitors and antithymocyte globulin, as well as promising approaches that target survival factors, cell homing or surface molecules, deplete the whole memory plasma cell pool, including cells that secrete protective antibodies. By contrast, we have developed a novel strategy that uses an affinity matrix to deplete pathogenic long-lived plasma cells in an autoantigen-specific manner without removing protective plasma cells. Targeting B-cell precursors to prevent replenishment of autoreactive long-lived plasma cells should also be considered.

PD-L1-expressing neutrophils as a novel indicator to assess disease activity and severity of systemic lupus erythematosus.

BackgroundIt is well-known that increased frequency of neutrophils was found in patients with systemic lupus erythematosus (SLE). However, the immunomodulatory roles and mechanisms of neutrophils in SLE are poorly understood.MethodsPatients with SLE were recruited from the First Affiliated Hospital of Nanchang University. The medical history, clinical manifestations, physical examination, laboratory measurements, therapeutic regimen and treatment response were recorded. The expression of costimulatory molecules including programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), T-cell immunoglobulin and mucin domain–containing protein 3 (Tim-3), CD40, T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains (TIGIT), CD80 and CD86 on neutrophils were determined by flow cytometry. The frequencies of PD-L1-expressing neutrophils in patients with SLE were further analyzed for their correlation with markers of autoimmune response, inflammation, disease activity and severity of SLE.ResultsThe frequency of PD-L1-expressing neutrophils was significantly elevated in SLE patients compared to the healthy controls (P < 0.0001). The frequency of PD-L1-expressing neutrophils in patients with SLE was increased significantly in subjects with high ANA titre, high anti-nRNP/Sm, high levels of inflammatory markers and high SLE Disease Activity Index (SLEDAI) score. Furthermore, the percentages of PD-L1-expressing neutrophils were significantly decreased in SLE patients that received a 15-day regular treatment with corticosteroids and immunosuppressive drugs (P = 0.0075).ConclusionThe frequency of PD-L1-expressing neutrophils is elevates in patients with SLE, correlates with the disease activity and severity of SLE, and may serves as a negative feedback mechanism preventing potential tissue damage caused by excessive autoimmune responses in patients with SLE.

Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura

BackgroundAcquired thrombotic thrombocytopenic purpura (TTP) is caused by aggregation of platelets on ultralarge von Willebrand factor multimers. This microvascular thrombosis causes multiorgan ischemia with potentially life-threatening complications. Daily plasma exchange and immunosuppressive therapies induce remission, but mortality and morbidity due to microthrombosis remain high.MethodsCaplacizumab, an anti–von Willebrand factor humanized single-variable-domain immunoglobulin (Nanobody), inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. In this phase 2, controlled study, we randomly assigned patients with acquired TTP to subcutaneous caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 days afterward. The primary end point was the time to a response, defined as confirmed normalization of the platelet count. Major secondary end points included exacerbations and relapses.ResultsSeventy-five patients underwent randomization (36 were assigned to receive caplacizumab, and 39 to receive placebo). The time to a response was significantly reduced with caplacizumab as compared with placebo (39% reduction in median time, P=0.005). Three patients in the caplacizumab group had an exacerbation, as compared with 11 patients in the placebo group. Eight patients in the caplacizumab group had a relapse in the first month after stopping the study drug, of whom 7 had ADAMTS13 activity that remained below 10%, suggesting unresolved autoimmune activity. Bleeding-related adverse events, most of which were mild to moderate in severity, were more common with caplacizumab than with placebo (54% of patients vs. 38%). The frequencies of other adverse events were similar in the two groups. Two patients in the placebo group died, as compared with none in the caplacizumab group.ConclusionsCaplacizumab induced a faster resolution of the acute TTP episode than did placebo. The platelet-protective effect of caplacizumab was maintained during the treatment period. Caplacizumab was associated with an increased tendency toward bleeding, as compared with placebo. (Funded by Ablynx; ClinicalTrials.gov number, NCT01151423.)