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ID PMID Title PublicationDate abstract
25180614 CCAAT/enhancer binding protein α (C/EBPα)(+) M2 macrophages contribute to fibrosis in Ig 2015 May IgG4-related disease (IgG4-RD) is a new disease entity characterized by type 2 helper T (Th2)-dominant inflammation and progressive fibrosis. We found the infiltration of strange cell populations in the fibrotic lesions of submandibular gland specimens obtained from 15 patients with IgG4-RD. These cells expressed CCAAT/enhancer binding protein a (C/EBPα). Many of the cell populations were identified with M2 macrophages. The degrees of infiltration of C/EBPα(+)M2 macrophages and the ratio of fibrotic lesions in the specimens were correlated (r(2) = 0.83, p < 0.01). We also analyzed the expression of C/EBPα in other chronic inflammatory disorders: synovium in rheumatoid arthritis (RA), liver tissue in chronic viral hepatitis, and mucosa in ulcerative colitis. The specimens from RA and chronic viral hepatitis showed infiltration of C/EBPα(+) cells, but there were few C/EBPα-positive cells in ulcerative colitis. Fibrosis is not a major issue in ulcerative colitis. In conclusion, we found the remarkable infiltration of C/EBPα(+)M2 macrophages in cases of chronic inflammation with fibrosis, including IgG4-RD. This primitive study also disclosed that most of C/EBPα(+)M2 macrophages localized in fibrotic lesions, and the degree of the infiltration and the ratio of fibrotic area were correlated.
27891294 Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: f 2016 Dec Cachexia is a serious clinical consequence of almost all chronic diseases when reaching advanced stages. Its prevalence ranges from 5-15% in end-stage chronic heart failure to 50-80% in advanced malignant cancer. Cachexia is also frequently occurring in patients with chronic kidney disease, chronic obstructive pulmonary disease (COPD) or neurological diseases, and rheumatoid arthritis. Mortality rates of patients with cachexia range from 15-25% per year in severe COPD through 20-40% per year in patients with chronic heart failure or chronic kidney disease to 20-80% in cancer cachexia. In the industrialized world (North America, Europe, and Japan) where epidemiological data are to some degree available, the overall prevalence of cachexia (due to any disease and not necessarily associated with hospital admission) is growing with the growth of the chronic illness prevalence, and it currently affects around 0.5-1.0% of the population, i.e. around 6-12 million people. From this, one can estimate that 1.5-2 million deaths are occurring in patients with cachexia per year. It is also a very significant health problem in other parts of the globe, but epidemiological data are scarce. The multifactorial nature of cachexia is now much better understood, and particularly, the role of inflammatory mediators and the imbalance of anabolism and catabolism are considered important therapeutic targets. Several approaches to develop cachexia and muscle wasting treatments have failed to be successful in phase III clinical trials, but new approaches are in development. Given the high prevalence and very high mortality associated with cachexia, advances are urgently needed for patients worldwide.
27886163 Alghedon Fentanyl Transdermal System. 2017 Apr The efficacy of transdermal fentanyl for cancer pain and chronic non-cancer pain (chronic lower back pain, rheumatoid arthritis, osteoarthritis, neuropathic pain) is well established. Several formulations of fentanyl transdermal systems have been developed to improve the drug delivery and prevent misuse of the active principle. The addition of a rate controlling membrane to the matrix system represented an important advance. The design and functional features of Alghedon patch are compared with other approved generic fentanyl transdermal systems, emphasizing the distinctiveness of Alghedon patch. Alghedon patch has no liquid component in the finished product, therefore no leakage of active ingredient from the system can occur. A rate-controlling membrane provides controlled release of the active substance from the matrix reservoir, ensuring that fentanyl delivery and entry into the microcirculation is not solely controlled by the skin's permeability to this active substance. Alghedon patch contains part of the drug (approximately 15%) in the skin-contact adhesive: this innovative solution allows to overcome a typical drawback of transdermal patches, i.e. the long lag-time before the drug appears in plasma after the first administration, and provides rapid analgesia during the first hours of administration. Alghedon Fentanyl Transdermal System employs materials commonly used in other transdermal applications and having established safety profiles. For each strength level, the fentanyl content - and, thus, the resulting residual fentanyl remaining in the patch after use - is at the lowest end of the range used in commercially available fentanyl patches, minimizing the potential for abuse and misuse.
27739111 Estimating the Size of the U.S. Population at Risk of Severe Adverse Events from Replicati 2017 May OBJECTIVE: To quantify the population at risk of serious adverse reactions to replicating smallpox vaccine. DESIGN AND SAMPLE: Conditions known or suspected to carry risk were identified via Centers for Disease Control and Prevention planning documents, other federal publications, and peer-reviewed literature. Conditions identified were categorized as historically recognized risks or more recently recognized immunocompromised states that may pose risk. Major historical risk factors were as follows: eczema/atopic dermatitis, pregnancy, HIV, and primary immunodeficiency. More recently identified states were as follows: rheumatoid arthritis, inflammatory bowel disease, dialysis, bone marrow transplant recipients within 24 months post-transplant, solid-organ transplant recipients within 3 months post-transplant, age under 1 year, and systemic lupus erythematosus. MEASURES: The estimated prevalence or absolute number of affected individuals for each condition was ascertained from peer-reviewed studies, vital statistics, and registry databases. RESULTS: An estimated 48,121,280 to 50,028,045 individuals (15.2-15.8% of the U.S. population) are potentially contraindicated to replicating smallpox vaccine. This rises to 119,244,531 to 123,669,327 (37.4-38.8%) if household contacts are included. CONCLUSIONS: These figures are significant and larger than the only previously published study. Understanding this number allows for improved clinical utilization, equitable attention to the health needs of a vulnerable population, and strategic vaccine stockpiling.
27591335 Costimulation Blockade in Autoimmunity and Transplantation: The CD28 Pathway. 2016 Sep 15 T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. TCR signaling in the absence of costimulatory signals can lead to an abortive attempt at activation and subsequent anergy. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic tool is one of the major success stories in modern immunology. Abatacept and belatacept are clinically approved agents for the treatment of rheumatoid arthritis and renal transplantation, respectively. Future interventions may include selective CD28 blockade to block the costimulatory potential of CD28 while exploiting the coinhibitory effects of CTLA-4.
27557899 MicroRNA epigenetic signatures in human disease. 2016 Oct MicroRNAs (miRNAs) are short non-coding RNAs that act as important regulators of gene expression as part of the epigenetic machinery. In addition to posttranscriptional gene silencing by miRNAs, the epigenetic mechanisms also include DNA methylation, histone modifications and their crosstalk. Epigenetic modifications were reported to play an important role in many disease onsets and progressions and can be used to explain several features of complex diseases, such as late onset and fluctuation of symptoms. However, miRNAs not only function as a part of epigenetic machinery, but are also epigenetically modified by DNA methylation and histone modification like any other protein-coding gene. There is a strong connection between epigenome and miRNome, and any dysregulation of this complex system can result in various physiological and pathological conditions. In addition, miRNAs play an important role in toxicogenomics and may explain the relationship between toxicant exposure and tumorigenesis. The present review provides information on 63 miRNA genes shown to be epigenetically regulated in association with 21 diseases, including 11 cancer types: cardiac fibrosis, cardiovascular disease, preeclampsia, Hirschsprung's disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, temporal lobe epilepsy, autism, pulmonary fibrosis, melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal, gastric, cervical, ovarian, prostate, lung, breast, and bladder cancer. The review revealed that hsa-miR-34a, hsa-miR-34b, and hsa-miR-34c are the most frequently reported epigenetically dysregulated miRNAs. There is a need to further study molecular mechanisms of various diseases to better understand the crosstalk between epigenetics and gene expression and to develop new therapeutic options and biomarkers.
27544229 Clinical outcome of posterior C1-C2 pedicle screw fixation and fusion for atlantoaxial ins 2016 Oct We retrospectively studied the clinical results of posterior C1-C2 pedicle screw fixation and fusion for 86 patients diagnosed with atlantoaxial instability from January 2002 to January 2013. The study population included 48 men and 38 women, with an average age of 42.6 (range, 16-69years old). The causes of atlantoaxial instability could be divided into traumatic fracture (44 patients), congenital malformation (17 patients), rheumatoid arthritis (15 patients), and other causes (nine patients). The mean follow-up duration was 33.9months (range, 13-72months). The average operative time was 133.0min (range, 90-290min), and the mean blood loss during the operation was 185.7ml (range, 110-750ml). No patient experienced neurological function worsening related to the surgical procedure. In addition, 63% of the patients who presented with neurological symptoms reported improvement after surgery. Screw placement and reduction was achieved satisfactorily in all the patients and their neck pain was greatly relieved. Plain radiography and CT scans indicated solid fusion after 12months in all the patients. We suggest that C1-C2 pedicle screw internal fixation is a reliable method for treating atlantoaxial instability.
27454074 New molecular targets for the treatment of sarcoidosis. 2016 Sep PURPOSE OF REVIEW: Sarcoidosis is a chronic granulomatous disease typically affecting the lung, lymph nodes, and other organ systems. Evidence suggests that the morbidity and mortality rates for sarcoidosis in the USA are rising, despite widespread use of anti-inflammatory therapies. In this review, we survey new therapies that target specific inflammatory pathways in other diseases (such as rheumatoid arthritis, Crohn's disease, and psoriasis) that are similar to pathways relevant to sarcoidosis immunopathogenesis, and therefore, represent potentially new sarcoidosis therapies. RECENT FINDINGS: Immunopathogenesis of sarcoidosis has been well elucidated over the past few years. There is abundant evidence for T-cell activation in sarcoidosis leading to activation of both Th1 and Th17 inflammatory cascades. Therapies targeting T-cell activation, Th1 pathways (such as the interleukin-6 inhibitors), Th17 pathway mediators, and others have been Food and Drug Administration approved or under investigation to treat a variety of autoimmune inflammatory diseases, but have not been studied in sarcoidosis. Targeting the p38 mitogen-activated protein kinases and the ubiquitine proteasome system with new agents may also represent a novel therapeutic option for patients with sarcoidosis. SUMMARY: Rising morbidity and mortality rates for patients with sarcoidosis strongly support the need to develop more effective anti-inflammatory therapies to treat chronic disease.
27382923 Assessment of fatigue in routine care on a Multidimensional Health Assessment Questionnair 2016 Sep OBJECTIVES: To characterise associations of fatigue with other variables within a multidimensional health assessment questionnaire (MDHAQ) in routine care of patients with different rheumatic diagnoses. METHODS: All patients complete MDHAQ, which includes fatigue on a 0-10 visual analogue scale (VAS), and routine assessment of patient index data (RAPID3), a composite of function, pain, and patient global. Physicians complete a RheuMetric checklist which includes 4 VAS for overall global status (DOCGL), inflammation, damage, and distress. Median score for fatigue and other MDHAQ and RheuMetric scores were compared in 4 diagnosis groups: rheumatoid arthritis (RA), osteoarthritis (OA), systemic lupus erythematosus (SLE), and fibromyalgia (FM), using a Kruskall-Wallis test. Associations of fatigue with other variables were analysed using Spearman correlations and multivariate regressions. RESULTS: 612 patients were included: 173 RA, 199 with OA, 146 with SLE, and 94 with FM. Median fatigue was significantly higher in FM (7) than in RA (4), OA (5), and SLE (5). Fatigue was correlated significantly with all other MDHAQ scores, at higher levels in RA and SLE versus OA and FM. Fatigue was correlated significantly with DOCGL in RA, OA, SLE, but not FM. In multivariate analyses, fatigue scores were explained independently by higher pain and symptom number in RA; lower age and higher symptom number in OA; only higher pain in SLE; and none of the variables in FM. CONCLUSIONS: Fatigue is common in rheumatic diseases and strongly associated with higher pain and number of symptoms. The MDHAQ provides a useful tool to assess fatigue in clinical settings.
27282429 Gold nanoparticles: A critical review of therapeutic applications and toxicological aspect 2016 Gold (Au) compounds have been utilized as effective therapeutic agents for the treatment of some inflammatory diseases such as rheumatoid arthritis. However, Au compound use has become limited due to associated high incidence of side effects. Recent development of nanomaterials for therapeutic use with Au-containing drugs is improving the beneficial actions and reducing toxic properties of these agents. Lower toxicity in conjunction with anti-inflammatory and antiangiogenic effects was reported to occur with gold nanoparticles (AuNP) treatment. However, despite this therapeutic potential, safety of AuNP remains to be determined, since the balance between therapeutic properties and development of adverse effects is not well established. Several variables that drive this benefit-risk balance, including physicochemical characteristics of nanoparticles such as size, shape, surface area, and chemistry, are poorly described in the scientific literature. Moreover, therapeutic and toxicological data were obtained employing nonstandardized or poorly described protocols with different experimental settings (animal species/cell type, route and time of exposure). In contrast, effective and safe application of AuNP may be established only after elucidation of various physicochemical properties of each specific AuNP, and determination of respective kinetics and interaction of compound with target tissue. This critical review conveys the state of the art, the therapeutic use, and adverse effects mediated by AuNP, with primary emphasis on anti-inflammatory and antiangiogenic potential, highlighting the limitations/gaps in the scientific literature concerning important points: (i) selection of experimental designs (in vitro and in vivo models) and (ii) consideration of different physicochemical properties of AuNP that are often disregarded in many scientific publications. In addition, prospects and future needs for research in this area are provided.
27226666 Small clonal B-cell population in the bone marrow as a possible tool in the diagnosis of o 2016 Mar 30 CASE DESCRIPTION: An 82-years old Hispanic woman with a past medical history significant for pulmonary thromboembolism on oral anticoagulation, rheumatoid arthritis, and hypertension developed a new onset thrombocytopenia. CLINICAL FINDINGS: Small clonal B-cells populations (SCBP) also known as monoclonal B-cell lymphocytosis was found as part of the workup for an idiopathic thrombocytopenia and lead ultimately to the diagnosis of parotid primary follicular lymphoma coexisting with Warthin tumor involving the bone marrow in a small extent and oncocytic papilloma located in the maxillary sinus. TREATMENT AND OUTCOME: Patient was treated with Rituximab monotherapy with improvement on her platelet count. CLINICAL RELEVANCE: Although it is unclear the role of this clonal cells, they may work as a possible diagnostic tool for occult lymphomas. Further prospective studies are needed to confirm this possible association.
27044681 FCGR3A-V158F polymorphism is a disease-specific pharmacogenetic marker for the treatment o 2017 Jun Psoriasis is a multifactorial skin disease affecting ~2% of world's population, causing a dramatic decrease in patients' quality of life and a significant increase in health-care expenses. Biological agents such as the anti-TNFα ones had an enormous impact in patients' therapy; however, a significant proportion of them do not respond well, an outcome attributed mainly to genetic factors. Recently, in a large European cohort of rheumatoid arthritis patients we have shown association with variation in the receptors that correspond to the Fc portion of the biological agents. As both diseases share common immunological fingerprints, we examined the hypothesis that they share common pharmacogenetic markers. Analysis of FCGR2A-H131R and FCGR3A-V158F polymorphisms in 100 psoriasis patients showed association only with respect to FCGR3A-V158F and response to etanercept (P=0.018). Interestingly, no association was found between FCGR2A-H131R and response to anti-TNFα therapy (P=0.882). This study suggests a role for FCGR3A-V158F polymorphism unique for psoriasis.
26947177 What rheumatologists should know about orofacial manifestations of autoimmune rheumatic di 2016 Feb 11 Orofacial manifestations occur frequently in rheumatic diseases and usually represent early signs of disease or of its activity that are still neglected in clinical practice. Among the autoimmune rheumatic diseases with potential for oral manifestations, rheumatoid arthritis (RA), inflammatory myopathies (IM), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), relapsing polychondritis (RP) and Sjögren's syndrome (SS) can be cited. Signs and symptoms such as oral hyposalivation, xerostomia, temporomandibular joint disorders, lesions of the oral mucosa, periodontal disease, dysphagia, and dysphonia may be the first expression of these rheumatic diseases. This article reviews the main orofacial manifestations of rheumatic diseases that may be of interest to the rheumatologist for diagnosis and monitoring of autoimmune rheumatic diseases.
26921132 The use of auto-antibody testing in the evaluation of interstitial lung disease (ILD)--A p 2016 Apr Interstitial lung diseases (ILD), also defined as diffuse parenchymal lung diseases (DPLD) include a heterogeneous group of pulmonary disorders. They may be caused by an underlying connective tissue disease (CTD), Rheumatoid Arthritis (RA) or ANCA-associated Vasculitis (AAV). Pulmonary manifestations of these conditions may also precede systemic onset and therefore, pulmonologists may be confronted with diagnosing a systemic rheumatic disease. For the discrimination of CTD-related ILD and idiopathic interstitial pneumonia (IIP), serological testing is recommended. After careful reviewing the available literature, we suggest a serologic diagnostic algorithm for pulmonologists dealing with ILD-patients. This algorithm depicts the consensus for antibody testing that was reached amongst authors. Obviously this consensus approach requires further validation in everyday practice and leaves room for local adaption of the diagnostic strategy depending on the availability of diagnostic capacity and cost. It is our hope, however, that the rational and stepwise approach of serological testing for ILD will ultimately save unnecessary expenses associated with general laboratory screening. Finally a broader consensus on the strategy for laboratory testing in ILD in general might also improve the detection level of these relatively rare diseases and this will ultimately improve management and care of patients suffering from these complex disorders.
26865172 Chronic Granulomatous Disease. 2016 Apr Chronic granulomatous disease (CGD) is the most common symptomatic phagocytic defect. It is caused by mutations in genes encoding protein subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD is characterized by a defective intracellular killing of phagocytosed organisms due to a defective oxidative burst in the neutrophils and macrophages. It is inherited in either X-linked recessive or autosomal recessive pattern. Staphylococcus aureus and Aspergillus species are the most common organisms reported. Infections with Burkholderia, Serratia, and Nocardia warrant a screen for CGD. Suppurative lymphadenitis, cutaneous abscesses, pneumonia and diarrhea constitute the most common problems in children with CGD. A small percentage of children develop autoimmune manifestations (e.g., rheumatoid arthritis, systemic lupus erythematosus, colitis, autoimmune hepatitis) and warrant immunosuppression. X-linked carriers of CGD are at an increased risk of developing autoimmune diseases. Nitroblue-tetrazolium dye reduction test and dihydro-rhodamine assay by flow cytometry are the screening tests for this disorder. While most children do well on long term antibiotic and antifungal prophylaxis, those with severe forms warrant hematopoietic stem cell transplant. The role of regular interferon-γ injections is debatable. Evidence for white cell transfusions is sparse, and gene therapy is under trial.This current review highlights various aspects and studies in CGD. X-linked form of CGD has been noted to carry a poorer prognosis compared to autosomal recessive variants. However, recent evidence suggests that outcome in CGD is determined by the amount of residual NADPH oxidase activity irrespective of mode of inheritance.
30090373 Dephosphorylation of Tak1 at Ser412 greatly contributes to the spermatocyte-specific testi 2016 Mar 1 (5R)-5-Hydroxytriptolide (LLDT-8), a novel triptolide derivative, will proceed to phase II clinical trials for the treatment of rheumatoid arthritis and cancer. However, the selection of disease and patients is largely limited by the testis toxicity, yet toxicity mechanisms are still poorly understood. In this study, LLDT-8 dose and time-dependently decreased the testes weight, germinal cell layers and induced abnormal spermatid development. Analysis of the germ cell-specific marker showed that spermatocytes were more sensitive to LLDT-8, which was confirmed by the in vitro sensitivity assay with spermatocyte-like GC-2spd and sertoli-like TM4 cells. In GC-2spd, LLDT-8 induced G1/S arrest and apoptosis. MAPK activity screening identified that TGF-β activated kinase 1 (Tak1) is critical in LLDT-8 induced apoptosis. LLDT-8 reduced the Tak1 protein and dephosphorylated Tak1 at Ser412 in GC-2spd and the testes, but not in TM4. RNAi mediated depletion or pharmacologic inhibition of Tak1 induced apoptosis in GC-2spd. Meanwhile, activating Tak1 rescued up to 50% of the GC-2spd cells from the apoptosis induced by LLDT-8. Altogether, our study firstly revealed the important role of Tak1 in the survival of spermatocytes, and dephosphorylation of Tak1 at Ser412 may contribute to the spermatocyte-specific testis toxicity induced by LLDT-8.
26641498 Association of Extrahepatic Manifestations with Autoimmune Hepatitis. 2015 For many patients with autoimmune hepatitis (AIH), the presence of extrahepatic features is well recognised both at the time of presentation and during long-term follow-up. Concomitant 'autoimmune disorders' have been described in 20-50% of patients with AIH, both in adults and children. Indeed, the presence of these associated phenomena has been incorporated into both the original and revised International AIH group scoring systems as an aid to codifying the diagnosis. In acute index presentations, non-specific joint pains sometimes flitting in nature have been reported in 10-60% of patients, and while joint swelling is uncommon, rheumatoid arthritis and mixed connective tissue disease have been reported in 2-4% of patients with AIH. For a majority of patients, these joint symptoms resolve within days of the introduction of immunosuppressive therapy. Rarer features at index presentation include a maculopapular skin rash and unexplained fever, which are features that tend to resolve quickly with treatment. Interestingly, joint pain and stiffness are also well recognised in the context of steroid withdrawal and cessation in AIH. The occasional co-presentation of AIH with coeliac disease is clinically important (1-6%), since for some patients, there is a risk of immunosuppression malabsorption, thus delaying effective treatment. Similarly, the co-existence of selective IgA deficiency (IgAD) can occur in patients with coeliac disease or in isolation. Selective IgAD as a co-existing extraheaptic feature seems to be more common in paediatric patients with AIH. For these patients, they are at an increased risk of respiratory and sinus infections. Although, typically associated with primary sclerosing cholangitis, the presence of inflammatory bowel disease (IBD; both Crohn's disease and ulcerative colitis) has been described in 2-8% of patients with AIH. Interestingly, for patients with autoimmune sclerosing cholangitis, a distinct pattern of IBD has been recently described. Other conditions have been reported at a lower frequency, including Sjogren's syndrome 1-7%, systemic lupus erythematosus 1-3% and glomerulonephritis 1%. Rarer still and at a frequency of <1% include fibrosing alveolitis, haemolytic anaemia, uveitis, mononeuritis multiplex, polymyositis and multiple sclerosis. In contrast, the reported associations between AIH and thyroiditis 8-23%, diabetes 1-10% and psoriasis 3% are commonly seen and notable in clinical practice.
26562453 AMSSM Scientific Statement Concerning Viscosupplementation Injections for Knee Osteoarthri 2016 Jan OBJECTIVE: Osteoarthritis (OA) is a disabling disease that produces severe morbidity reducing physical activity. Our position statement on treatment of knee OA with viscosupplementation injection [hyaluronic acid (HA)] versus steroid [intra-articular corticosteroid (IAS)] and placebo [intra-articular placebo (IAP)] is based on the evaluation of treatment effect by examining the number of subjects within a treatment arm that met the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria, which is different and more relevant than methods used in other reviews which examined if the average change across the treatment groups was clinically different. DATA SOURCES: We performed a systematic literature search for all relevant articles from 1960 to August 2014 in the MEDLINE, EMBASE, and Cochrane CENTRAL. We performed a network meta-analysis (NMA) of the relevant literature to determine if there is a benefit from HA as compared with IAS and IAP. MAIN RESULTS: Eleven articles met the inclusion criteria from the search strategy. On NMA, those subjects receiving HA were 15% and 11% more likely to respond to treatment by the OMERACT-OARSI criteria than those receiving IAS or IAP, respectively (P < 0.05 for both). CONCLUSIONS: In light of the aforementioned results of our NMA, the American Medical Society for Sport Medicine recommends the use of HA for the appropriate patients with knee OA.
26497517 The era of the immunoglobulin A Fc receptor FcαRI; its function and potential as target i 2015 Nov Immunoglobulin A (IgA) is the most prevalent antibody at mucosal sites, and has an important role in defense by preventing invasion of pathogens. Traditionally, IgA has been thought of as a non-inflammatory antibody that helps to maintain homeostasis in the mucosa. However, in the last decade it has become clear that IgA is a very potent stimulus to initiate pro-inflammatory cellular processes, especially after triggering the IgA Fc receptor (FcαRI) on neutrophils. It was furthermore described that FcαRI acts as a regulator between anti- and pro-inflammatory responses of IgA. Although neutrophil activation is beneficial in (mucosal) infections, abnormal or excessive IgA immune complexes can induce disproportionate neutrophil migration and in this way initiate a perpetuating neutrophil recruitment and activation loop, which will result in severe tissue damage. Increasing evidence on this process plays a detrimental role in several diseases, including autoimmune IgA blistering diseases, a subtype of rheumatoid arthritis and ulcerative colitis. Inhibiting FcαRI-mediated activation may dampen inflammation in these patients. This process also opens up the possibility of targeting FcαRI in antibody immunotherapy of cancer. Thus, interfering with IgA-mediated FcαRI activation may represent an attractive novel therapeutic strategy for multiple maladies.
26341110 BTK Signaling in B Cell Differentiation and Autoimmunity. 2016 Since the original identification of Bruton's tyrosine kinase (BTK) as the gene defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) in 1993, our knowledge on the physiological function of BTK has expanded impressively. In this review, we focus on the role of BTK during B cell differentiation in vivo, both in the regulation of expansion and in the developmental progression of pre-B cells in the bone marrow and as a crucial signal transducer of signals downstream of the IgM or IgG B cell antigen receptor (BCR) in mature B cells governing proliferation, survival, and differentiation. In particular, we highlight BTK function in B cells in the context of host defense and autoimmunity. Small-molecule inhibitors of BTK have very recently shown impressive anti-tumor activity in clinical studies in patients with various B cell malignancies. Since promising effects of BTK inhibition were also seen in experimental animal models for lupus and rheumatoid arthritis, BTK may be a good target for controlling autoreactive B cells in patients with systemic autoimmune disease.