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ID PMID Title PublicationDate abstract
25606553 Long-term outcome of low contact stress total knee arthroplasty with different mobile bear 2014 Jul PURPOSE: to evaluate the differences in clinical outcome and survivorship of three different mobile bearings for total knee arthroplasty. METHODS: a retrospective study was conducted in 60 patients (53 females, 7 males, mean age: 68 years and 5 months) each submitted to total knee replacement using one of the three different mobile bearings of the LCS system (Depuy Johnson & Johnson, Warsaw, IN). The diagnosis was knee osteoarthritis in 57 cases and rheumatoid arthritis in three cases. Three different groups of 20 cases each were identified: total knee arthroplasties with mobile menisci (group 1); total knee arthroplasties with the rotating platform (group 2); and total knee arthroplasties with the anteroposterior glide platform (group 3). As regards the component fixation, 33 implants were cementless, three were cemented, and in 24 only the tibial component was cemented. The patella was not replaced. RESULTS: although the duration of follow-up differed between the three groups, the clinical and radiological results at final follow-up showed no revision of femoral and/or tibial components for mechanical or septic reasons, and no signs of impending failure. One meniscal bearing, showing polyethylene wear after 17 years, was successfully replaced. CONCLUSIONS: the present retrospective study confirmed the long-term effectiveness of knee implants with mobile bearings, in which the congruity of the surfaces makes it possible to overcome the problem of high contact stresses that may result in polyethylene wear and osteolysis; at the same time, these implants eliminate constraint forces thereby reducing the risk of mechanical loosening. LEVEL OF EVIDENCE: Level III, retrospective comparative study.
25453655 Hemophagocytic lymphohistiocytosis: a case series of a Brazilian institution. 2014 Nov OBJECTIVE: To describe the clinical and laboratory presentation of hemophagocytic lymphohistiocytosis in children treated at a referral institution. METHODS: A retrospective descriptive study was carried out of seven children diagnosed with hemophagocytic lymphohistiocytosis between 2010 and 2012. The criteria for diagnosis were those proposed by the Histiocyte Society. When indicated, immunochemotherapy was prescribed according to the HLH94 and HLH2004 protocols of the Histiocyte Society. RESULTS: The patients' ages at diagnosis ranged from one month to nine years. All patients had splenomegaly, fever, anemia, thrombocytopenia, hyperferritinemia and hypertriglyceridemia. Bone marrow hemophagocytosis was detected in six patients. In six cases, infectious diseases triggered the syndrome. In two cases, associated with visceral leishmaniasis, remission was achieved after treatment of the underlying infection. Three patients, who had Epstein-Barr-related hemophagocytic lymphohistiocytosis, required treatment with immunochemotherapy. They are alive and in remission; one patient had symptoms of juvenile rheumatoid arthritis and another, who was suspected of having primary hemophagocytic lymphohistiocytosis, entered into remission after bone marrow transplantation. Two deaths (28.6%) occurred in patients with suspected primary hemophagocytic lymphohistiocytosis; one whose clinical picture was triggered by cytomegalovirus infection did not respond to immunochemotherapy and the other died before any specific treatment was provided. CONCLUSION: As reported before, hemophagocytic lymphohistiocytosis has a multifaceted presentation with nonspecific signs and symptoms. In secondary forms, remission may be achieved by treating the underlying disease. In the primary forms, remission may be achieved with immunochemotherapy, but bone marrow transplantation is required for cure.
25449677 The mechanisms behind helminth's immunomodulation in autoimmunity. 2015 Feb The incidence of autoimmune diseases has risen throughout the last half a century, mostly in the industrialized world. Helminths and their derivatives were found to have a protective role in autoimmunity and inflammatory conditions, as they manipulate the immune network, attenuating the host's cellular and humoral responses. Indeed, various helminth species used in several human and animal models were shown to limit inflammatory activity in a variety of diseases including inflammatory bowel disease, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis. Our review will focus on the main mechanisms by which helminths and their secreted molecules modulate the host's immune system. The main pathways induce a shift from Th1 to Th2 phenotype, accelerate T regulatory and B regulatory phenotypes, and attenuate the levels of the inflammatory cytokines, leading to a tolerable scenario.
25424335 [Relaxation treatments and biofeedback for anxiety and somatic stress-related disorders]. 2014 Sep INTRODUCTION: Relaxation techniques (TR) and biofeedback (BFB) are widely used in psychiatric and psychological practice for the treatment for anxiety and stress-related disorders. METHODS: An examination of studies focusing on the correlates of psychophysiology of relaxation and biofeedback has been done, in addiction to controlled therapeutic studies that describes clinical aspects, efficacy and limits. RESULTS: There are different TR and BFB procedures, but they have the same goal and same physiological modifications, resulting in stress and anxiety reduction. There is a proven action to musculoskeletal, neuroendocrine and autonomic nervous system, showing similar results. Very few data on immune changes are available. Meta-Analysis show superior efficacy to no treatment or placebo in anxiety disorders, tension headache, bruxism, temporomandibular pain syndrome, rehabilitation and prevention of ischemic heart disease. Moderate efficacy is shown for chronic low back pain, cancer-related pain, rheumatoid arthritis and gastrointestinal disorders; data for essential hypertension are controversial. Variability of techniques, procedures, sampling problems, non-systematic make definitive conclusions difficult. TR and BFB are often used in combination with cognitive-behavioral and educational techniques. The association of the active relaxation technique facilitates generalization and self-control during stress situation and outside the training session. CONCLUSIONS: TR and BFB are effective for anxiety and somatic stress-related disorders, associated with coping and quality of life improvement and affordable costs; they are minimally invasive but needing an active participation in the treatment process. Some limits are responders' prediction, continuity of practice and limited effectiveness for depression disorders. Finally, it is shown that they are real psychosomatic therapies that are able to produce somatic peripheral changes (neuroendocrine, neurovegetative and muscular systems) generated by the mind and secondary to the involvement of central neurotransmitter circuits.
25381328 Natural antisense RNAs are involved in the regulation of CD45 expression in autoimmune dis 2015 Mar CD45 is a transmembrane protein tyrosine phosphatase that is specifically expressed in hematopoietic cells and can initiate signal transduction via the dephosphorylation of tyrosine. Alternatively spliced transcript variants of this gene encode distinct isoforms, which indicate different functional states of CD45. Among these variants, CD45RO, which contains neither exon 4, 5, or 6, is over-expressed in lymphocytes in autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type I diabetes. The CD45 RO serves as a marker of the immune response activity and lymphocyte development. Previous studies have indicated that exon splicing is generally correlated with local hypermethylated DNA and acetylated histone modification, while autoimmune diseases are commonly associated with global hypomethylation and histone deacetylation in lymphocytes. Thus, the question arises of how exons 4, 5, and 6 of CD45RO are excluded under the status of global DNA hypomethylation and histone deacetylation in these autoimmune diseases. On the basis of the analyses of the context sequence of CD45 and its natural antisense RNA in GenBank, we proposed that the long noncoding RNA encoded by the natural antisense gene of CD45 contributes to the expressional regulation of the CD45RO splicing variant via recruitment of DNA methyltransferase and histone modification modulators specific to the sense gene CD45; thus, it is associated with the over-expression of CD45RO and the functional regulation of lymphocytes in the pathogenic development of autoimmune diseases.
25251383 Synthesis of [(3) H], [(13) C3 , (15) N], and [(14) C]SCH 900567: an inhibitor of TNF-α ( 2014 Sep SCH 900567 is a specific inhibitor of tumor necrosis factor-alpha converting enzyme and is a potential candidate for the treatment of rheumatoid arthritis. [(3) H]SCH 900567 was synthesized to support the initial drug metabolism and pharmacokinetics studies. Stable isotope-labeled [(13) C3 , (15) N]SCH 900567 was requested by the bioanalytical group as an internal standard for Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development as well as by the drug metabolism and pharmacokinetics group for a potential microdose study. [(13) C3 , (15) N]SCH 900567 is synthesized via a linear sequence of seven steps from commercially available materials in 2.6% overall yield. [(14) C]SCH 900567 was needed for a quantitative whole body autoradiography studies and was prepared from unlabeled Active Pharmaceutical Ingredient (API) via hydrolysis of the hydantoin moiety followed by rebuilding the hydantoin ring using potassium [(14) C]cyanate to give the desired product in 42.8% overall yield. Activation of the hydantoin moiety of SCH 900567 to achieve hydrolysis followed by derivatization of the resulting amino acid to avoid decarboxylation during cyclization is also discussed.
25245056 The protocol for the isolation and cryopreservation of osteoclast precursors from mouse bo 2016 Jan Osteoclasts are responsible for physiological bone remodeling as well as pathological bone destruction in osteoporosis, periodontitis and rheumatoid arthritis, and thus represent a pharmacological target for drug development. We aimed to characterize and compare the cytokine-induced osteoclastogenesis of bone marrow and spleen precursors. Established protocols used to generate osteoclasts from bone marrow were modified to examine osteoclastogenesis of the spleen cells of healthy mice. Osteoclast formation was successfully induced from spleen precursors using receptor activator of nuclear factor κB ligand (50 ng/ml) and macrophage colony stimulating factor (50 ng/ml). Compared to bone marrow cultures, differentiation from spleen required a longer cultivation time (9 days for spleen, as compared to 5 days for marrow cultures) and a higher plating density of non-adherent cells (75,000/cm(2) for spleen, as compared to 50,000/cm(2) for bone marrow). Osteoclasts generated from spleen precursors expressed osteoclast marker genes calcitonin receptor, cathepsin K and matrix metalloproteinase 9 and were capable of resorbing hydroxyapatite. The differentiation capacity of spleen and bone marrow precursors was comparable for BALB/c, C57BL/6 and FVB mice. We also developed and tested a cryopreservation protocol for the osteoclast precursors. While 70-80 % of cells were lost during the first week of freezing, during the subsequent 5 weeks the losses were within 2-5 % per week. Osteoclastogenesis from the recovered bone marrow precursors was successful up to 5 weeks after freezing. Spleen precursors retained their osteoclastogenic capacity for 1 week after freezing, but not thereafter. The described protocol is useful for the studies of genetically modified animals as well as for screening new osteoclast-targeting therapeutics.
25129049 Secretory expression of a bispecific antibody targeting tumor necrosis factor and ED-B fib 2014 Dec Specific targeting of tumor necrosis factor (TNF)-α antagonist to the inflamed site could increase its efficacy and reduce side-effects. Here, we constructed a bispecific diabody (BsDb) that targets TNF-α and ED-B-containing fibronectin, a fibronectin isoform specifically expressed in the pannus of the inflamed synovium in rheumatoid arthritis. BsDb was secreted from Pichia pastoris as functional protein and was purified to homogeneity. BsDb could simultaneously bind to human TNF-α and B-FN and neutralize TNF-α action. Additionally, BsDb showed a significant gain both in the antigen-binding affinity and in TNF-α-neutralizing ability as compared to its original antibodies, L19 and anti-TNF-α scFv, which were produced in E. coli. BsDb was constructed and was endowed with enhanced bioactivities and improved production processing. Therefore, it holds great potential for in vivo applications.
24959806 Material awareness on natural feeding. 2014 INTRODUCTION: Natural breastfeeding is the only proper way to feed newborns and infants because it ensures their proper development. Breastfeeding enhances health and protects against the development of many diseases in childhood and adulthood. The primary benefits of breastfeeding include reduced incidences of infection in the respiratory system as well as a reduction in gastrointestinal and systemic infections. The benefits of breastfeeding also include decreased inflammation and improved immunity to disease in the infant. Further benefits of breastfeeding are reduced incidences of type 1 diabetes, Crohn's disease, and rheumatoid arthritis. OBJECTIVE: The aim of the study was to assess the degree of knowledge on maternal breastfeeding among current expecting mothers. MATERIALS AND METHOD: The study comprtisded 147 mothers hospitalized in the Gynecology-Obstetrics Hospital University of Medical Sciences in Poznań, Poland, during late July - August 2012. RESULTS: For 139 (93.88%) of the surveyed women, breastfeeding was a priority regarding the health of the child. Respondents most often used professional literature in order to gain knowledge about breastfeeding (63.27%). The least popular way of acquiring knowledge was through the media (27.21%). CONCLUSIONS: Analysis of the collected material on the surveyed women showed that women have a diverse range of knowledge about breastfeeding. Currently, breastfeeding is required to be promoted and supported by midwives, paediatricians and other health professionals.
24955272 Septic bursitis in an 8-year-old boy. 2014 Background. The prepatellar bursa can become inflamed owing to repeated trauma. Prepatellar bursitis is extremely rare in children. Methods. We report the case of an 8-year-old boy who was treated for an erythematous, swollen, and severely painful right knee, fever, inability to bear weight on the leg, and purulent material draining from a puncture wound. We describe the differential diagnosis for tender swollen knee, including infection, gout, rheumatoid arthritis, and osteoarthritis. If untreated, prepatellar bursitis can progress to patellar osteomyelitis. Results. Wound cultures grew Streptococcus pyogenes, with the infection resolving with amoxicillin. Conclusions. A high index of suspicion is necessary in children presenting with prepatellar bursitis to prevent potentially devastating sequelae of infection of the septic joint.
24924726 [Polymyalgia rheumatica in daily routine practice]. 2014 Jun DEFINITION AND EPIDEMIOLOGY: Polymyalgia rheumatica (PMR) is a very painful inflammatory disease which regularly affects the shoulder region but in 70% of cases the pelvic girdle region is also affected. The disease occurs in people over the age of 50 years and reaches a peak at 72 years old. Women are affected twice as often as men. The prevalence is estimated to be 0.3-0.7% in the Caucasian population over 50 years old. DIAGNOSTICS AND CLASSIFICATION: Misdiagnosis of PMR is common. The differential diagnosis primarily includes impingement syndrome, osteoarthritis of the shoulders, calcifying tendinitis of the rotator cuff, bursitis, omarthritis or inflammatory rheumatic diseases, such as rheumatoid arthritis. Taking a structured medical history and performing a thorough clinical examination are crucial. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are usually highly elevated and should be investigated particularly in patients who present with new onset bilateral shoulder pain and pronounced general impairment of movement. Imaging shows characteristic inflammatory changes around the shoulders and hip joints. The new European League Against Rheumatism and American College of Rheumatology (EULAR/ACR) classification criteria of PMR including ultrasound imaging are superior to previous classification and diagnostic criteria in terms of positive and negative predictive values. THERAPY: Glucocorticoids are still the mainstay of treatment. Recommended daily prednisolone starting doses are between 15 mg and 25 mg with a weekly dose reduction until 10 mg/day and then further dose reductions of 1 mg per month. Methotrexate can aid reducing prednisolone doses in patients who fail to reach doses below the Cushing threshold quickly enough, which can have major side effects.
24896264 A novel phage-library-selected peptide inhibits human TNF-α binding to its receptors. 2014 Jun 3 We report the identification of a new human tumor necrosis factor-alpha (TNF-α) specific peptide selected by competitive panning of a phage library. Competitive elution of phages was obtained using the monoclonal antibody adalimumab, which neutralizes pro-inflammatory processes caused by over-production of TNF-α in vivo, and is used to treat severe symptoms of rheumatoid arthritis. The selected peptide was synthesized in monomeric and branched form and analyzed for binding to TNF-α and competition with adalimumab and TNF-α receptors. Results of competition with TNF-α receptors in surface plasmon resonance and melanoma cells expressing both TNF receptors make the peptide a candidate compound for the development of a novel anti-TNF-α drug.
24854413 Targeting inflammation in the treatment of type 2 diabetes: time to start. 2014 Jun The role of inflammation in the pathogenesis of type 2 diabetes and associated complications is now well established. Several conditions that are driven by inflammatory processes are also associated with diabetes, including rheumatoid arthritis, gout, psoriasis and Crohn's disease, and various anti-inflammatory drugs have been approved or are in late stages of development for the treatment of these conditions. This review discusses the rationale for the use of some of these anti-inflammatory treatments in patients with diabetes and what we could expect from their use. Future immunomodulatory treatments may not target a specific disease, but could instead act on a dysfunctional pathway that causes several conditions associated with the metabolic syndrome.
24781610 First metatarsophalangeal joint fusion using a Fyxis plate. 2014 Apr PURPOSE: To report the outcome of fusion of the first metatarsophalangeal joint (MTPJ) using the Fyxis plate and compression screws. METHODS: Medical records of 12 men and 39 women (54 feet) aged 28 to 74 (mean, 58) years who underwent primary fusion of the first MTPJ using the Fyxis plate and compression screws for hallux rigidus (n=38), severe hallux valgus (n=8), or rheumatoid arthritis (n=8) were reviewed. The outcome measures included the fusion rate, time to fusion, complication rate, hallux valgus angle, dorsiflexion angle, and the American Orthopaedic Foot and Ankle Society (AOFAS) scale. RESULTS: The mean follow-up was 14.8 (range, 12-20) months. The mean time to fusion was 3.2 months. 48 feet achieved complete fusion at 3 months, 5 at 6 months, and one had non-union at 12 months, which was treated with revision surgery. The mean hallux valgus angle improved from 23º to 12º. The mean dorsiflexion angle improved from 22º to 23º. The mean AOFAS scale score improved from 31 to 86. 98% of the feet achieved a score of >72. One patient with non-union had a score of 59. Two feet developed superficial wound infection, which resolved with antibiotic treatment. Two other feet developed numbness over the medial aspect of the great toe, which persisted after one year. CONCLUSION: The outcome of fusion of the first MTPJ using the Fyxis plate and compression screws was good.
24779686 Mechanisms of pathogenesis in allergic asthma: role of interleukin-23. 2014 Jul Asthma is a chronic airway inflammatory disease characterized by intense leukocyte and eosinophilic infiltration accompanied by mucus hypersecretion and tissue hyperresponsiveness. Recent evidence suggests that T-helper (Th)2 cells and their cytokine products orchestrate the pathology of asthma. In addition, Th17 cells are implicated in the pathogenesis of antigen-induced airway inflammation. The Th17 related cytokine interleukin (IL)-23 plays important roles in many immunological diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, psoriasis and inflammatory bowel disease. Several reports describe the role of IL-23 in the pathogenesis of allergic asthma in both human and mice. IL-23 leads to neutrophil infiltration in the airway of asthmatic mice, which is characteristic of severe asthma resulting from Th17 development and subsequently IL-17 secretion. IL-23 can also promote eosinophil infiltration in the airway, which is a hallmark of allergic asthma. These studies suggest that IL-23 could be a promoting factor in the development of allergic asthma and likewise would be a target for asthma therapy. In support of this view, trials of anti-IL-23 therapy have been attempted in human and mouse asthma models with encouraging outcomes. This review presents the role of IL-23 in asthma according to recent clinical trials and animal model studies. The proposed mechanisms of IL-23-induced airway inflammation and the agents currently being tested that target IL-23 related pathways are discussed.
24606515 Metabolism of HDL and its regulation. 2014 Epidemiological studies have shown that low plasma levels of High Density Lipoprotein Cholesterol (HDL-C) are associated with an increased risk for myocardial infarction. These studies suggested that by increasing HDL-C levels one could reduce cardiovascular risk. However, emerging evidence from studies in animals and humans indicate that high levels of HDL-C are not sufficient to confer atheroprotection but that the functionality of the HDL particles is equally important. The picture is complicated further by the finding that HDL functionality is compromised in patients with chronic inflammatory diseases such as Coronary Artery Disease (CAD), diabetes and rheumatoid arthritis. Despite these obstacles, HDL raising is still a promising strategy for the reduction of CAD risk. Low HDL-C can be caused by inactivating mutations in apoA-I, ATP Binding Cassette Transporter A1 (ABCA1) or Lecithin-Cholesterol Acyl Transferase (LCAT) which affect HDL biogenesis and maturation whereas high HDL-C can be caused by mutations in Cholesteryl Ester Transfer Protein (CETP) or Scavenger receptor Class B Type I (SR-BI). Recent studies suggest that heterogeneity in HDL levels in the population is polygenic in origin. One approach to raise plasma HDL-C is to increase the rate of HDL biosynthesis by capitalizing on the mechanisms that control the transcription of genes that play key roles in HDL biogenesis. We review some of the genetic and non-genetic factors that affect plasma HDL levels and functions and discuss the mechanisms that regulate HDL metabolism at the level of gene transcription in the liver focusing on apoA-I, ABCA1 and apoM.
24470159 Prospective virtual screening in a sparse data scenario: design of small-molecule TLR2 ant 2014 Apr Toll-like receptors (TLRs) are critical signaling molecules with roles in various severe clinical conditions such as sepsis and rheumatoid arthritis, and have therefore been advocated as promising drug targets for the treatment of these diseases. The aim of this study was to discover small-molecule antagonists of TLR2 by computer-aided drug design. This goal poses several challenges due to the lack of available data on TLR2 modulators. To overcome these hurdles we developed a combined structure- and ligand-based virtual screening approach. First, we calculated molecular interaction fields of the TLR2 binding site to derive a structure-based 3D pharmacophore, which was then used for virtual screening. We then performed a two-step shape- and feature-based similarity search using known TLR2 ligands as query structures. A selection of virtual screening hits was biologically tested in a cell-based assay for TLR2 signaling inhibition, leading to the identification of several compounds with antagonistic activity (IC50 values) in the low-micromolar range.
24418763 Epigenetics in 2013. DNA methylation and miRNA: key roles in systemic autoimmunity. 2014 Feb Several advances in 2013 have improved our understanding of how epigenetic mechanisms affect autoimmune disorders. Many new insights were made into the regulation of gene expression by DNA methylation in systemic lupus erythematosus. For rheumatoid arthritis, complex interrelationships between DNA methylation and microRNAs in regulating gene expression were described.
24242851 Seven nonsynonymous SNPs in the gene encoding human deoxyribonuclease II may serve as a fu 2013 Dec Many nonsynonymous SNPs in the human DNase II gene (DNASE2), potentially relevant to autoimmunity in conditions such as rheumatoid arthritis, have been identified, but only limited population data are available and no studies have evaluated whether such SNPs are functional. Genotyping of all the 15 nonsynonymous human DNase II SNPs was performed in three ethnic groups including 16 different populations using the PCR-restriction fragment length polymorphism technique. A series of constructs corresponding to each SNP was examined. Fifteen nonsynonymous SNPs in the gene, except for p.Val206Ile in a Korean population, exhibited a mono-allelic distribution in all of the populations. On the basis of alterations in the activity levels resulting from the corresponding amino acid substitutions, four activity-abolishing and five activity-reducing SNPs were confirmed to be functional. The amino acid residues in activity-abolishing SNPs were conserved in animal DNase II. All the nonsynonymous SNPs that affected the catalytic activity of human DNase II showed extremely low genetic heterogeneity. However, a minor allele of seven SNPs producing a loss-of-function or extremely low activity-harboring variant could serve as a genetic risk factor for autoimmune dysfunction. These functional SNPs in DNASE2 may have clinical implications in relation to the prevalence of autoimmune diseases.
24117236 The Fc receptor-like 3 gene polymorphisms and susceptibility to autoimmune diseases: an up 2013 Dec Previous studies have identified several single nucleotide polymorphisms (SNPs) of Fc receptor-like 3 (FCRL3), an excellent susceptibility gene, as predisposing factors for human autoimmune diseases (ADs). However, the results remain inconclusive. To assess the effect of four selected SNPs (rs7528684, rs11264799, rs945635 and rs3761959), we conducted a meta-analysis with 34 case-control studies. Summary odd ratios (ORs) and 95% confidence intervals (95% CIs) for the polymorphisms in FCRL3 and ADs risk were evaluated. Furthermore, this meta-analysis was performed by using allele comparisons, as well as stratified analyses by ethnicity and disease phenotypes under different genetic models. Our data showed that the TC, TT + TC genotypes of rs7528684 contributed to a lower risk of ADs, compared with the CC carriers (OR = 0.91, 95% CI = 0.85-0.97; OR = 0.91, 95% CI = 0.85-0.98). In comparison with rs7528684 TC genotype, the TT + CC carriers were significantly associated with higher ADs risk (OR = 1.03, 95% CI = 1.00-1.07). In terms of stratified analyses by ethnicity and disease phenotypes, there were significant associations of rs7528684 polymorphism both with ADs in Asians and Europeans, and with rheumatoid arthritis, Graves' disease, type-1 diabetes, and other ADs under different genetic models. Moreover, significant associations were also found to be correlated with ADs risk for the SNP rs11264799 in mixed subgroup, for rs945635 in Europeans, North Americans and mixed group, and for rs3761959 in North Americans. These findings indicate that the polymorphisms in FCRL3 may play a role in the pathogenesis of ADs.