IgG Ratio Research Articles

Cytomegalovirus infection and atherosclerosis risk: A meta-analysis.

Human cytomegalovirus (HCMV) infection is an important risk factor for atherosclerosis (AS). Numerous studies have been conducted to analyze the association between HCMV infection and risk of AS, but no clear consensus has been reached. So the objective of this paper was aimed to demonstrate the relationship between HCMV and AS by doing a meta-analysis. Relative literature was searched through the electronic databases PubMed, Embase, and CNKI. Data were accurately assessed and analyzed independently by two investigators. Ultimately, the 30 studies, involving 3328 cases and 2090 controls were included in our meta-analysis. The positive ratio of HCMV IgG, IgM, DNA and pp65 were, respectively, 63.26% (923/1459), 25.46% (69/271), 33.69% (381/1131), and 50.32% (158/314) in case patients. Meanwhile the positive ratio of HCMV IgG, IgM, DNA, and pp65 were, respectively, 52.12% (541/1038), 1.55% (3/194), 13.72% (79/576), and 12.26% (28/229) in control subjects. The positive ratio of HCMV infection was higher in atherosclerosis group than that in non-atherosclerosis group. Especially in Asian group, calculated odds ratios for the presence of HCMV infection in IgG-based HCMV tests, IgM-based tests, PCR-based tests, and pp65-based tests, expressed as OR (95% confidence intervals, 95%CI), were 3.07(95%CI 2.09-4.51), 8.92(95%CI 3.17-25.11), 6.75 (95%CI 3.50-13.02), and 5.72(95%CI 1.51-21.58), respectively. The meta-analysis results showed that HCMV infection is significant connected with an increased risk for AS.

IgG4-related disease involving the esophagus: a clinicopathological study.

Immunoglobulin G4 (IgG4)-related disease is a recently coined systemic disease characterized by specific histopathologic findings of an intense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis in the presence of predominant IgG4-positive plasma cells. Although IgG4-related disease has been described in many organs, involvement of the esophagus is very rare. In this study, we describe the clinicopathologic characteristics of eight patients with IgG4-related esophagitis. We evaluated chronic esophagitis specimens with lymphoplasmacytic infiltrate obtained over the past 6 years (from January 2011 to February 2017) using a chart review, pathologic examination, and IgG4 immunohistochemical staining. The diagnoses of the specimens were either confirmed as IgG4-related esophagitis (IgG4-RE) or chronic esophagitis, not otherwise specified (CENOS), and the clinicopathologic data from each group were compared. Eight patients were diagnosed with IgG4-RE and 10 controls were identified and diagnosed with CENOS. In the IgG4-RE group, esophageal strictures were identified in three patients, two patients had postmyotomy treated achalasia, one patient had erosive esophagitis and another presented with an esophageal nodule. Only one patient had an unremarkable mucosa on endoscopy. In the CENOS group, four patients had esophageal strictures, six had erosive esophagitis, one patient had mild esophagitis. The IgG4-RE group had significantly higher numbers of IgG4-positive plasma cells (66.9±21.9 vs. 4.7±2.4 per high power field; P<0.001) and a greater IgG4: IgG ratio 0.76±0.13 vs. 0.06±0.05; P<0.001) when compared to CENOS patients. Two of the patients with recurrent esophageal strictures in the IgG4-RE group showed initial response to steroid therapy and are currently on immunosuppressive therapy which has significantly reduced the need for multiple esophageal dilatations. The presentation of IgG4-related esophageal disease can vary and the key to diagnosis is dependent on histopathology. These observations highlight the need for IgG4 immunohistochemical staining of esophageal biopsies especially in patients with mucosal ulceration, chronic inflammation, and plasmacytosis on biopsy. This will prevent unwarranted esophagectomies and failed medical treatment due to lack of recognition of this entity.

Prognostic significance of IgG4+ plasma cell infiltrates following neoadjuvant chemoradiation therapy for esophageal adenocarcinoma

Lymphoplasmacytic infiltrates in esophageal adenocarcinoma (EAC) tissue following chemoradiotherapy (CRT) reflect alterations in the tumor immunoenvironment. The presence and role of plasma cells in this process are poorly understood. Our aim was to characterize the IgG4+ plasma cell population in EAC following CRT. Seventy-one esophagectomy specimens post-CRT were compared with a surgery-only group of 31 EACs. The distribution, density, and ratio of IgG4+ and IgG+ plasma cells were evaluated by immunohistochemistry and correlated with clinicopathologic features, treatment response, and survival. In the CRT group, the presence of higher numbers of IgG4+ (≥ median of 94/high-power field) and IgG+ (≥ median of 225/high-power field) plasma cells and increased IgG4+/IgG+ ratio (≥ median of 41%) within ulcers was associated with complete or near-complete treatment response (P = .0077, P = .0503, and P = .0063, respectively). Lower tumor grade, smaller tumor size, and higher levels of IgG4+ plasma cells in posttherapy ulcers significantly correlated with better overall survival, whereas pretherapy clinical stage, posttherapy pathologic stage, smaller tumor size, and lower tumor grade were associated with longer recurrence-free survival. Multivariate analysis revealed that both posttherapy pathologic stage and high IgG4+ plasma cells in ulcers were independent predictors of overall survival (P = .05 and P = .01), whereas only posttherapy pathologic stage was associated with recurrence-free survival (P < .01). This is the first study describing a dense IgG4+ plasma cell infiltrate in EAC following CRT. The presence of increased IgG4+ plasma cells may be a novel reliable factor to predict prognosis of EAC patients following CRT.

Parasitic Infections in Pregnancy Decrease Placental Transfer of Antipneumococcus Antibodies.

Many factors can influence maternal placental antibody transfer to the fetus, which confers important immune protection to the newborn infant. However, little is known about the effect of maternal parasitic infection on placental antibody transfer. To investigate this, we selected from a parent study of 576 pregnant Kenyan women four groups of women with term deliveries (≥37 weeks), including uninfected women (n = 30) and women with solo infections with malaria (n = 30), hookworm (n = 30), or schistosomiasis (n = 10). Maternal plasma at delivery and infant cord blood were tested via multiplex fluorescent bead assay for IgG against 10 pneumococcal serotypes (PnPs 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F), diphtheria toxoid, and Haemophilus influenzae type B. Infants born to mothers with prenatal malaria, hookworm, or Schistosoma haematobium infections were associated with a significantly reduced ratio of maternal to infant cord blood antibody concentration for Streptococcus pneumoniae serotypes 1, 4, 5, 6B, 7F, 9V, and 18C compared to infants of uninfected mothers. Anti-diphtheria toxoid and anti-H. influenzae type B IgG ratios were not significantly different among infection groups. Prenatal parasitic infections decrease the transfer of maternal IgG antibodies to infants for several serotypes of S. pneumoniae.

Seroprevalence of Hepatitis E Among Boston Area Travelers, 2009-2010.

AbstractWe determined the prevalence of IgG antibodies to hepatitis E virus (anti-HEV IgG) among travelers attending Boston-area travel health clinics from 2009 to 2010. Pre-travel samples were available for 1,356 travelers, with paired pre- and post-travel samples for 450 (33%). Eighty of 1,356 (6%) pre-travel samples were positive for anti-HEV IgG. Compared with participants who had never lived in nor traveled to a highly endemic country, the pre-travel prevalence odds ratio (POR) of anti-HEV IgG among participants born in or with a history of previous travel to a highly endemic country was increased (POR = 4.8, 95% CI = 2.3-10.3 and POR = 2.6, 95% CI = 1.4-5.0, respectively). Among participants with previous travel to a highly endemic country, anti-HEV IgG was associated with age > 40 years (POR = 3.7, 95% CI = 1.3-10.2) and travel history to ≥ 3 highly endemic countries (POR = 2.7, 95% CI = 1.2-5.9). Two participants may have contracted HEV infection during their 2009-2010 trip.

Serum IgG4:IgG Ratio Predicts Recurrence of Patients with Hepatocellular Carcinoma after Curative Resection.

Aim: IgG4 is associated with a Th1-to-Th2 switch, which plays a vital role in metastasis, in patients with malignances; thus, we aimed to investigate its clinical significance in predicting hepatocellular carcinoma (HCC) recurrence in the present study.Methods: The correlation between serum IgG4:IgG ratio and recurrence was analyzed in a cohort of 195 patients undergoing curative resection in 2012. Another 100 patients were analyzed in a prospective independent cohort during 2012-2013 to validate the value of serum IgG4. Serum IgG4 and total IgG concentrations were measured with an automatic immune analyzer and the optimal cutoff value for serum IgG4 levels was determined by X-tile software.Results: Our data revealed that serum IgG4:IgG were significantly elevated in patients with tumor recurrence (P<0.05). A cutoff IgG:IgG4 ratio of 0.08 was set to stratify HCC patients into high (>0.08) and low (≤0.08) groups. High serum IgG4:IgG ratio correlated with significantly shorter time-to-recurrence (median 11.85 months vs. 39.20, P=0.005). Univariate and multivariate analyses demonstrated that serum IgG4:IgG ratio is an independent indicator of tumor recurrence and this retained its clinical significance even in conventional low-recurrence-risk subgroups, including patients with low α-fetoprotein and early-stage diseases.Conclusion: Our results demonstrated that elevated serum IgG4:IgG ratio is associated with poor clinical outcomes in HCC patients and therefore, and can serve as a novel prognostic predictor for HCC patients undergoing resection. Analyzing serum IgG4 would be useful to tailor individualized therapies for patients.

Hevylite and Freelite Normalisation Is a Surrogate Marker for MRD Negativity Post-ASCT

IntroductionEvaluation of minimal residual disease (MRD) in multiple myeloma (MM) by multi-parameter flow cytometry (MFC) is a biomarker for risk of relapse. Applicability of MFC in routine practice has been challenging with suboptimal marrow samples and sampling needed at multiple time points. Sensitive serological assays which can detect MRD and have prognostic utility are needed to optimize the management of MM patients. The HevyliteTM assay (The Binding Site, UK) evaluates serum heavy/light chain ratios for IgG, IgA and IgM. We hypothesised the normalisation of serological markers is a good surrogate for plasma cell reconstitution in a healthy bone marrow (BM) microenvironment. The aim of this study was to prospectively compare Hevyliteand FreeliteTM assays with MFC of BM plasma cells from patients receiving autologous stem cell transplants (ASCT). We wanted to investigate if a correlation exists between MFC MRD negativity and the serological normalisation of Hevylite plus Freelite assays.MethodsHevylite, Freelite, SPEP, IFE on serum and MFC on bone marrow were performed on 23 patients post induction therapy and at a median of 90 days post-ASCT. Serological tests were performed again in available patients at 275 days post-ASCT. The combination of Freelite and Hevylite, which measures involved (iHLCr) and uninvolved (uHLCr) heavy light chain (HLC)-pairs, allows investigation of plasma cell reconstitution and its prognostic value in transplant patients. Six-colour MFC was performed as previously published (Rawstron et al. JCO 2013). IMWG uniform response criteria were used to categorise patients. Kaplan Meier estimates of Progression Free Survival (PFS) from time of transplantation until disease progression or death (whichever came first) were calculated and log-rank test was used for comparisons across groups. Sensitivity, specificity and ROC area analysis were used to assess performance of serologic response tests against flow MRD negativity, which is considered gold standard.ResultsTotal of 23 patients were recruited to the study, 8 female (34.8%), 15 male (65.2%), with median age 61 (46-71). Isotype and ISS distribution were as follows; 11 IgG (47.8%), 4 IgA (17.4%), 1 IgM (4.35%), 7 LC only (30.4%) and 8 ISS1 (34.8%), 6 ISS2 (26.1%), 9 ISS3 (39.1%). Median marrow PC involvement at diagnosis was 45%, (20-90%) (N=18). At diagnosis, median LDH levels 192 IU/L, (153-475), median Hb 109.5 g/l, (72-152), with renal impairment noted in 6/23 (26.1%) and abnormal skeletal survey 15/23 (65.2%). High risk MM FISH was reported in 1/23 (4.35%), unknown 11/23 (47.8%) with rest determined to have standard risk. Median time from start of induction to HDM/ASCT 8 months (6.5-20) and median number of lines of treatment before HDM/ASCT was 1. Two deaths were noted on study. Median follow-up of surviving patients from diagnosis was 31 months (10-42). VGPR or better was achieved in 18/23 (88%) patients post-transplant by IMWG criteria.Hevylite ratio (iHLCr and uHLCr) normalised in 11/23 (48%) patients, with Freelite ratio (FLCr) normalisation in 14/23 (61%). MFC MRD negativity at 3 months post-ASCT was noted in 6/23 (26%) patients, in whom the post-ASCT Hevylite ratio and FLCr were also normalised. Comparing response assessments post-ASCT using standard IMWG criteria, MFC MRD, HLCr normalisation and FLCr normalisation, we found that MFC MRD is more sensitive to pick up residual disease over other tests. MFC MRD positivity correlates with early disease progression as MRD negativity significantly improves PFS outcomes (not reached vs 21 months) p=0.01 (Figure 1a). Patients with both HCLr and FLCr normalisation have significantly better PFS outcomes (not reached vs 21 months) p=0.04 (Figure 1b). ROC curve comparison of MFC MRD negativity and HLCr and FLCr normalisation tests, shows a 100% (95% CI 54.1% - 100%) sensitivity and 82% specificity (95% CI 56.6 - 96.2%) for serological normalisation. This demonstrates that HLCr and FLCr normalisation serves as a useful surrogate marker for MFC MRD negativity in our study.ConclusionsWe report the first prospective study demonstrating HLCr and FLCr normalisation post-transplant is a useful surrogate marker for flow MRD negativity, which is a widely accepted gold standard. This data requires further validation in a larger cohort of post-ASCT MM patients. [Display omitted] DisclosuresRamasamy:Celgene: Honoraria, Research Funding.

Immunoglobulin G4 related thyroid disorders: Diagnostic challenges and clinical outcomes.

Ig-G4 related disease (IgG4RD) is a heterogeneous disorder with multi-organ involvement recognised as a separate entity at the start of this century only. It is currently one of the hottest areas of clinical and translational research across specialties. Thyroid involvement in IgG4RD is rare, believed to occur in less than 4% of cases, may be isolated or may be associated with other organ involvement. As of today Riedel's thyroiditis, fibrosing variant of Hashimoto's thyroiditis, and few patients of Graves' orbitopathy represent the types of IgG4-related thyroid disease (IgG4RTD). This disorder is frequently confused with malignancy due to the intense sclerosis of thyroid resulting in hard texture on palpation compounded by often-associated compressive symptoms. Diagnosis involves establishing high circulating levels of IgG4 > 135 mg/dL, increased serum IgG4 to IgG ratio of > 8%, immunohistochemistry showing dense lymphoplasmacellular inflammatory infiltrate consisting of IgG4-positive plasma cells with storiform fibrosis and obliterative phlebitis, and increased IgG4 positive plasma cell > 10 cells per high-power field when at least three fields are evaluated. Glucocorticoids are the primary form of therapy in IgG4RD. However, their role in IgG4RTD needs to be evaluated. As of today levothyroxine supplementation for resulting hypothyroidism, appropriate management of Graves' disease, and surgical excision of thyroid in case of compressive symptoms remain the primary treatment options. (Endokrynol Pol 2016; 67 (5): 520-524).

Comprehensive Assessment of M-Proteins Using Nanobody Enrichment Coupled to MALDI-TOF Mass Spectrometry

Electrophoretic separation of serum and urine proteins has played a central role in diagnosing and monitoring plasma cell disorders. Despite limitations in resolution and analytical sensitivity, plus the necessity for adjunct methods, protein gel electrophoresis and immunofixation electrophoresis (IFE) remain front-line tests. We developed a MALDI mass spectrometry-based assay that was simple to perform, automatable, analytically sensitive, and applicable to analyzing the wide variety of monoclonal proteins (M-proteins) encountered clinically. This assay, called MASS-FIX, used the unique molecular mass signatures of the different Ig isotypes in combination with nanobody immunoenrichment to generate information-rich mass spectra from which M-proteins could be identified, isotyped, and quantified. The performance of MASS-FIX was compared to current gel-based electrophoresis assays. MASS-FIX detected all M-proteins that were detectable by urine or serum protein electrophoresis. In serial dilution studies, MASS-FIX was more analytically sensitive than IFE. For patient samples, MASS-FIX provided the same primary isotype information for 98% of serum M-proteins (n = 152) and 95% of urine M-proteins (n = 55). MASS-FIX accurately quantified M-protein to <1 g/dL, with reduced bias as compared to protein electrophoresis. Intraassay and interassay CVs were <20% across all samples having M-protein concentrations >0.045 g/dL, with the ability to detect M-proteins <0.01 g/dL. In addition, MASS-FIX could simultaneously measure κ:λ light chain ratios for IgG, IgA, and IgM. Retrospective serial monitoring of patients with myeloma posttreatment demonstrated that MASS-FIX provided equivalent quantitative information to either protein electrophoresis or the Hevylite(™) assay. MASS-FIX can advance how plasma cell disorders are screened, diagnosed, and monitored.

IgG4-Related Lung Disease: Retrospective Review of 9 Cases

SESSION TITLE: Pulmonary Manifestation of Systemic Disease SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 26, 2016 at 01:30 PM - 02:30 PM PURPOSE: IgG4-related disease is a corticosteroid-responsive systemic fibroinflammatory disease that affects various organs. Although pancreatic involvement is the most common presentation, pulmonary manifestation, known as IgG4-related lung disease (IgG4-RLD) has been increasingly recognized. While many reports are from Asian populations, we aimed to clarify the clinical and pathologic aspects of IgG4-RLD in non-Asian populations. METHODS: A retrospective review was conducted of cases with biopsy-proven IgG4-RLD encountered from January 1994 till February 2016 at an academic medical center. IgG4-RLD was defined as meeting at least 2 out of 3 characteristic histopathological features (IgG4-positive lymphoplasmacytic infiltration, fibrosis, and obliterative phlebitis) with IgG4+ cell counts of more than 50 per high power field (HPF) in either surgical or nonsurgical specimens and IgG4+: IgG+ ratio of greater than 0.4 in combination with compatible clinicoradiologic features. We also included cases manifesting at least one histopathologic feature, IgG4+ cell counts per HPF of more than 50 in a surgical specimen or more than 20 in a nonsurgical specimen, with IgG4+: IgG ratio of greater than 0.4, if either elevated serum IgG4 level or initial favorable corticosteroid responsiveness (or complete surgical resection) was seen along with compatible clinicoradiologic features. RESULTS: A total of 9 patients with IgG4-RLD were identified, of which 8 were male and all were Caucasians. The median age at diagnosis was 64 years (interquartile range [IQR], 59-70). Serum IgG4 measurement was available in 8 patients, and the median peak serum IgG4 level was 234 mg/dL (IQR, 93-479). Five patients had respiratory symptoms on presentation, of which cough (N=4) and dyspnea (N=4) were most common, followed by nasal congestion (N=3). The main radiographic abnormality that led to biopsy was seen in the parenchyma (mass or nodule) in 7 patients, the central airway (stenosis) in 1 patient, and the pleura (pleural thickening and effusion) in 1 patient. The secondary radiographic abnormality was seen in 5 patients; 4 had mediastinal and/or hilar lymphadenopathy, and 1 had bronchial stenosis. The median count of IgG4+ cells was 65 (IQR, 49-117) per HPF, and the median IgG4+:IgG+ ratio was 0.56 (IQR, 0.47-0.74). No medical treatment was immediately necessary in 4 patients who underwent complete surgical resection of the pulmonary lesion. Among those patients; however, 3 had a recurrence of IgG4-RLD and received either corticosteroids or steroid-sparing agents during the clinical follow-up. The remaining 5 patients received corticosteroids immediately after the diagnosis of IgG4-RLD. All 5 patients subsequently developed either recurrence of IgG4-RLD or experienced the re-emergence of IgG4-related disease in the extra-pulmonary organs. CONCLUSIONS: IgG4-RLD is the pulmonary manifestation of IgG4-related disease, which commonly affects middle-aged or elderly men, with a high propensity for recurrence. Majority of patients present with mass or nodule with associated lymphadenopathy. CLINICAL IMPLICATIONS: IgG4-RLD mimics malignancy or other infectious or inflammatory conditions in its presentation. DISCLOSURE: The following authors have nothing to disclose: Reina Suzuki, Eunhee Yi, Jay Ryu, Hiroshi Sekiguchi No Product/Research Disclosure Information

IgG4-related hepatobiliary disease: an overview.

IgG4-related hepatobiliary diseases are part of a multiorgan fibroinflammatory condition termed IgG4-related disease, and include IgG4-related sclerosing cholangitis (IgG4-SC) and IgG4-related hepatopathy. These diseases can present with biliary strictures and/or mass lesions, making them difficult to differentiate from primary sclerosing cholangitis (PSC) or other hepatobiliary malignancies. Diagnosis is based on a combination of clinical, biochemical, radiological and histological findings. However, a gold standard diagnostic test is lacking, warranting the identification of more specific disease markers. Novel assays - such as the serum IgG4:IgG1 ratio and IgG4:IgG RNA ratio (which distinguish IgG4-SC from PSC with high serum IgG4 levels), and plasmablast expansion to recognize IgG4-SC with normal serum IgG4 levels - require further validation. Steroids and other immunosuppressive therapies can lead to clinical and radiological improvement when given in the inflammatory phase of the disease, but evidence for the efficacy of treatment regimens is limited. Progressive fibrosclerotic disease, liver cirrhosis and an increased risk of malignancy are now recognized outcomes. Insights into the genetic and immunological features of the disease have increased over the past decade, with an emphasis on HLAs, T cells, circulating memory B cells and plasmablasts, chemokine-mediated trafficking, as well as the role of the innate immune system.

House Dust Mite Allergens: New Discoveries and Relevance to the Allergic Patient.

Recent findings on house dust allergens and their contribution to knowledge that will significantly impact on current and future allergy treatments are appraised. Quantitation of IgE binding to a spectrum of allergen components in several independent studies in varying locations has largely affirmed the main components as the groups 1 and 2 and possibly 23 allergens with mid-tier contributions from the groups 4, 5, 7, and 21. Prevalent binding to Der p 23 has been recapitulated sometimes with low titers. The IgE of non-asthmatic atopic subjects binds at lower titer and to fewer components than that of asthmatics, and their IgG binding relative to IgE is higher especially for children hospitalized for exacerbation. The higher IgG ratios were associated with increased IL-10 a cytokine more readily induced from T cells of allergic subjects. Peptides representing the groups 1 and 2 allergens can be used to stimulate ex vivo T cells showing responses correlating with IgE binding and providing a valuable tool for ascertaining the contribution of IgE and T cells to disease. Also, the induction of Th2 and follicular helper T cells are shown to make different contributions in mice. Cross-reactivity of IgE binding assays with high-titer cross-reactive antibodies induced by scabies is a problem in the many areas of the world where scabies is highly prevalent and endemic and from recent increases in immigration. In the last few years, allergen research has produced results that warrant rapid translation into diagnostic tools and the formulation of allergen components for immunotherapy.

Blood B Lymphocyte Stimulator (BLyS)/BAFF levels may reflect natural immunity to HIV in highly exposed uninfected Beninese Commercial Sex Workers.

We have previously shown that excess B lymphocyte Stimulator (BLyS)/BAFF in plasma and on surface of blood dendritic cells (DC) of HIV-infected progressors coincides with B-cell dysregulations and increased frequencies of “precursor” innate marginal zone (MZ)-like B-cells. In contrast, both blood BLyS levels and frequencies of this population remained unaltered in HIV elite-controllers. Based on these observations, we hypothesized that control of BLyS and innate B-cell status could be associated with natural immunity against HIV infection. Therefore, we assessed blood BLyS levels and B-cell status in HIV highly-exposed commercial sex workers (CSWs) from Benin. We found blood BLyS levels of HIV-uninfected CSWs were lower than those observed in both HIV-infected CSW and HIV-uninfected non-CSW groups. Furthermore, levels of BLyS expression on blood T-cells and monocytes were lower in HIV-uninfected CSWs when compared to HIV-infected CSWs, but higher than those observed for HIV-uninfected non-CSWs. Concomitantly, HIV-infected CSWs presented a dysregulated blood B-cell compartment, characterized by increased total IgG1, increased frequencies of populations presenting immature and/or innate profiles and a higher ratio of IgG+/IgA+ plasmablasts. In contrast, relatively low levels of BLyS in the blood of HIV-uninfected CSWs coincided with a rather preserved B-cell compartment.

Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study

Objective A task force of scientists at the International Congress on Antiphospholipid Antibodies recognized that phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) might contribute to a better identification of antiphospholipid syndrome (APS). Accordingly, initial and replication retrospective, cross-sectional multicentre studies were conducted to ascertain the value of aPS/PT for APS diagnosis. Methods In the initial study (eight centres, seven countries), clinical/laboratory data were retrospectively collected. Serum/plasma samples were tested for IgG aPS/PT at Inova Diagnostics (Inova) using two ELISA kits. A replication study (five centres, five countries) was carried out afterwards. Results In the initial study ( n = 247), a moderate agreement between the IgG aPS/PT Inova and MBL ELISA kits was observed ( k = 0.598). IgG aPS/PT were more prevalent in APS patients (51%) than in those without (9%), OR 10.8, 95% CI (4.0-29.3), p < 0.0001. Sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio of IgG aPS/PT for APS diagnosis were 51%, 91%, 5.9 and 0.5, respectively. In the replication study ( n = 214), a moderate/substantial agreement between the IgG aPS/PT results obtained with both ELISA kits was observed ( k = 0.630). IgG aPS/PT were more prevalent in APS patients (47%) than in those without (12%), OR 6.4, 95% CI (2.6-16), p < 0.0001. Sensitivity, specificity, LR + and LR- for APS diagnosis were 47%, 88%, 3.9 and 0.6, respectively. Conclusions IgG aPS/PT detection is an easily performed laboratory parameter that might contribute to a better and more complete identification of patients with APS.

Enhanced IgG4 production by follicular helper 2T cells and the involvement of follicular helper 1T cells in the pathogenesis of IgG4-related disease.

BackgroundThe aim of this study was to elucidate the function of circulating follicular helper T (Tfh) cell subsets in helping B cells in patients with active, untreated IgG4-related disease (IgG4-RD) and determine their relationship with disease activity.MethodsSeventeen consecutive patients with active, untreated IgG4-RD, 20 with primary Sjögren syndrome (pSS), 5 with multicentric Castleman’s disease (MCD), and 12 healthy controls (HC) were enrolled. Tfh cell subset function was evaluated by co-culture with naïve B cells in vitro. Activated Tfh cell subsets were defined as a CCR7lowPD-1high subset among Tfh cell subsets. Disease activity was evaluated by IgG4-RD responder index (IgG4-RD RI) score.ResultsThe number of Tfh2 cells was significantly higher in IgG4-RD compared to pSS, MCD, or HC, and correlated with serum IgG4 level or the number of plasmablasts. In vitro, Tfh2 cells more efficiently induced the differentiation of naïve B cells into plasmablasts compared to Tfh1 or Tfh17 cells. Of note, while IgG production in culture supernatants of Tfh2 cells was comparable between IgG4-RD and HC, IgG4 production was significantly higher with Tfh2 cells from patients with IgG4-RD than in those from HC. Accordingly, the IgG4:IgG ratio in culture supernatants was also significantly higher with Tfh2 cells from IgG4-RD compared to HC. Moreover, the number of activated Tfh2 cells was higher in IgG4-RD compared to pSS, MCD, or HC, and strongly correlated with IgG4-RD RI score in the baseline active phase. Particularly, the number of activated Tfh2 cells was associated with the number of affected organs and serum IgG4 level. Importantly, the number of activated Tfh2 cells was decreased after glucocorticoid treatment and paralleled disease improvement. Moreover, the number of activated Tfh1 cells was also increased in IgG4-RD compared to pSS, MCD, or HC, correlating with IgG4-RD RI score, but not with serum IgG4 level.ConclusionsTfh2 cells, but not Tfh1 or Tfh17 cells, induce the differentiation of naïve B cells into plasmablasts and enhanced production of IgG4 in patients with active, untreated IgG4-RD. Furthermore, activated Tfh2 cells reflect disease activity, suggesting the involvement of this T cell subset in the pathogenesis of IgG4-RD. Interestingly, the number of activated Tfh1 cells was also increased in IgG4-RD, correlating with disease activity but not with serum IgG4 level, suggesting the involvement of Tfh1 cells but not in the process of IgG4 production in patients with IgG4-RD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1064-4) contains supplementary material, which is available to authorized users.

Cytomegalovirus Infection and Pre-Eclampsia

Abstract Introduction: Pre-eclampsia is a pregnancy-specific disease characterized by hypertension after 20 weeks of gestation and proteinuria. It is a major cause of maternal and perinatal morbidity and mortality. The pathogenesis of pre-eclampsia is not completely understood. In our study we investigated if there is a potential link between cytomegalovirus infection and pre-eclampsia and if cytomegalovirus infection is the triggering factor of pre-eclampsia. Material and methods: This study was carried out in a secondary care hospital between January 2014 and July 2015. We included two groups of pregnant women: 66 with pre-eclampsia and 62 without pre-eclampsia. Enzyme linked immunosorbent assay (ELISA) technique was performed to detect cytomegalovirus Immunoglobulin G levels in maternal serum. Results: The p-value between median values of positive cytomegalovirus IgG in pre-eclamptic women and in controls was not significant (p:0.867). Odds ratio for cytomegalovirus IgG in pre-eclamptic group (OR:0.967; 95%CI:0.535-1.748) do not differ greatly from the value recorded in the control group (OR:1.036; 95%CI:0.571-1.880). The risk for preterm birth in pre-eclamptic women with cytomegalovirus IgG positive values (OR:1.009; 95%CI:0.329-3.090) was greater than those which had term delivery (OR:0.994; 95%CI:0.472-2.095) but the two values are not very high. We found a positive correlation coefficient (0.217) at a “p” value of 0.08 between white blood cells, but a negative correlation coefficient between the percentage of neutrophils and cytomegalovirus infection. Conclusion: Cytomegalovirus infection may be associated with pre-eclampsia but it is unlikely to be the triggering factor of pre-eclampsia.

Clinical features of 16 patients with idiopathic retroperitoneal fibrosis

Objectives The aim of this investigation is to explore clinical features, diagnosis, treatment and sequelae of idiopathic retroperitoneal fibresis (iRPF), and to serve for improvement of clinical diagnosis and treatment. Methods Retrospective analysis were done in 16 cases with iRPF in the affiliated hospital of Qingdao University, including 9 patients with IgG4–related RPF. Results iRPF was more common in middle–aged and old males. The most common clinical presentations were renal failure, abdominal pain, and body weight loss. There were no significant differences of Hb, Scr, ESR and CRP between the IgG4–RPF and non–IgG4–RPF patients.CT or MRI scans showed retroperitoneal masses in all 16 cases, however, muti–organs injuries, such as submandibular gland, deep lymph nodes, pancreas, bile ducts, thymus glands, renal interstitium and thyroid glands, were common in IgG4–RPF patients. Pathological investigations displayed that all patients presented the same alterations, such as the elevated IgG4+ plasm cells, IgG4+ /IgG ratio of cells and storiform fibrosis, in vary involved organs.8 patients were treated with corticosteroids and immunosuppressive agents; 6 patients were treated with corticosteroids and surgical intervention.These 14 patients presented good response to corticosteroids , except 2 cases who relapsed after corticosteroids withdrawal.2 patients who accpted surgical intervention, and there was the risk of repeated episodes. Conclusions IgG4–related disease accounts for a substantial percentage of patients with idiopathic RPF.Histopathologic features such as elevated IgG4/total IgG ratios, IgG4+ plasma cells per high–power field and storiform fibrosis are critical to identify this disease. Key words: Retroperitoneal Fibrosis; Immunoglobulin G

Broadly neutralizing antibody specificities detected in the genital tract of HIV-1 infected women.

Broadly neutralizing antibodies (bNAbs) targeting conserved epitopes on the HIV envelope glycoprotein have been identified in blood from HIV-1 infected women. We investigated whether antibodies in the genital tract from these women share similar epitope specificities and functional profiles as those in blood. Immunoglobulin (Ig)G and IgA antibodies were isolated from cervicovaginal lavages or Softcups from 13 HIV-infected women in the CAPRISA cohort using Protein G and Peptide M, respectively. Binding antibodies to envelope antigens were quantified by ELISA and binding antibody multiplex assay. Neutralizing antibody titers and epitope targets were measured using the TZM-bl assay with Env-pseudotyped wild-type and mutated viruses. HIV-specific IgG, but not IgA, was detected in genital secretions and the ratio of total IgG to HIV-specific IgG was similar to plasma. HIV-specific IgG reacted with multiple envelope antigens, including V1V2, gp120, gp140 and gp41. Two women had high plasma titers of HIV-specific IgG3 which was also detected in their genital tract samples. IgG from the genital tract had neutralizing activity against both Tier 1 and Tier 2 primary HIV-isolates. Antibodies targeting well known glycan epitopes and the membrane proximal region of gp41 were detected in genital secretions, and matched specificities in plasma. Women with plasma bNAbs have overlapping specificities in their genital secretions, indicating that these predominantly IgG isotype antibodies may transudate from blood to the genital tract. These data provide evidence that induction of systemic HIV-specific bNAbs can lead to antiviral immunity at the portal of entry.

Identification of an OmpW homologue in Burkholderia pseudomallei, a protective vaccine antigen against melioidosis

Burkholderia pseudomallei is the causative agent of melioidosis, which is associated with a range of clinical manifestations, including sepsis and fatal pneumonia and is endemic in Southeast Asia and Northern Australia. Treatment can be challenging and control of infection involves prolonged antibiotic therapy, yet there are no approved vaccines available to prevent infection. Our aim was to develop and assess the potential of a prophylactic vaccine candidate targeted against melioidosis. The identified candidate is the 22kDa outer membrane protein, OmpW. We previously demonstrated that this protein was immunoprotective in mouse models of Burkholderia cepacia complex (Bcc) infections. We cloned Bp_ompW in Escherichia coli, expressed and purified the protein. Endotoxin free protein administered with SAS adjuvant protected Balb/C mice (75% survival) relative to controls (25% survival) (p<0.05). A potent serological response was observed with IgG2a to IgG1 ratio of 6.0. Furthermore C57BL/6 mice were protected for up to 80 days against a lethal dose of B. pseudomallei and surpassed the efficacy of the live attenuated 2D2 positive control. BpompW is homologous across thirteen sequenced B. pseudomallei strains, indicating that it should be broadly protective against B. pseudomallei. In conclusion, we have demonstrated that BpOmpW is able to induce protective immunity against melioidosis and is likely to be an effective vaccine antigen, possibly in combination with other subunit antigens.

Chronic HIV-1 Infection Induces B-Cell Dysfunction That Is Incompletely Resolved by Long-Term Antiretroviral Therapy.

To determine the effect of long-term antiretroviral therapy (ART) on HIV-1-induced B-cell dysfunction. Comparative study of ART-naive and ART-treated HIV-infected patients with non-HIV controls. B-cell dysfunction was examined in patients with HIV-1 infection (n = 30) who had received ART for a median time of 9.25 years (range: 1.3-21.7) by assessing proportions of CD21 B cells (a marker of B-cell exhaustion) and proportions of tumor necrosis factor-related apoptosis-inducing ligand or B and T lymphocyte attenuator B cells, and serum levels of immunoglobulin free light chains (markers of B-cell hyperactivation). The association of these markers with serum levels of IgG1 and IgG2, and production of IgG antibodies after vaccination with pneumococcal polysaccharides were also examined. ART-naive patients with HIV (n = 20) and controls (n = 20) were also assessed for comparison. ART-treated patients had increased proportions of CD21 and tumor necrosis factor-related apoptosis-inducing ligand B cells and, furthermore, although proportions of B and T lymphocyte attenuator B cells were not significantly different from controls, they correlated negatively with CD21 B cells. Proportions of CD21 B cells also correlated negatively with current CD4 T-cell counts. In ART-naive patients with HIV, free light chains correlated with CD21 B cells and IgG1, but not IgG2. Serum IgG2:IgG1 ratios were substantially lower than normal in patients with HIV and did not resolve on ART. In ART-treated patients, IgG antibody responses to pneumococcal polysaccharides after vaccination were not associated with markers of B-cell dysfunction. B-cell dysfunction persists in patients with HIV receiving long-term ART. The causes and consequences of this require further investigation.