Asymptomatic Dengue Infection in a Cuban Population Confirms the Protective Role of the RR Variant of the FcγRIIa Polymorphism

The role of human Fcγ receptors (FcγR) has been recognized considerably over the last years. These receptors vary in their affinity for IgG subclasses and the intracellular signals elicited by them. Allelic variants of FcγR genes may influence the biological phagocyte activity, accounting for an inherited pre-disposition to disease. The specific FcγRIIa (CD32) contains a polymorphic variant (H/R131) that has been associated to a reduced risk for developing dengue hemorrhagic fever (DHF). Here, we investigated the role of this polymorphism in a very well-characterized group of Cuban individuals with antecedents of DHF, dengue fever (DF), or subclinical dengue infection. The HH131 genotype was significantly associated with dengue disease, either DF (*P = 0.016; odds ratio = 4.425; 95% confidence interval = 1.10–20.52) or DHF (P = 0.00018; odds ratio = 10.56; 95% confidence interval = 2.33–54.64) with respect to the subclinical infection.     

Differential Clinical Outcome of Dengue Infection among Patients with and without HIV Infection: A Matched Case–Control Study

Clinical characteristics and outcome among dengue patients with and without human immunodeficiency virus (HIV) infection remain elusive. A total of 10 dengue virus (DENV)–HIV Chinese patients were compared with 40 Chinese dengue patients without HIV, who were matched for age, gender, type of care received, methods, and year of dengue diagnosis from 2005 to 2008. Univariate and multivariate conditional logistics regression were applied. DENV-HIV patients were significantly associated with the World Health Organization (WHO) 2009 severe dengue (conditional odds ratio [COR] = 5.72; 95% confidence interval [CI] = 1.01–32.64) but not with the WHO 1997 dengue hemorrhagic fever/dengue shock syndrome (COR = 0.40; 95% CI = 0.09–1.71). This is mainly due to severe plasma leakage and the lack of hemorrhagic manifestations. Hospitalization duration was longer for DENV-HIV patients (10.5 days; interquartile range [IQR] = 5.5–26.3 days) compared with dengue patients (5 days; IQR = 4–6 days). There were no significant differences in presentation of clinical warning signs and symptoms at admission and during hospitalization, except for rash (adjusted COR [ACOR] = 0.06; 95% CI = 0.03–0.92). DENV-HIV patients were associated with higher pulse rate (ACOR = 1.13; 95% CI = 1.02–1.25), eosinophils proportion (ACOR = 3.07; 95% CI = 1.12–8.41) and lower hematocrit level (ACOR = 0.79; 95% CI = 0.64–0.98) compared with dengue patients. Even though DENV-HIV patients may present similarly to dengue patients, they may be more likely to have severe dengue outcome. Hence, close monitoring of DENV-HIV patients is highly recommended as part of dengue clinical care and management.     

Variation in platelet expression of FcγRIIa after myocardial infarction

Journal of Thrombosis and Thrombolysis - FcγRIIa amplifies platelet activation and greater platelet expression of FcγRIIa identifies patients at greater risk of subsequent cardiovascular...     

FcγRIIa and FcγRIIIa genetic polymorphisms in a group of pediatric immune thrombocytopenic purpura in Egypt

Immune thrombocytopenic purpura (ITP) is an acquired autoimmune disorder caused by the production of antiplatelet antibodies. The current case-control study aimed at detecting the frequency of FcγRIIa-131H/R and FcγRIIIa-158F/V genes polymorphism in Egyptian children with ITP as genetic markers for ITP risk, and to clear out their possible role in choosing the treatment protocols of ITP. To achieve this aim, FcγRIIa genotyping was tested by PCR-restriction fragment length polymorphism (RFLP) technique, whereas FcγRIIIa genotyping was tested by nested PCR followed RFLP analysis. The current case-control study was conducted on 92 children with ITP; 12 acute and 80 chronic cases and 90 controls. The V allele and FcγRIIIa FV heterotype were significantly higher in ITP patients and conferred increased ITP risk [odds ratio (OR) = 1.96 and 2.55, respectively]. The frequency of FcγRIIa H allele was significantly higher among chronic ITP patients. In conclusion, FcγRIIIa gene polymorphism may contribute to susceptibility to ITP. Moreover, analysis of the FcγR polymorphisms in ITP patients could influence the effectiveness of medications and selection of the line of treatment.     

Association of IFN-¹ Gene Polymorphism with Type 1 Diabetes in Iranian Patients

Background: Type 1 Diabetes (T1D) is a chronic and progressive autoimmune disorder. Cytokines play a critical role in the pathogenesis of T1D.   Objective: IFN-¹ polymorphism was investigated in T1D and compared with normal controls.   Methods: Thirty patients suffering from T1D and 40 normal controls were studied simultaneously using PCR technique. IFN-   ¹ gene was evaluated at position 5’UTR +5644. Results: There was a significant difference between patient and control groups in TT genotype (P<0.05). Conclusion: In this study, we found a negative association between IFN-¹ gene at position 5’UTR +5644 and T1D in Iranian patients pointing to T allele as a protective factor against T1D.     

Clinical Impact of Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae in Patients with Biliary Tract Infection

Background

Clinical outcomes associated with Gram-negative bacterial isolates with extended spectrum beta-lactamase (ESBL) in patients with biliary tract infection are largely unknown. The objective of the present study was to compare the demographics, risk factors, and clinical outcomes between patients with biliary tract infection caused by ESBL-producing and non-producing Klebsiella pneumoniae and Escherichia coli.

Methods

Between February 2005 and August 2010, we collected 159 cases with biliary tract infection caused by K. pneumoniae and E. coli identified by blood or bile cultures obtained before endoscopic or surgical treatment performed at our institution. We also retrospectively collected the data of patients’ demographic characteristics, co-morbid conditions, antimicrobial therapy, and clinical outcomes.

Results

Among the 159 strains isolated, 21 strains (13.2 %) were positive for phenotypical ESBL-test. Sepsis was more common in ESBL-positive strains, but did not reach statistical significance (23.8 % for ESBL-positive strains and 9.4 % for ESBL-negative strains, P = 0.066). Thirty-day mortality was significantly higher in ESBL-positive strains (3/21, 14.3 %) compared to ESBL-negative strains (4/138, 2.9 %, P = 0.049). However, there were no significant differences in overall survival between ESBL-positive and ESBL-negative strains. By multivariate analysis, inadequate antimicrobial therapy (HR 4.06, 95 % CI 1.08–16.46, P = 0.049) and sepsis (HR 6.54, 95 % CI 1.26–33.85, P = 0.025) were independent and significant predictors of 30-day mortality.

Conclusion

ESBL status of bacterial isolates for patients with biliary tract infection caused by K. pneumoniae and E. coli has clinical impact, especially on the short-term outcomes of those patients.     

Structure of FcγRI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding

Fc gamma receptor I (FcγRI) contributes to protective immunity against bacterial infections, but exacerbates certain autoimmune diseases. The sole high-affinity IgG receptor, FcγRI plays a significant role in immunotherapy. To elucidate the molecular mechanism of its high-affinity IgG binding, we determined the crystal structure of the extracellular domains of human FcγRI in complex with the Fc domain of human IgG₁. FcγRI binds to the Fc in a similar mode as the low-affinity FcγRII and FcγRIII receptors. In addition to many conserved contacts, FcγRI forms additional hydrogen bonds and salt bridges with the lower hinge region of Fc. Unique to the high-affinity receptor-Fc complex, however, is the conformation of the receptor D2 domain FG loop, which enables a charged KHR motif to interact with proximal carbohydrate units of the Fc glycans. Both the length and the charge of the FcγRI FG loop are well conserved among mammalian species. Ala and Glu mutations of the FG loop KHR residues showed significant contributions of His-174 and Arg-175 to antibody binding, and the loss of the FG loop–glycan interaction resulted in an ∼20- to 30-fold decrease in FcγRI affinity to all three subclasses of IgGs. Furthermore, deglycosylation of IgG₁ resulted in a 40-fold loss in FcγRI binding, demonstrating involvement of the receptor FG loop in glycan recognition. These results highlight a unique glycan recognition in FcγRI function and open potential therapeutic avenues based on antibody glycan engineering or small molecular glycan mimics to target FcγRI for certain autoimmune diseases.IgGs and pentraxins are circulating immune components that directly recognize pathogens. On formation of immune complexes or opsonization, they activate cellular response through Fc receptors (FcRs) (1, 2). The FcRs for IgGs include FcγRI (CD64); FcγRII (CD32) with A, B, and C isoforms; and FcγRIII (CD16) with two isoforms (3). Most of these are activating receptors either containing an intracellular immunoreceptor tyrosine-based activation motif or associated with an FcR common γ chain (4). FcγRIIB is an inhibitory receptor that contains an intracellular immunoreceptor tyrosine-based inhibitory motif. FcγRIIIB does not have a cytosolic domain and is anchored to the plasma membrane through glycosylphosphatidylinositol linkage. The binding affinity to IgG ranges from 10⁻⁸ M for FcγRI to 10⁻⁵–10⁻⁷ M for FcγRII and III (3).FcγRI plays an important role in the protection against bacterial infections, but also exacerbates certain autoimmune diseases (5). Owing to its high-affinity antibody binding, FcγRI is important in antibody therapy as well (6, 7). To date, the structure of the ligand-bound high-affinity receptor has not been determined, however. Consequently, the mechanism of its high-affinity antibody recognition remains to be elucidated. The role of glycan in antibody function has been a subject of intense study. Differential glycosylation of Fc, notably fucosylated Fc, is known to affect Fc receptor binding (8, 9). Furthermore, sialylated IgGs have been shown to be anti-inflammatory components of intravenous immunoglobulin (10, 11), and glycosylation affects their binding to the low-affinity FcγRIIB and FcγRIII (11–13). Structural evidence suggests that the conserved glycosylation at Asn-297 of the constant region of IgG₁ is important to maintain the conformation of Fc for receptor binding (12, 14). Whether Fc receptors make significant glycan contacts for their IgG affinity is not clear, however.Structures of the low-affinity Fcγ receptors have been determined with bound IgG-Fc (15–18). Unlike the other two-domain FcγRs, FcγRI contains three extracellular Ig-like domains, designated D1, D2, and D3. Earlier mutational analysis suggests that D2 and D3 domains are important to confer high-affinity antibody binding (19). Recently, the structure of human FcγRI showed a close packing of the FcγRI D1 and D2 domains resembling that of FcεRI, and mutations in the FG loop of the FcγRI D2 domain reduced its IgG binding affinity (20). The mechanism of the high-affinity FcγRI ligand recognition remains unresolved. To provide further insight into the high-affinity antibody recognition by FcγRI, and to facilitate the development of FcγRI-mediated immunotherapy, we determined the structure of the extracellular domains of human FcγRIA in complex with the Fc domain of human IgG₁. Our study identifies a structural mechanism for high-affinity IgG binding by the receptor.     

Association of Serum TGF-β1 Levels with Different Clinical Phenotypes of Cystic Fibrosis Exacerbation

Purpose

Cystic Fibrosis (CF) is a multi-organ genetic disorder and Transforming Growth Factor (TGF-β1) is a modifier gene which modulates lung pathology in CF. There is great phenotypic variability among CF patients who even have similar genotype. The aim of the present study was to associate the serum levels of TGF-β1 with several clinical phenotypes of CF.

Methods

The diagnosed cases of CF were recruited and the blood sample was withdrawn at different time points: during exacerbation (n = 26), non-exacerbation (n = 9) and after antibiotic therapy (n = 11). The concentration of the total TGF-β1 in serum was measured with commercial ELISA kit. The ΔF508 mutation was assessed by the Amplification Refractory Mutation System (ARMS-PCR).

Results

The levels of TGF-β1 were increased in exacerbation phase (119.89 ± 29.64 ng/mL), infection with P. aeruginosa (121.8 ± 28.83 ng/mL) and in subjects with ΔF508 mutation (139.2 ± 19.59 ng/mL). The levels of TGF-β1 in CF patients with Allergic Bronchopulmonary Aspergillosis (ABPA) (109.97 ± 27.71 ng/mL) were decreased as compared to CF patients without ABPA (123.55 ± 30.20 ng/mL). It was observed that the serum levels of TGF-β1 were decreased significantly after antibiotic therapy (p < 0.05).

Conclusions

The present study has determined that the serum levels of TGF-β1 vary with the type of infections, ΔF508 CFTR mutation, presence of ABPA and response to therapy.

     

Ultrasonographic Gallbladder Abnormality of Primary Epstein–Barr Virus Infection in Children and Its Influence on Clinical Outcome

The incidence of pediatric acute inflammatory gallbladder (GB) disease without gallstone such as acute acalculous cholecystitis has increased with the development of improved diagnostic modalities. Although Epstein–Barr virus (EBV) infection is common in general population, only few cases of GB diseases caused by EBV infection have been reported. This study analyzed ultrasonographic characteristics of primary EBV infection in children and evaluated the influence of EBV-associated GB disease on clinical course and outcome of EBV infection.Between March 2004 and January 2013, 94 of 287 pediatric patients with EBV infection underwent abdominal ultrasonography (USG); clinical features, laboratory data, and USG findings were collected and analyzed retrospectively.Of 94 children, ultrasonographic thick GB wall was observed in 24 (25.3%). Platelet counts were lower in the thickened GB wall group than in the normal GB wall thickness group (P = 0.004). Direct bilirubin, alanine aminotransferase, and γ-glutamyl transferase levels were higher in the thickened GB wall group (P = 0.000, P = 0.041, and P = 0.001, respectively). The duration of hospitalization was longer in patients with thickened GB wall (P = 0.043).Radiologic findings of acute acalculous inflammatory GB disease such as thickened GB wall caused by primary EBV infection are more common than previously reported. Consideration of EBV infection in the differential diagnosis of children suspected with acute acalculous GB diseases may avoid unnecessary surgical intervention.     

No Association of SERPINE1 ?675 Polymorphism With Sepsis Susceptibility: A Meta-Analysis

The serine protease inhibitor clade E member 1 (SERPINE1) gene has been suggested to exert great influence on the development of sepsis. But there is little overlap in the results of association between SERPINE1 −675 4G/5G polymorphism and sepsis.To get a more precise estimation of this association, we conducted a meta-analysis with a relatively larger sample size including 1806 cases and 2239 controls. Odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the relationship between −675 4G/5G polymorphism and sepsis susceptibility. Subgroup analyses were conducted based on ethnicity and source of controls.The results showed that there was no association of the SERPINE1 polymorphism and sepsis susceptibility (5G5G vs 4G4G: OR = 0.87, CI = 0.75–1.03; 5G5G+4G5G vs 4G4G: OR = 0.93, CI = 0.84–1.02; 5G5G vs 4G4G+4G5G: OR = 0.96, CI = 0.83–1.11; 5G vs 4G: OR = 0.94, CI = 0.86–1.01; 4G5G vs 4G4G: OR = 0.90, CI = 0.80–1.01). Nor did any subgroup analysis indicate a significant association.In conclusion, −675 4G/5G polymorphism in the SERPINE1 gene may not be associated with the risk of sepsis.     

Association of G-308A TNF-α Polymorphism with Bronchial Asthma in a North Indian Population

Bronchial asthma is an inflammatory disorder in which genetic and environmental factors play an important role. Several susceptible genes have been identified using whole genome scan and candidate gene approaches. Tumor necrosis factor alpha, a pro-inflammatory cytokine, is one such gene that figures prominently in such investigations. The secreted levels of this cytokine are under genetic control and attributed to the presence of single nucleotide polymorphism G-308 A in the promoter region of its gene. However, the association of this polymorphism varies from population to population. As there are no data available on North Indians, the present study aims to fill this void. For this, 366 subjects (155 asthmatic and 211 normal control subject) were genotyped using Amplification Refractory Mutation System Analysis (ARMS–PCR) and agarose gel electrophoresis. The distribution of G/A alleles between the two groups revealed statistically significant differences (p = 0.016). Furthermore, the asthma patients categorized on the basis of pattern (Seasonal versus Perennial) and age of onset of disease (Childhood versus Late Onset) revealed significant association with only seasonal (p = 0.021) and late onset asthmatic groups (p = 0.039). The data from the present study strongly suggest an association between TNF-α and asthma in the North Indian population.     

Olanzapine-induced neutropenia in a patient with systemiclupus erythematosus: a role of FcγRIIIb polymorphism?

In this study, we report the case of a Chinese patient with systemic lupus erythematosus (SLE) who developed neutropenia after treatment by olanzapine for the SLE-related psychiatric symptoms. The relationship between agranulocytosis, SLE and olanzapine is still unknown. Fcγ receptor IIIb (FcγRIIIb) is a low-affinity receptor, constitutively expressed only by neutrophils; NA1 and NA2 have been identified as representing polymorphisms of FcγRIIIb. NA1 is associated with the incidence of autoimmune neutropenia and is particularly frequent in Asiatic ethnic groups. The Chinese patient resulted to be homozygous for NA1. We suggest that the presence of NA1 allele may be a predisposing factor to olanzapine-induced agranulocytosis in patients with SLE. Hence, the analysis of FcγRIIIb polymorphism should be investigated in other cases of antipsychotic-induced agranulocytosis.     

Expression of CD64 (FcγRI) in skin of patients with acute GVHD

GVHD remains a major problem in allo-SCT. We explored the presence of APC in skin biopsies of GVHD patients, using the IgG receptor CD64 expression as a hallmark for activated APC. By immunohistochemistry we demonstrated CD64 to be upregulated on host APC in skin biopsies of patients with acute GVHD and, less prominently, in chronic GVHD. Double staining for CD32 polymorphism revealed CD64-positive cells to be mainly of host origin. The majority of CD64-positive cells coexpressed CD68, indicating a macrophage phenotype. Given its very restricted cellular distribution, CD64 may represent an excellent target for APC-directed therapies in GVHD.     

Prevention of hospital-associated venous thromboembolism — Insight from the Getting It Right First Time thrombosis survey in England

A national Venous Thromboembolism (VTE) Prevention Programme was introduced in England in 2010, with limited subsequent study of its impact. Whilst the National Outcomes Framework reports VTE deaths related to hospitalisation annually, there are little data regarding VTE prevention practice or non-fatal VTE associated with hospitalisation. We report the first national thrombosis survey undertaken in collaboration with Getting It Right First Time. 98 Trusts (103 sites, 67% of 144 invited) participated in at least one survey, contributing data regarding VTE prevention in 9553 patients. Anti-coagulant thromboprophylaxis was prescribed to 88% (when indicated), with 8.1% of patients missing doses. Written patient information was provided to 31%. Of 4595 episodes of hospital-associated VTE, 13% were considered potentially preventable. The survey highlights the success of the national programme and areas for improvement in delivery of thromboprophylaxis and patient information.     

Formation of Infectious Dengue Virus–Antibody Immune Complex In Vivo in Marmosets (Callithrix jacchus) After Passive Transfer of Anti-Dengue Virus Monoclonal Antibodies and Infection with Dengue Virus

Infection with a dengue virus (DENV) serotype induces cross-reactive, weakly neutralizing antibodies to different dengue serotypes. It has been postulated that cross-reactive antibodies form a virus–antibody immune complex and enhance DENV infection of Fc gamma receptor (FcγR)-bearing cells. We determined whether infectious DENV–antibody immune complex is formed in vivo in marmosets after passive transfer of DENV-specific monoclonal antibody (mAb) and DENV inoculation and whether infectious DENV–antibody immune complex is detectable using FcγR-expressing cells. Marmosets showed that DENV–antibody immune complex was exclusively infectious to FcγR-expressing cells on days 2, 4, and 7 after passive transfer of each of the mAbs (mAb 4G2 and mAb 6B6C) and DENV inoculation. Although DENV–antibody immune complex was detected, contribution of the passively transferred antibody to overall viremia levels was limited in this study. The results indicate that DENV cross-reactive antibodies form DENV–antibody immune complex in vivo, which is infectious to FcγR-bearing cells but not FcγR-negative cells.     

Clinical Expression of ‘Silent’ Hepatitis B Virus Infection in a Patient with Visceral Leishmaniasis

A 69-year-old male was hospitalized in January 1999 because of viszeral leishmaniasis. He had also suffered from anti-hepatitis C virus (HCV)-positive chronic hepatitis for years. All serum hepatitis B virus (HBV) antigens and antibodies were negative except for anti-HBc. The patient was treated with amphotericin B cholesteryl sulfate (2 mg/kg twice a day for 7 days, iv). Fever disappeared on the 3rd day of treatment, the clinical condition improved rapidly and the patient recovered. In May 1999 the patient developed iteric HBsAg-negative acute hepatitis (aspartate aminotransferase 722 U/l; alanine aminotransferase 988 U/l). Anti-HBc IgM was positive and HBV-DNA was detected in serum by PCR. Anti-HAV IgM was negative. A serum sample obtained on presentation and stored at −80°C was retrospectively tested and found positive for HBV-DNA. In July 1999, complete remission of acute hepatitis and seroconversion to anti-HBs was observed. We suppose that a moderate depression of the immune system, probably associated with leishmaniasis, may have enhanced HBV replication in the patient who had an HBsAg-negative ‘silent’ HBV infection. Restoration of the immune system after successful antiprotozoan therapy might have induced cell-mediated necrosis of the HBV-infected hepatocytes and seroconversion to anti-HBs. Received: June 6, 2000 · Revision accepted: February 16, 2001