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Periodontitis is one of the most common inflammatory human diseases with a strong genetic component. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWASs) of chronic periodontitis (CP) have largely been unsuccessful in identifying common susceptibility factors. A combination of quantitative trait loci (QTL) mapping in mice with association studies in humans has the potential to discover novel risk loci. To this end, we assessed alveolar bone loss in response to experimental periodontal infection in 25 lines (286 mice) from the Collaborative Cross (CC) mouse population using micro-computed tomography (µCT) analysis. The orthologous human chromosomal regions of the significant QTL were analyzed for association using imputed genotype data (OmniExpress BeadChip arrays) derived from case-control samples of aggressive periodontitis (AgP; 896 cases, 7,104 controls) and chronic periodontitis (CP; 2,746 cases, 1,864 controls) of northwest European and European American descent, respectively. In the mouse genome, QTL mapping revealed 2 significant loci (-log P = 5.3; false discovery rate = 0.06) on chromosomes 1 ( Perio3) and 14 ( Perio4). The mapping resolution ranged from ~1.5 to 3 Mb. Perio3 overlaps with a previously reported QTL associated with residual bone volume in F2 cross and includes the murine gene Ccdc121. Its human orthologue showed previously a nominal significant association with CP in humans. Use of variation data from the genomes of the CC founder strains further refined the QTL and suggested 7 candidate genes ( CAPN8, DUSP23, PCDH17, SNORA17, PCDH9, LECT1, and LECT2). We found no evidence of association of these candidates with the human orthologues. In conclusion, the CC populations enabled mapping of confined QTL that confer susceptibility to alveolar bone loss in mice and larger human phenotype-genotype samples and additional expression data from gingival tissues are likely required to identify true positive signals.

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Periodontitis is a common dysbiotic inflammatory disease with an estimated heritability of 50%. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWAS) of chronic periodontitis (CP) have been unsuccessful in discovering susceptibility factors. A strategy that combines agnostic GWAS with a well-powered candidate-gene approach has the potential to discover novel loci. We combined RNA-seq data from gingival tissues with quantitative trait loci (QTLs) that were identified in a F2-cross of mice resistant and susceptible to infection with oral bacterial pathogens. Four genes, which were located within the mapped QTLs, showed differential expression. The chromosomal regions across the human orthologous were interrogated for putative periodontitis-associated variants using existing GWAS data from a German case-control sample of aggressive periodontitis (AgP; 651 cases, 4,001 controls), the most severe and early onset form of periodontitis. Two haplotype blocks, one upstream to the coding region of UGT2A1 (rs146712414, P = 9.1 × 10-5; odds ratio [OR], 1.34; 95% confidence interval [CI], 1.16-1.56) and one downstream of the genes PF4/PPBP/CXCL5 (rs1595009, P = 1.3 × 10-4; OR, 1.32; 95% CI, 1.15-1.52), were associated with AgP. The association of rs1595009 was validated in an independent cohort of CP of European Americans (1,961 cases and 1,864 controls; P = 0.03; OR, 1.45; 95% CI, 1.01-1.29). This association was further replicated in another sample of 399 German CP cases (disease onset <60 y of age) and 1,633 controls ( P = 0.03; OR, 1.75; 95% CI, 1.06-2.90). The combined estimates of association from all samples were P = 2.9 × 10-5 (OR, 1.2; 95% CI, 1.1-1.3). This study shows the strength of combining QTL mapping and RNA-Seq data from a mouse model with association studies in human case-control samples to identify genetic risk variants of periodontitis.

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INTRODUCTION: A diverse range of human diseases, including allergy, asthma, autoimmune disease, cancer and chronic neurologic diseases, notably multiple sclerosis and endogenous depression, is becoming more prevalent in industrialized countries. It has been postulated that environmental factors associated with improved standards of hygiene play a leading role in this process since the immune system seems to need extrinsic challenges for its proper maturation. THE INNER WORLD: An added dimension has now emerged--the impact on disease of the inner world, principally the numerous endogenous retroviruses (HERVs) within the human genome. Taking melanoma as an example, we propose a framework for understanding how a complex infectious and immunological background can induce or inhibit expression of a HERV-related disease process. The central role of a failure to induce or to maintain certain populations of self-specific CD8(+) T-cells mediating immune surveillance, the expression of HERV-encoded peptides on affected cells and pathological mechanisms directly attributable to HERV proteins are discussed. CONCLUSIONS: The presented concepts explain events preceding the clinical manifestation of diseases by several years and provide a rationale for the use of currently available vaccines to protect against certain HERV-induced diseases, especially melanoma. Criteria for establishing the causal role of HERVs in a given disease are proposed.

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BCG vaccine, vaccinia vaccine and certain pathogens that were shown in previous studies to protect against melanoma have antigenic determinants homologous in their amino acids sequence with the melanoma antigen HERV-K-MEL, encoded by a human endogenous retrovirus K (HERV-K), which is expressed in about 95% of malignant melanocytes. Yellow fever vaccine (YFV) likewise contains an antigenic determinant with a close homology to HERV-K-MEL and might therefore also confer protection against melanoma. To investigate this possibility we carried out a cohort study (28,306 subjects) and a nested case-control study (37 melamona cases and 151 tumors not expressing HERV-K-MEL) in Veneto region (North-Eastern Italy). The standardized incidence ratio was 1.33 (95% confidence interval, 0.84-2.11), 1.59 (0.97-2.59) and 0.59 (0.19-1.84), while the age- gender-adjusted odds ratios were 1.00, 0.96 (0.43-2.14) and 0.26 (0.07-0.96), at 0-4, 5-9, and > or =10 years elapsed from YFV administration, respectively. The risk of melanoma may therefore be lowered 10 years after vaccination with yellow fever vaccine.

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We studied seroprevalence and concentrations of Epstein-Barr virus (EBV) antibodies in 147 pediatric patients with multiple sclerosis (MS) and paired controls. The children with MS showed a near-complete seropositivity for EBV antibody against virus capsid antigen (98.6% vs 72.1% in controls, p = 0.001) but did not display serologic evidence for a recent EBV infection. EBV antibody concentrations of pediatric patients with MS were significantly higher vs controls.

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BACKGROUND: Baló's concentric sclerosis (BCS) is a demyelinating disorder believed to be a rare variant of multiple sclerosis (MS). Human herpesvirus 6 (HHV-6) is a highly neurotropic virus causing severe central nervous system (CNS) infections predominantly following reactivation of latent HHV-6 in immunocompromised individuals. Primary infection with HHV-6 usually occurs in early childhood manifesting as exanthema subitum. The clinical spectrum of primary infection in adolescents or adults has not yet been evaluated. CASE REPORT: A previously healthy 13 year old girl developed acute hemianopsia and anomia 5 days after an episode of fever and malaise of unknown origin. Cerebral MRI revealed three white matter lesions, one with ring-like contrast enhancement. Lumbar puncture showed mononuclear pleocytosis of 30 cells/microl, oligoclonal IgG, and a normal protein level. Follow up cerebral MRI scans revealed lamellar concentric hemispheric lesions characteristic of BCS. The first neurological symptoms of the patient coincided with primary HHV-6 CNS infection, diagnosed by a positive PCR test of the CSF together with seroconversion. Response to antiviral and corticosteroid treatment was only temporary, but immunoglobulin treatment has so far been followed by clinical stability for 30 months. CONCLUSIONS: To our knowledge, this is the first report both of an association between HHV-6 and BCS and of immunoglobulin treatment of BCS. A late primary infection with HHV-6 might be associated with BCS. Further studies in patients with this rare disease are needed to confirm this association and to evaluate the efficacy of antiviral and immunoglobulin treatment.

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There is increasing evidence that infections and vaccinations play an important role in the normal maturation of the immune system. It was therefore of interest to determine whether these immune events also affect the prognosis of melanoma patients. A cohort study of 542 melanoma patients in six European countries and Israel was conducted. Patients were followed up for a mean of 5 years and overall survival was recorded. Biometric evaluations included Kaplan-Meier estimates of survival over time and Hazard Ratios (HRs), taking into account all known prognostic factors. During the follow-up between 1993 and 2002, 182 of the 542 patients (34%) died. Survival curves, related to Breslow's thickness as the most important prognostic marker, were in accordance with those observed in previous studies where the cause of death was known to be due to disseminated melanoma. In a separate analysis of patients, vaccinated with vaccinia or Bacille Calmette-Guerin (BCG), HRs and the corresponding 95% Confidence Intervals (CIs) were 0.52 (0.34-0.79) and 0.69 (0.49-0.98), respectively. Joint analyses yielded HRs (and 95% CIs) of 0.55 (0.34-0.89) for patients vaccinated with vaccinia, 0.75 (0.30-1.86) with BCG, and 0.41 (0.25-0.69) with both vaccines. In contrast, infectious diseases occurring before the excision of the tumour had little, or, at the most, a minor influence on the outcome of the melanoma patients. These data reveal, for the first time, that vaccination with vaccinia in early life significantly prolongs the survival of patients with a malignant tumour after initial surgical management. BCG vaccination seems to have a similar, although weaker, effect. The underlying immune mechanisms involved remain to be determined.

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A significant correlation between a reduced risk of melanoma and BCG and vaccinia vaccination in early childhood or infectious diseases later in life has already been reported from the FEBrile Infections and Melanoma (FEBIM) multicentre case-control study. This correlation is further evaluated in this study based on 603 incident cases of malignant melanoma and 627 population controls in six European countries and Israel by means of a joint analysis of the influence of vaccinations and infectious diseases. In addition, the previously unconsidered impact of influenza vaccinations is evaluated for the whole study population. The strong effects of the frequently given BCG and vaccinia vaccinations in early childhood, as well as of uncommon previous severe infectious diseases, were apparently not cumulative. With the Odds Ratio (OR) being set at 1 in the absence of vaccinations and infectious diseases, the OR dropped to 0.37 (95% Confidence Interval (CI): 0.10-1.42) when subjects had experienced one or more severe infectious diseases, associated with a fever of > 38.5 degrees C, and had not been vaccinated with BCG or vaccinia. The OR was 0.29 (CI: 0.15-0.57) in those who had had a severe infectious disease and were vaccinated with either BCG or vaccinia and 0.33 (CI: 0.17-0.65) for those with 1 or more severe infectious diseases and who had received both vaccinations. We conclude that both vaccinations as well as previous episodes of having a severe infectious disease induced the same protective mechanism with regards to the risk of melanoma. Because of a 'masking effect' by the vaccinia vaccination, the protective effect of the BCG vaccination and of certain infectious diseases against cancer has remained undetected. The vaccinations contributed more to the protection of the population than a previous episode of having an infectious disease. In view of the termination of vaccinations with vaccinia in all countries and of BCG in many of them, these findings call for a re-evaluation of vaccination strategies.

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Stimulation of Epstein-Barr virus (EBV) genome-positive Burkitt lymphoma cells with the ganglioside IV3NeuAc-nLcOse4Cer leads to the induction of cell differentiation processes and activates the EBV lytic viral cycle. In cells of the Burkitt lymphoma line Raji differential expression of host cell genes was analysed in the early phase (150 min) post stimulation with the ganglioside to display the cell activities that precede the activation of the EBV lytic cycle using the differential display reverse transcription-polymerase chain reaction technique. Multiple fragment cDNAs derived from control cells and ganglioside-stimulated cells were amplified using random primers and displayed via polyacrylamide gel electrophoresis. The expression pattern of 8,400 bands was analysed. Eleven differentially expressed fragment cDNAs were reamplified and identified by nucleotide sequencing. Six of these could be identified as coding for proteins that may take part in virus reactivation and differentiation. The most striking finding was the induction of s-adenosylhomocysteine hydrolase (AHCY) expression. The cellular enzyme AHCY plays an important role in transmethylation reactions controlling the replication of several viruses. Thus. an involvement in EBV replication can be suggested.

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OBJECTIVES: To assess the prognostic value of determining anti-endotoxin core antibodies (EndoCab) immunoglobulin (Ig)G and IgM in medical patients with sepsis syndrome in order to identify patient subgroups that may profit from endotoxin-neutralizing therapy. The findings were correlated with clinical outcome, endotoxin levels and sepsis score. DESIGN: Cohort study with a follow-up period of 30 days. SETTING: Medical intensive care units (2) of a university hospital. PATIENTS AND METHODS: Twenty-nine patients who fulfilled the criteria of sepsis syndrome and did not present with septic shock or had not been treated with antibiotics for more than 3 days were included in the study. Twenty-one intensive care patients without infections served as controls for antibody concentrations. INTERVENTIONS: Blood samples were obtained from indwelling arterial catheters or direct venipuncture on admission and daily thereafter until transfer to a regular unit. Sepsis scores were determined daily. RESULTS: The mortality rate at 30 days was 44.8% (13 out of 29). Sepsis patients had significantly lower initial EndoCab IgM and IgG concentrations than controls. Initial EndoCab IgG concentrations were significantly lower in non-survivors of sepsis syndrome but not in survivors compared to controls (median concentrations 51.5 vs 110.1 vs 245.4 MU/ml). EndoCab IgM and IgG were lower in non-survivors compared to survivors, though that difference failed to reach significance (p = 0.11 in both cases). Depletion of initial EndoCab IgM concentrations (defined as a value below the 10th percentile of a control population) was present in 15 patients, 9 of whom died, and depletion of IgG in five patients, four of whom died. EndoCab IgM and IgG concentrations rose concordantly in survivors and non-survivors in the course of the disease. Endotoxin levels were significantly higher in non-survivors compared to controls but not in survivors. A sepsis score of 21 and higher was associated with 90.9% mortality (specificity 93.8%, sensitivity 76.9%). CONCLUSIONS: Decreased EndoCab IgG concentrations are associated with increased mortality in medical patients with sepsis syndrome. The measurement of initial anti-endotoxin antibodies may provide a useful tool to identify septic patients who profit potentially from endotoxin neutralizing therapy, however considerable overlap of antibody concentrations warrants additional parameters. The sepsis score is easy to determine and useful in the evaluation of medical patients with sepsis.

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HBsAg is known to bind to human serum albumin polymerized by glutaraldehyde, human serum albumin has been found in preparations of HBsAg by several investigators. However, it is not yet known whether natural human serum albumin binds to hepatitis B virus under physiological conditions. We studied the binding between natural or recombinant HBsAg and monomeric human serum albumin by immunological, biochemical and biophysical methods. The binding capacity of 20-nm HBs spheres was variable but ranged up to six molecules HSA/sphere. A reversible binding site for human serum albumin was exclusively localized in the preS2 domain, whereas the S domain was inactive in vitro. Human serum albumin copurified with HBsAg of human origin during gel chromatography or sucrose-gradient centrifugation. This human serum albumin was monomeric in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The preS2-bound part of the human serum albumin could be removed from HBsAg by high-salt, such as CsCl centrifugation, but another part could only be removed by treatment with a disulfide cleaving reagent. Most of this covalently bound human serum albumin was retained at the HBsAg particle after complete cleavage of medium-sized HBs protein with trypsin. This indicates a second way in which albumin binds irreversible to cysteine(s) of the small HBs protein (SHBs, P24 and GP27).

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The current recombinant hepatitis B vaccines are safe and effective. However, the occurrence of non-responders and difficulties in immunizing immunodeficient persons suggest the need for further improvements. Recent data suggest that the pre-S2 and pre-S1 domains of hepatitis B virus induce protective antibodies. The good T-helper cell response against pre-S1 epitopes would also improve the antibody response against the small surface antigen protein. An even better T-cell priming could be achieved by including hepatitis B core (HBc) proteins or peptides. An optimal immunogen would contain all three proteins comprising hepatitis B surface antigen in their natural conformation and glycosylation as well as the major T-cell epitopes of HBc.

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