Salivary dysbiosis and the clinical spectrum in anti-Ro positive mothers of children with neonatal lupus.

Mothers giving birth to children with manifestations of neonatal lupus (NL) represent a unique population at risk for the development of clinically evident pathologic autoimmunity since many are asymptomatic and only become aware of anti-SSA/Ro positivity (anti-Ro+) based on heart block in their fetus. Accordingly, we hypothesized that the microbiome in saliva is associated with the development of autoreactivity and in some cases the progression in health status from benign to overt clinical disease including Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE). The study comprised a clinical spectrum of anti-Ro+ mothers, all of whom gave birth to a child with NL: 9 were asymptomatic or had an undifferentiated autoimmune disease (Asym/UAS) and 16 fulfilled criteria for SS and/or SLE. Microbial diversity was reduced across all levels from kingdom to species for the anti-Ro+ mothers vs healthy controls; however, there were no significant differences between Asym/UAS and SS/SLE mothers. Relative abundance of Proteobacteria and more specifically class Betaproteobacteria decreased with clinical severity (healthy controls < Asym/UAS < SS/SLE). These ordered differences were maintained through the taxonomic hierarchy to three genera (Lautropia, Comamonas, and Neisseria) and species within these genera (L. mirabilis, N. flavescens and N. oralis). Biometric analysis comparing von Willebrand Factor domains present in human Ro60 with L. mirabilis proteins support the hypothesis of molecular mimicry. These data position the microbiome in the development of anti-Ro reactivity and subsequent clinical spectrum of disease.

Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

[Scalp cooling for chemotherapy-induced alopecia]. / Hoofdhuidkoeling tegen alopecia door chemotherapie.

Alopecia is a very common side effect of cytostatic therapy and is considered one of the most emotionally distressing effects. To prevent alopecia scalp cooling is currently used in some indications in medical oncology in 59 hospitals in the Netherlands. The success of scalp cooling depends on various factors such as type of chemotherapy, dose, infusion time, number of treatment cycles and combinations of drugs. In general, scalp cooling is well tolerated. The reported side-effects are headache, coldness, dizziness and sometimes claustrophobia. An increase in the risk of scalp metastases has not been demonstrated. Proceeding from the South Netherlands Comprehensive Cancer Centre a national working group is put together in order to draw up a national guideline for chemotherapy-induced alopecia.

Replication of the BANK1 genetic association with systemic lupus erythematosus in a European-derived population.

Systemic lupus erythematosus (SLE) is an autoimmune disease with highly variable clinical presentation. Patients suffer from immunological abnormalities that target T-cell, B-cell and accessory cell functions. B cells are hyperactive in SLE patients. An adapter protein expressed in B cells called BANK1 (B-cell scaffold protein with ankyrin repeats) was reported in a previous study to be associated with SLE in a European population. The objective of this study was to assess the BANK1 genotype-phenotype association in an independent replication sample. We genotyped 38 single nucleotide polymorphisms (SNPs) in BANK1 on 1892 European-derived SLE patients and 2652 European-derived controls. The strongest associations with SLE and BANK1 were at rs17266594 (corrected P-value=1.97 x 10(-5), odds ratio (OR)=1.22, 95% CI 1.12-1.34) and rs10516487 (corrected P-value=2.59 x 10(-5), OR=1.22, 95% CI 1.11-1.34). Our findings suggest that the association is explained by these two SNPs, confirming previous reports that these polymorphisms contribute to the risk of developing lupus. Analysis of patient subsets enriched for hematological, immunological and renal ACR criteria or the levels of autoantibodies, such as anti-RNP A and anti-SmRNP, uncovers additional BANK1 associations. Our results suggest that BANK1 polymorphisms alter immune system development and function to increase the risk for developing lupus.

Genetic associations of LYN with systemic lupus erythematosus.

We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case-control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 x 10(-4), odds ratio (OR)=0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism (SNP) is located in the 5' untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 x 10(-3), OR=0.75 (95% CI: 0.62-0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.

Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans.

Increased expression of interferon (IFN)-inducible genes is implicated in the pathogenesis of systemic lupus erythematosus (SLE). One transcription factor responsible for regulating IFN, interferon regulatory factor-5 (IRF5), has been associated with SLE in genetic studies of Asian, Caucasian and Hispanic populations. We genotyped up to seven polymorphic loci in or near IRF5 in a total of 4870 African-American and Caucasian subjects (1829 SLE sporadic cases and 3041 controls) from two independent studies. Population-based case-control comparisons were performed using the Pearson's chi(2)-test statistics and haplotypes were inferred using HaploView. We observed significant novel associations with the IRF5 variants rs2004640 and rs3807306 in African Americans and replicated previously reported associations in Caucasians. While we identified risk haplotypes, the majority of haplotypic effects were accounted for by one SNP (rs3807306) in conditional analyses. We conclude that genetic variants of IRF5 associate with SLE in multiple populations, providing evidence that IRF5 is likely to be a crucial component in SLE pathogenesis among multiple ethnic groups.

Short- and long-term action of multiple doses of ivermectin on loiasis microfilaremia.

One hundred nine Gabonese patients infected with Loa loa microfilariae were treated with ivermectin (200 microg/kg of body weight) at the Parasitology, Mycology and Tropical Medicine Department (Faculte de Medecine et des Sciences de la Sante, Libreville, Gabon). Each was given one dose per month for six consecutive months. The peripheral blood microfilaria (mf) count before and after each dose showed an average decrease in the microfilaremia of 87.3% (short-term-single dose). An annual single-dose mass treatment with 200 microg/kg of ivermectin was sufficient to control the parasite in populations with low (< 400/ml) L. loa mf counts. One month after the sixth dose (short-term-multiple doses), the average microfilaremia rate had decreased by 99.2% compared with the initial infection (35 patients). Samples were taken from 28 patients one month after the first dose and one month after the sixth dose. The average mf count decreased by 96.4% after the first dose and by 99.6% after the sixth dose (average residual mf counts = 13.7 and 1.5 mf/ml, respectively). The mf count after the sixth dose was only 11.2% of the count after the first dose. The low mf count persisted for more than six months after the sixth treatment (long-term-multiple doses). Thus, mass treatment with multiple doses is more appropriate for areas where the blood mf count is very high. These results show that the number of the annual treatments used in mass chemotherapy with ivermectin can be adapted to each population to provide efficient protection.

[Leuconostocs in raw milk: isolation and identification of species rapidly utilizing lactose]. / Leuconostocs en leche cruda: aislamiento e identificación de especies de utilización rápida de lactosa.

Fast lactose fermenting Leuconostoc species and subspecies were isolated from raw milk. Samples were obtained from dairy farms of the surroundings of Buenos Aires city. A lactose, non selective, isolation medium was employed (YCL). Differentiation of leuconostocs from Lactobacillus viridescens and L. confusus was avoided on account of the use of this medium. 801 typical colonies of lactic acid bacteria were selected from YCL agar; 710 of them were identified as lactic acid bacteria from which 114 strains belonged to the genus Leuconostoc. These last strains were then tested for species and subspecies differentiation by dextran production and sugar fermentation. Leuconostoc mesenteroides subsp. dextranicum and L. lactis were identified. Four strains identified as Leuconostoc spp do not belong to any known species.

Leuconostocs en leche cruda: aislamiento e identificación de especies de utilización rápida de lactosa. / [Leuconostocs in raw milk: isolation and identification of species rapidly utilizing lactose]

Fast lactose fermenting Leuconostoc species and subspecies were isolated from raw milk. Samples were obtained from dairy farms of the surroundings of Buenos Aires city. A lactose, non selective, isolation medium was employed (YCL). Differentiation of leuconostocs from Lactobacillus viridescens and L. confusus was avoided on account of the use of this medium. 801 typical colonies of lactic acid bacteria were selected from YCL agar; 710 of them were identified as lactic acid bacteria from which 114 strains belonged to the genus Leuconostoc. These last strains were then tested for species and subspecies differentiation by dextran production and sugar fermentation. Leuconostoc mesenteroides subsp. dextranicum and L. lactis were identified. Four strains identified as Leuconostoc spp do not belong to any known species.