Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation.

Allergic asthma is a chronic, inflammatory lung disease. Some forms of allergic asthma are characterized by T helper type 2 (Th2)-driven eosinophilia, whereas others are distinguished by Th17-driven neutrophilia. Stimulation of Toll-like receptor 4 (TLR4) on hematopoietic and airway epithelial cells (AECs) contributes to the inflammatory response to lipopolysaccharide (LPS) and allergens, but the specific contribution of TLR4 in these cell compartments to airway inflammatory responses remains poorly understood. We used novel, conditionally mutant Tlr4(fl/fl) mice to define the relative contributions of AEC and hematopoietic cell Tlr4 expression to LPS- and allergen-induced airway inflammation. We found that Tlr4 expression by hematopoietic cells is critical for neutrophilic airway inflammation following LPS exposure and for Th17-driven neutrophilic responses to the house dust mite (HDM) lysates and ovalbumin (OVA). Conversely, Tlr4 expression by AECs was found to be important for robust eosinophilic airway inflammation following sensitization and challenge with these same allergens. Thus, Tlr4 expression by hematopoietic and airway epithelial cells controls distinct arms of the immune response to inhaled allergens.

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.

The curiously suspicious: a role for Epstein-Barr virus in lupus.

While the events initiating the development of autoantibodies in systemic lupus erythematosus (SLE) have not yet been convincingly established, newly developed tools for molecular investigation make such an undertaking increasingly practical. Applied to the earliest events in the sequence culminating in lupus autoimmunity, we present a critical potential role for Epstein-Barr virus (EBV) in the development and perhaps perpetuation of SLE. The expected properties for an environmental risk factor for SLE are found in this virus and the human host response against it. Existing data show the molecular progression to autoimmunity observed in SLE patient sera, the discovery of the first autoimmune epitopes in the Sm and Ro autoantigen systems, and the possible emergence of these autoantibodies from the heterologous antibodies against Epstein-Barr nuclear antigen-1 (EBNA-1). Further, existing data demonstrate association of SLE with EBV infection, even preceding the development of autoimmunity. Finally, the data are consistent with a proposed model of lupus pathogenesis that begins with antibodies to EBNA-1, predisposing to immune responses that develop crossreactive autoantibodies that culminate in the development of SLE autoimmunity.

A genetic marker within the CD44 gene confirms linkage at 11p13 in African-American families with lupus stratified by thrombocytopenia, but genetic association with CD44 is not present.

Systemic lupus erythematosus (SLE) is complicated from both a clinical and genetic standpoint. We have stratified SLE families by the presence of thrombocytopenia, which is associated with increased mortality among SLE patients, and found genetic linkage at chromosome 11p13 in African-American families. In the present study we have evaluated CD44, a gene very close (0.5 cM) to the peak LOD score marker, as a candidate gene. Using a newly identified short DNA repeat within the CD44 gene, we find a LOD score of 2.7, which confirms linkage within this genetic interval. However, using a panel of four single nucleotide markers spanning the CD44 gene, we find no genetic association with SLE. Therefore, these data further suggest an SLE susceptibility gene at 11p13, but also imply that an ancestral mutation in the CD44 gene does not account for the linkage.