B Cell Activation in Insulin Resistance and Obesity

Our group has demonstrated that inflammatory diseases such as type 2 diabetes (DM), inflammatory bowel disease (IBD), and periodontal disease (PD) are associated with altered B cell function that may contribute to disease pathogenesis. B cells were found to be highly activated with characteristics of inflammatory cells. Obesity is a pre-disease state for cardiovascular disease and type 2 diabetes and is considered a state of chronic inflammation. Therefore, we sought to better characterize B cell function and phenotype in obese patients. We demonstrate that (Toll-like receptor) TLR4 and CD36 expression by B cells is elevated in obese subjects, suggesting increased sensing of lipopolysaccharide (LPS) and other TLR ligands. These ligands may be of microbial, from translocation from a leaky gut, or host origin. To better assess microbial ligand burden and host response in the bloodstream, we measured LPS binding protein (LBP), bacterial/permeability increasing protein (BPI), and high mobility group box 1 (HMGB1). Thus far, our data demonstrate an increase in LBP in DM and obesity indicating increased responses to TLR ligands in the blood. Interestingly, B cells responded to certain types of LPS by phosphorylating extracellular-signal-regulated kinases (ERK) 1/2. A better understanding of the immunological state of obesity and the microbial and endogenous TLR ligands that may be activating B cells will help identify novel therapeutics to reduce the risk of more dangerous conditions, such as cardiovascular disease

The Dripping Sunlight : The Case of MIKI Rofu\u27s Poems

筆者は、同じ表題で、すでに二つの論文を公にしているが、「ある詩語の水脈」「北原白秋の場合」という副題をそれぞれに付して、区別してある。三編目の今回は、「三木露風の場合」である。室生犀星の「したたり止まぬ日のひかり/うつうつまはる水ぐるま」(「寂しき春」) という表現に集約的に完成されるところの、水をではなく光りを、したたるものとして捉えるという、特異な発想の出没の跡を追跡する試みの一部である

The complexity of diagnosing latent tuberculosis infection in older adults in long-term care facilities

Objectives: In the USA, tuberculosis disease rates are highest in older adults. Diagnostic testing for latent tuberculosis infection (LTBI) has not been evaluated carefully in this group. The aim of this study was to define the relationship between tuberculin skin test (TST) results, T-SPOT.TB results, and T-cell responses to Mycobacterium tuberculosis antigens. Methods: Long-term care facility residents with known prior TST results (positive or negative) were retested with TSTs and T-SPOT.TB. Prior exposure to M. tuberculosis was assessed by quantifying T-cell activation to mycobacterial antigens in vitro. Results: The median age of the 37 participants was 77 years (range 57–98 years). Among 18 participants with a prior positive TST, three (16.7%) had a negative TST when retested (TST reversion); two had a negative T-SPOT.TB. Of the 15 who were historically and currently TST-positive, four (26.7%) had a negative T-SPOT.TB and one (6.7%) had a borderline result. Percentages of CD4+ T-cells responding to mycobacterial antigens were higher in participants with positive TST and T-SPOT.TB (18.2%) compared to those with a positive TST but negative T-SPOT.TB (6.4%, p = 0.16) and negative TST and T-SPOT.TB (5.9%, p < 0.001). Conclusions: LTBI testing in older adults is complicated by TST reversion and TST-positive/T-SPOT.TB-negative discordance, which may reflect clearance of infection or waning immunity

B cells from periodontal disease patients express surface Toll-like receptor 4

Chronic systemic inflammation links periodontal disease (PD) to increased incidence of cardiovascular disease. Activation of TLRs, particularly TLR4, promotes chronic inflammation in PD by stimulating myeloid cells. B cells from healthy individuals are generally refractory to TLR4 agonists as a result of low surface TLR4 expression. Unexpectedly, a significantly increased percentage of gingival and peripheral blood B cells from patients with PD expressed surface TLR4. Surface expression correlated with an active TLR4 promoter that mimicked the TLR4 promoter in neutrophils. B cells from PD patients were surface myeloid differentiation protein 2-positive and also packaged the enhancer of a proinflammatory cytokine, IL-1β, into an active structure, demonstrating that these cells harbor key characteristics of proinflammatory cell types. Furthermore, B cells lacked activating signatures of a natural IL-1β inhibitor, IL-1 receptor antagonist. Surprisingly, despite multiple signatures of proinflammatory cells, freshly isolated B cells from PD patients had decreased expression of TLR pathway genes compared with B cells from healthy individuals. Decreases in inflammatory gene expression were even more dramatic in B cells stimulated with a TLR4 ligand from a periodontal pathogen, Porphyromonas gingivalis LPS 1690. In contrast, B cell TLR4 was not activated by the prototypic TLR4 ligand Escherichia coli LPS. These findings raise the unexpected possibility that TLR4 engagement modulates B cell activation in PD patients

Correlation between Eosinophils and Protection against Reinfection with Schistosoma mansoni and the Effect of Human Immunodeficiency Virus Type 1 Coinfection in Humans

Longitudinal investigations of an adult male population of Kenyan car washers who have heavy and quantifiable occupational exposure to Schistosoma mansoni cercariae revealed that some individuals develop resistance to reinfection while others remain highly susceptible. We sought to characterize immune correlates associated with host protection in this population. Previous studies have demonstrated an association of peripheral eosinophilia with resistance to reinfection with schistosomes. Thus, we investigated the relationship between the percentage of circulating eosinophils and the effect of human immunodeficiency virus type 1 (HIV-1) coinfection on the susceptibility of the car washers to reinfection with schistosomes. Elevated percentages of circulating eosinophils were associated with resistance to reinfection by S. mansoni in HIV-1-seronegative persons. In the HIV-1-seropositive cohort, low CD4(+)-T-cell counts were associated with a less intense eosinophilia. Moreover, eosinophils from the car washers expressed high levels of FcεRI β chain, a molecule important in immunoglobulin E (IgE)-mediated immunity. Levels of FcεRI β chain expression correlated with serum levels of total and antigen-specific IgE for HIV-1-negative car washers, but this was not the case for individuals coinfected with HIV-1. Overall, these data further implicate eosinophils as having a potential role in development of protective immunity against schistosomes and suggest that changes associated with HIV-1 coinfection increase susceptibility to reinfection