Background: Autophagy is essential for ␤-cell function and survival. Results: Autophagic turnover is impaired in ␤-cells when treated with metabolic stressors. Conclusion: Diminished autophagy leads to apoptotic ␤-cell death. Significance: Therapeutic interventions using pharmacological agents, which can improve ER folding capacity, as well as target the autophagy machinery, could provide promising strategies for treating human diseases such as T2D.

Methamphetamine (Meth) is a widely abused stimulant and its users are at increased risk for multiple infectious diseases. To determine the impact of meth on the immune system, we utilized a murine model that simulates the process of meth consumption in a typical addict. Our phenotypic analysis of leukocytes from this dose escalation model revealed that meth affected key immune subsets. Meth administration led to a decrease in abundance of natural killer (NK) cells and the remaining NK cells possessed a phenotype suggesting reduced responsiveness. Dendritic cells (DCs) and Gr-1high monocytes/macrophages were also decreased in abundance while Gr-1low monocytes/macrophages appear to show signs of perturbation. CD4 and CD8 T cell subsets were affected by methamphetamine, both showing a reduction in antigen-experienced subsets. CD4 T cells also exhibited signs of activation, with increased expression of CD150 on CD226-expressing cells and an expansion of KLRG1+, FoxP3− cells. These results exhibit that meth has the ability to disrupt immune homeostasis and impact key subsets of leukocytes which may leave users more vulnerable to pathogens.

Type 1A diabetes (T1D) is believed to be caused by immune-mediated destruction of β-cells, but the immunological basis for T1D remains controversial. Microbial diversity promotes the maturation and activation of certain immune subsets, including CD161bright CD8+ mucosal associated invariant T (MAIT) cells, and alterations in gut mucosal responses have been reported in type 1 diabetics (T1Ds). We analyzed T cell populations in peripheral blood leukocytes from juvenile T1Ds and healthy controls. We found that proportion and absolute number of MAIT cells were similar between T1Ds and controls. Furthermore, while MAIT cell proportions increased with age among healthy controls, this trend was not observed among long-standing T1Ds. Additionally, the CD27- MAIT cell subset is significantly increased in T1Ds and positively correlated with HbA1c levels. However, after T1Ds are stratified by age, the younger group has significantly increased proportions of CD27- MAIT cells compared to age-matched controls, and this proportional increase appears to be independent of HbA1c levels. Finally, we analyzed function of the CD27- MAIT cells and observed that IL-17A production is increased in CD27- compared to CD27+ MAIT cells. Overall, our data reveal disparate MAIT cell dynamics between T1Ds and controls, as well as signs of increased MAIT cell activation in T1Ds. These changes may be linked to hyperglycemia and increased mucosal challenge among T1Ds.

Type 1 diabetes (T1D) is a chronic disease characterized by autoimmune-mediated destruction of pancreatic insulin-producing beta cells. Interleukin (IL)-18 is a pro-inflammatory cytokine implicated in the pathogenesis of a number of inflammatory diseases. Here, we analyzed IL-18 levels in the plasma of juveniles with T1D. Compared to control subjects, IL-18 levels were significantly elevated in patients with T1D. On the other hand, levels of IL-18 binding protein (IL-18BP) and IL-37, two negative regulators of IL-18 function, remained unchanged when comparing T1D to control samples. Notably, however, although IL-18BP levels were not elevated, IL-18 and IL-18BP were found to be positively correlated in type 1 diabetics. Even so, free, unbound IL-18 remained significantly increased in diabetic patients. Additionally, correlation studies also revealed that IL-18 and IL-18BP are positively correlated with HbA1c levels in T1D patients, suggesting a potential link between IL-18 and metabolic control in these patients. Finally, we observed a significant increase in IL-18 protein expression within human pancreatic islet specimens collected from type 1 diabetics. These results further expand our knowledge of the role of IL-18 in T1D, may give insight into common pathogenic mechanisms associated with metabolic control in both T1D and T2D, and suggest that targeting this cytokine may improve therapeutic outcomes for T1D patients.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by dysregulated autoantibody production and complement activation leading to multi-organ damage. The disease is associated with increased intestinal permeability. In this study, we tested the hypothesis that SLE subjects have increased systemic exposure to bacteria. Since bacteria induce the expression of antimicrobial response factors (ARFs), we measured the levels of a series of clinically relevant ARFs in the plasma of SLE subjects. We found that levels of sCD14, lysozyme, and CXCL16 were significantly elevated in SLE subjects. A strong positive correlation was also observed between sCD14 and SELENA-SLEDAI score. Interestingly, the ratio of EndoCAb IgM:total IgM was significantly decreased in SLE and this ratio was negatively correlated with sCD14 levels. Although, there were no significant differences in the levels of lipopolysaccharide binding protein (LBP) and fatty acid binding protein 2 (FABP2), we observed significant positive correlations between lysozyme levels and sCD14, LBP, and FABP2. Moreover, galectin-3 levels also positively correlate with lysozyme, sCD14, and LBP. Since our SLE cohort comprised 43.33% males, we were able to identify gender-specific changes in the levels of ARFs. Overall, these changes in the levels and relationships between ARFs link microbial exposure and SLE. Approaches to reduce microbial exposure or to improve barrier function may provide therapeutic strategies for SLE patients.