by
Matthew Triplette;
Amy Justice;
Engi F. Attia;
Janet Tate;
Sheldon T. Brown;
Matthew Bidwell Goetz;
Joon W. Kim;
Maria C. Rodriguez-Barradas;
Guy W. Soo Hoo;
Cherry Wongtrakool;
Kathleen Akgun;
Kristina Crothers
Objective: Aging people living with HIV (PLWH) face an increased burden of comorbidities, including chronic obstructive pulmonary disease (COPD). The impact of COPD on mortality in HIV remains unclear. We examined associations between markers of COPD and mortality among PLWH and uninfected study participants. Design: Longitudinal analysis of the Examinations of HIV-Associated Lung Emphysema (EXHALE) cohort study. Methods: EXHALE includes 196 PLWH and 165 uninfected smoking-matched study participants who underwent pulmonary function testing and computed tomography (CT) to define COPD and were followed. We determined associations between markers of COPD with mortality using multivariable Cox regression models, adjusted for smoking and the Veterans Aging Cohort Study (VACS) Index, a validated predictor of mortality in HIV. Results: Median follow-up time was 6.9 years; the mortality rate was 2.7/100 person-years among PLWH and 1.7/100 person-years among uninfected study participants (P = 0.11). The VACS Index was associated with mortality in both PLWH and uninfected study participants. In multivariable models, pulmonary function and CT characteristics defining COPD were associated with mortality in PLWH: Those with airflow obstruction (forced expiratory volume in 1 s/ forced vital capacity <0.7) had 3.1 times the risk of death [hazard ratio 3.1 (95% confidence interval 1.4-7.1)], compared with those without; those with emphysema (>10% burden) had 2.4 times the risk of death [hazard ratio 2.4 (95% confidence interval 1.1-5.5)] compared with those with ≤ 10% emphysema. In uninfected subjects, pulmonary variables were not significantly associated with mortality, which may reflect fewer deaths limiting power. Conclusion: Markers of COPD were associated with greater mortality in PWLH, independent of the VACS Index. COPD is likely an important contributor to mortality in contemporary PLWH.
Sepsis is a leading cause of death in the United States, but the mechanisms underlying sepsis-induced immune dysregulation remain poorly understood. 2B4 (CD244, SLAM4) is a cosignaling molecule expressed predominantly on NK cells and memory CD8+ T cells that has been shown to regulate T cell function in models of viral infection and autoimmunity. In this article, we show that 2B4 signaling mediates sepsis lymphocyte dysfunction and mortality. 2B4 expression is increased on CD4+ T cells in septic animals and human patients at early time points. Importantly, genetic loss or pharmacologic inhibition of 2B4 significantly increased survival in a murine cecal ligation and puncture model. Further, CD4-specific conditional knockouts showed that 2B4 functions on CD4+ T cell populations in a cell-intrinsic manner and modulates adaptive and innate immune responses during sepsis. Our results illuminate a novel role for 2B4 coinhibitory signaling on CD4+ T cells in mediating immune dysregulation.
In order to study human acute lung injury and pneumonia, it is important to develop animal models to mimic various pathological features of this disease. Here we have developed a mouse lung injury model by intra-tracheal injection of bacteria Pseudomonas aeruginosa (P. aeruginosa or PA). Using this model, we were able to show lung inflammation at the early phase of injury. In addition, alveolar epithelial barrier leakiness was observed by analyzing bronchoalveolar lavage (BAL); and alveolar cell death was observed by Tunel assay using tissue prepared from injured lungs. At a later phase following injury, we observed cell proliferation required for the repair process. The injury was resolved 7 days from the initiation of P. aeruginosa injection. This model mimics the sequential course of lung inflammation, injury and repair during pneumonia. This clinically relevant animal model is suitable for studying pathology, mechanism of repair, following acute lung injury, and also can be used to test potential therapeutic agents for this disease.
The model of asthma as a single entity has now been replaced by a much more complex biological network of distinct and interrelating inflammatory pathways. The term asthma is now considered an umbrella diagnosis for several diseases with distinct mechanistic pathways (endotypes) and variable clinical presentations (phenotypes). The precise definition of these endotypes is central to asthma management due to inherent therapeutic and prognostic implications. This review presents the molecular mechanisms behind the heterogeneity of airway inflammation in asthmatic patients. Asthma endotypes may be broadly regarded as type 2 (T2) high or T2-low. Several biologic agents have been approved for T2-high asthma, with numerous other therapeutics that are incipient and similarly targeted at specific molecular mechanisms. Collectively, these advances have shifted existing paradigms in the approach to asthma to tailor novel therapies.
Background Preterm (PT) infants are at greater risk for severe influenza infection and experience decrements in long-term antibody responses to vaccines. This may related to defects in antibody secreting cell (ASC) generation. Objective To investigate the relationships among the frequencies of influenza-specific antibody secreting cells, ASC numbers and subsets, and antibody responses to influenza vaccines (IV) among PT and full-term (FT) infants. Design/methods We enrolled 11 former PT (≤32 weeks′ gestation, ≤1500 g′ birth weight) and 11 FT infants, 6–17 months of age, receiving their first influenza immunizations. Infants received two doses of inactivated trivalent (T)IV or quadrivalent (Q)IV during the 2012–2013 and 2013–2014 influenza seasons, respectively, at 0 and 28 days, and blood was drawn at 0, 10, 35, and 56 days and 9 months. Vaccine-specific antibody was measured by hemagglutination inhibition (HAI) at 0 and 56 days and 9 months, vaccine-specific ASC numbers by enzyme linked immunospot (ELISPOT) at 10 and 35 days, and ASC subsets by flow cytometry at 0, 10 and 35 days. Results PT infants had post-vaccine HAI titers to all 4 vaccine strains at least equal to FT infants at 56 days and 9 months after beginning immunization. Influenza-specific ASC ELISPOT responses at 35 days were higher among PT than FT infants (median 100 v. 30 per 106PBMC, p = 0.04). ASC numbers at 35 days were positively correlated with serum HAI titers at 56 days (ρ = 0.50–0.80). There were no statistical differences between PT and FT infants in the frequency of five ASC subsets and no specific ASC subset correlated with durability of serum antibody titers. Conclusions Influenza-specific ASC numbers in both FT and PT infants correlated with peak antibody titers, but ASC subsets did not correlate with durability of antibody response.
by
Jessica L. Halliley;
Christopher Tipton;
Jane Liesveld;
Alexander F. Rosenberg;
Jaime Darce;
Ivan V. Gregoretti;
Lana Popova;
Denise Kaminiski;
Christopher F. Fucile;
Igor Albizua-Santin;
Shuya Kyu;
Kuang-Yueh Chiang;
Kyle Bradley;
Richard Burack;
Mark Slifka;
Erika Hammarlund;
Hao Wu;
Liping Zhao;
Edward E. Walsh;
Ann R. Falsey;
Troy D. Randall;
Wan Cheung Cheung;
Ignacio Sanz;
Frances Lee
Antibody responses to viral infections are sustained for decades by long-lived plasma cells (LLPCs). However, LLPCs have yet to be characterized in humans. Here we used CD19, CD38, and CD138 to identify four PC subsets in human bone marrow (BM). We found that the CD19−CD38hiCD138+ subset was morphologically distinct, differentially expressed PC-associated genes and exclusively contained PCs specific for viral antigens to which the subjects had not been exposed for over 40 years. Protein sequences of measles- and mumps-specific circulating antibodies were encoded for by CD19−CD38hiCD138+ PCs in the BM. Finally, we found that CD19−CD38hiCD138+ PCs had a distinct RNA transcriptome signature and human immunoglobulin heavy chain (VH) repertoire that was relatively uncoupled from other BM PC subsets and likely represents the B cell response’s “historical record” of antigenic exposure. Thus, our studies define human LLPCs and provide a mechanism for the life-long maintenance of anti-viral antibodies in the serum.
by
Matthew Triplette;
Engi Attia;
Kathleen Akgun;
Monica Campo;
Maria Rodriguez-Barradas;
Sudhakar Pipavath;
Shahida Shahrir;
Cherry Wongtrakool;
Matthew Bidwell Goetz;
Joon Kim;
Guy W. Soo Hoo;
Sheldon T. Brown;
Kristina Crothers
Background: Emphysema is more prevalent in HIV-infected (HIV+) patients independent of smoking behavior. Nonetheless, health effects of emphysema in this population are poorly understood. We determined whether emphysema is associated with a greater burden of pulmonary symptoms and a lower 6-minute walk distance (6MWD) in HIV+ compared with HIV-uninfected (HIV-) subjects. Methods: We performed a cross-sectional analysis of 170 HIV+ and 153 HIV- subjects in the Examinations of HIV-Associated Lung Emphysema (EXHALE) cohort study. Subjects completed a self-assessment of respiratory symptoms, pulmonary function testing, and 6MWD testing as well as a chest computed tomography to determine emphysema severity. We used regression models to determine the association of emphysema with respiratory symptoms and 6MWD in HIV+ subjects and compared this to HIV- subjects. Results: Models stratified by HIV status demonstrated an association between > 10% radiographic emphysema and chronic cough and/or phlegm and 6MWD in HIV+ subjects. These associations persisted among the subset without airflow obstruction: those with emphysema had 4.2 (95% confidence interval: 1.3 to 14) times the odds of chronic cough and/or phlegm and walked 60 m (95% confidence interval: 26 to 93) less distance than those without emphysema. There was no association between > 10% emphysema and symptoms or 6MWD in HIV- subjects. Conclusions: In our cohort, > 10% radiographic emphysema was associated with chronic cough and/or phlegm and lower 6MWD in HIV+ but not HIV- subjects. These findings were robust even among HIV+ subjects with milder forms of emphysema and those without airflow obstruction, highlighting the clinical impact of emphysema in these patients.
The mechanisms underlying the association between chronic psychological stress, development of metabolic syndrome (MetS), and behavioral impairment in obesity are poorly understood. The aim of the present study was to assess the effects of mild chronic psychological stress on metabolic, inflammatory, and behavioral profiles in a mouse model of diet-induced obesity. We hypothesized that (1) high-fat high-fructose diet (HFHF) and psychological stress would synergize to mediate the impact of inflammation on the central nervous system in the presence of behavioral dysfunction, and that (2) HFHF and stress interactions would impact insulin and lipid metabolism. C57Bl/6 male mice underwent a combination of HFHF and two weeks of chronic psychological stress. MetS-related conditions were assessed using untargeted plasma metabolomics, and structural and immune changes in the gut and liver were evaluated. Inflammation was measured in plasma, liver, gut, and brain. Our results show a complex interplay of diet and stress on gut alterations, energetic homeostasis, lipid metabolism, and plasma insulin levels. Psychological stress and HFHF diet promoted changes in intestinal tight junctions proteins and increases in insulin resistance and plasma cholesterol, and impacted the RNA expression of inflammatory factors in the hippocampus. Stress promoted an adaptive anti-inflammatory profile in the hippocampus that was abolished by diet treatment. HFHF increased hippocampal and hepatic Lcn2 mRNA expression as well as LCN2 plasma levels. Behavioral changes were associated with HFHF and stress. Collectively, these results suggest that diet and stress as pervasive factors exacerbate MetS-related conditions through an inflammatory mechanism that ultimately can impact behavior. This rodent model may prove useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders.
The pathogenic profile of Pseudomonas aeruginosa is related to its ability to secrete a variety of virulence factors. Quorum sensing (QS) is a mechanism wherein small diffusible molecules, specifically acyl-homoserine lactones, are produced by P. aeruginosa to promote virulence. We show here that macrophage clearance of P. aeruginosa (PAO1) is enhanced by activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ). Macrophages treated with a PPARγ agonist (pioglitazone) showed enhanced phagocytosis and bacterial killing of PAO1. It is known that PAO1 QS molecules are inactivated by PON-2. QS molecules are also known to inhibit activation of PPARγ by competitively binding PPARγ receptors. In accord with this observation, we found that infection of macrophages with PAO1 inhibited expression of PPARγ and PON-2. Mechanistically, we show that PPARγ induces macrophage paraoxonase 2 (PON-2), an enzyme that degrades QS molecules produced by P. aeruginosa. Gene silencing studies confirmed that enhanced clearance of PAO1 in macrophages by PPARγ is PON-2 dependent. Further, we show that PPARγ agonists also enhance clearance of P. aeruginosa from lungs of mice infected with PAO1. Together, these data demonstrate that P. aeruginosa impairs the ability of host cells to mount an immune response by inhibiting PPARγ through secretion of QS molecules. These studies define a novel mechanism by which PPARγ contributes to the host immunoprotective effects during bacterial infection and suggest a role for PPARγ immunotherapy for P. aeruginosa infections.
Acute systemic lupus erythematosus (SLE) courses with surges of antibody-secreting cells (ASCs) whose origin, diversity and contribution to serum autoantibodies remain unknown. Here, deep sequencing, proteomic profiling of autoantibodies and single-cell analysis demonstrated highly diversified ASCs punctuated by clones expressing the variable heavy-chain region V<inf>H</inf>4-34 that produced dominant serum autoantibodies. A fraction of ASC clones contained autoantibodies without mutation, a finding consistent with differentiation outside the germinal centers. A substantial ASC segment was derived from a distinct subset of newly activated naive cells of considerable clonality that persisted in the circulation for several months. Thus, selection of SLE autoreactivities occurred during polyclonal activation, with prolonged recruitment of recently activated naive B cells. Our findings shed light on the pathogenesis of SLE, help explain the benefit of agents that target B cells and should facilitate the design of future therapies.