Frontiers in immunology
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Frontiers in immunology · Jan 2019
Rheumatoid Synovial Fluids Regulate the Immunomodulatory Potential of Adipose-Derived Mesenchymal Stem Cells Through a TNF/NF-κB-Dependent Mechanism.
Introduction: Adipose-derived mesenchymal stem cells (ADSC) have been shown to have remarkable immune-modulating effects. However, their efficacy in clinical trials has yet to be fully demonstrated. This could be due to a lack of a proper inflammatory environment in vivo that primes ADSC. ⋯ The clinical use of ADSC in affected joints should take into account the influence of the local articular environment on their potential. Having a sufficient pro-inflammatory microenvironment will determine whether optimal immunoregulatory response should be expected. Direct ADSC intra-articular delivery to patients could be a potential strategy to properly prime their immunomodulatory potential and enhance their clinical benefits.
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Frontiers in immunology · Jan 2019
Opposite Profiles of Complement in Antiphospholipid Syndrome (APS) and Systemic Lupus Erythematosus (SLE) Among Patients With Antiphospholipid Antibodies (aPL).
APS is the association of antiphospholipid antibodies (aPL) with thromboses and/or recurrent pregnancy loss (RPL). Among patients with SLE, one-third have aPL and 10-15% have a manifestation of secondary APS. Animal studies suggested that complement activation plays an important role in the pathogenesis of thrombosis and pregnancy loss in APS. ⋯ Compared with non-RPL females, RPL had significantly higher frequency of thrombosis and elevated C4 protein levels. Female patients with homozygous C4A deficiency all experienced RPL (p = 0.0001) but the opposite was true for patients with homozygous C4B deficiency (p = 0.017). These results provide new insights and biomarkers for diagnosis and management of APS and SLE.
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Frontiers in immunology · Jan 2019
Different Levels of Incomplete Terminal Pathway Inhibition by Eculizumab and the Clinical Response of PNH Patients.
Background: Eculizumab blocks the lytic complement pathway by inhibiting C5 and has become the standard of care for certain complement-mediated diseases. Previously, we have shown that strong complement activation in vitro overrides the C5 inhibition by Eculizumab, which accounts for residual terminal pathway activity. Results: Here we show that the levels of residual hemolysis in ex vivo assays differ markedly (up to 3.4-fold) across sera collected from different paroxysmal nocturnal hemoglobinuria (PNH) patients on Eculizumab treatment. ⋯ Furthermore, the clinical history of nine out of 14 PNH patients showed intravascular breakthrough hemolysis at the time of documented infections despite ample amounts of administered Eculizumab and/or experimentally determined excess over C5. Conclusion: The occurrence of extraordinary high levels of residual terminal pathway activity in PNH patients receiving Eculizumab is rare, but can impair the suppression of hemolysis. The commonly observed low levels of residual terminal pathway activity seen for most PNH patients can exacerbate during severe infections and, thus, can cause pharmacodynamic breakthrough hemolysis in PNH patients treated with Eculizumab.
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Frontiers in immunology · Jan 2019
Diurnal Variation in Systemic Acute Inflammation and Clinical Outcomes Following Severe Blunt Trauma.
Animal studies suggest that the time of day is a determinant of the immunological response to both injury and infection. We hypothesized that due to this diurnal variation, time of injury could affect the systemic inflammatory response and outcomes post-trauma and tested this hypothesis by examining the dynamics of circulating inflammatory mediators in blunt trauma patients injured during daytime vs. nighttime. From a cohort of 472 blunt trauma survivors, two stringently matched sub-cohorts of moderately/severely injured patients [injury severity score (ISS) >20] were identified. ⋯ DyNA demonstrated elevated network complexity in the mNight vs. the mDay group. DyBN suggested that cortisol and sST2 were central nodes upstream of TGF-β1, chemokines, and Th17/protective mediators in both groups, with IL-6 being an additional downstream node in the mNight group only. Our results suggest that time of injury affects clinical outcomes in severely injured patients in a manner associated with an altered systemic inflammation program, possibly implying a role for diurnal or circadian variation in the response to traumatic injury.
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Frontiers in immunology · Jan 2019
Tissue-Resident Macrophages Limit Pulmonary CD8 Resident Memory T Cell Establishment.
Tissue resident memory CD8 T cells (TRM) serve as potent local sentinels and contribute significantly to protective immunity against intracellular mucosal pathogens. While the molecular and transcriptional underpinnings of TRM differentiation are emerging, how TRM establishment is regulated by other leukocytes in vivo is largely unclear. Here, we observed that expression of PPAR-γ in the myeloid compartment was a negative regulator of CD8 TRM establishment following influenza virus infection. ⋯ Further, the magnitude of the effector response could not explain these observations. These data indicate local regulation of pulmonary TRM differentiation is alveolar macrophage dependent. These, findings could aid in vaccine design aimed at increasing TRM density to enhance protective immunity, or deflating their numbers in conditions where they cause overt or veiled chronic pathologies.