Frontiers in immunology
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Frontiers in immunology · Jan 2018
Streptococcus Suis Serotype 2 Stimulates Neutrophil Extracellular Traps Formation via Activation of p38 MAPK and ERK1/2.
Streptococcus suis serotype 2 is a major pathogen of swine streptococcicosis, which result in serious economic loss worldwide. SS2 is an important zoonosis causing meningitis and even death in humans. Neutrophil extracellular traps (NETs) constitute a significant bactericidal strategy of innate immune. ⋯ Blocking TLR4 signaling could further inhibit the activation of ERK1/2, but not p38 MAPK; however, TLR4 signaling inhibition reduced NETs formation induced by SS2. In conclusion, SS2 could be recognized by TLR2 and/or TLR4, initiating NETs formation signaling pathways in a NADPH oxidase derived ROS dependent manner. ROS will activate p38 MAPK and ERK1/2, which ultimately induces NETs formation.
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Frontiers in immunology · Jan 2018
Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry.
Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. ⋯ Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.
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Frontiers in immunology · Jan 2018
Analysis of Serum Interleukin (IL)-1β and IL-18 in Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by biological and clinical heterogeneity. The interleukin (IL)-1 superfamily is a group of innate cytokines that contribute to pathogenesis in many autoimmune diseases. IL-1β and IL-18 are two members that have been shown to play a role in murine lupus-like models, but their role in human SLE remains poorly understood. ⋯ High baseline serum IL-18 levels were associated with organ damage at the subsequent visit. Serum IL-1β levels were not significantly elevated in SLE patients when compared to HCs and had no association with overall or organ-specific disease activity or organ damage in cross-sectional and longitudinal analyses. Our data suggest that serum IL-18 and IL-1β have different clinical implications in SLE, with IL-18 being potentially associated with active renal disease.
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Frontiers in immunology · Jan 2018
ReviewTargeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy.
The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. ⋯ Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.
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Frontiers in immunology · Jan 2018
ReviewCheckpoint Inhibition in Myeloma: Opportunities and Challenges.
Despite major improvements in the treatment landscape, most multiple myeloma (MM) patients eventually succumb to the underlying malignancy. Immunotherapy represents an attractive strategy to achieve durable remissions due to its specificity and capacity for long term memory. Activation of immune cells is controlled by a balance of agonistic and inhibitory signals via surface and intracellular receptors. ⋯ However, some of these studies were transiently halted in 2017 due to concern for a possible safety signal with IMiD-PD1 combination. The capacity of the immune system to control MM has been further reinforced by recent success of adoptive cell therapies, such as T cells redirected by chimeric-antigen receptors (CAR-Ts). There remains an unmet need to better understand the immunologic effects of checkpoint blockade, delineate mechanisms of resistance to these therapies and identify optimal combination of agonistic signaling, checkpoint inhibitors as well as other therapies including CAR-Ts, to realize the potential of the immune system to control and prevent MM.