ABSTRACT
IVIG preparations consisting of pooled IgG are increasingly used for the treatment of autoimmune diseases. IVIG is known to regulate the viability of immune cells, including neutrophils. We report that plasma-derived IgA efficiently triggers death of neutrophils primed by cytokines or TLR agonists. IgA-mediated programmed neutrophil death was PI3K-, p38 MAPK-, and JNK-dependent and evoked anti-inflammatory cytokines in macrophage cocultures. Neutrophils from patients with acute Crohn's disease, rheumatoid arthritis, or sepsis were susceptible to both IgA- and IVIG-mediated death. In contrast to IVIG, IgA did not promote cell death of quiescent neutrophils. Our findings suggest that plasma-derived IgA might provide a therapeutic option for the treatment of neutrophil-associated inflammatory disorders.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Crohn Disease/drug therapy , Immunoglobulin A/pharmacology , Neutrophils/drug effects , Sepsis/drug therapy , Animals , Apoptosis/drug effects , Apoptosis/immunology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/immunology , Cell Survival/drug effects , Cell Survival/immunology , Cells, Cultured , Coculture Techniques , Crohn Disease/blood , Crohn Disease/immunology , Humans , Immunoglobulin A/therapeutic use , Immunoglobulins, Intravenous/pharmacology , Immunoglobulins, Intravenous/therapeutic use , Macrophages , Mice , Neutrophils/immunology , Primary Cell Culture , Sepsis/blood , Sepsis/immunologyABSTRACT
Mild modification of intravenous immunoglobulin (IVIG) has been reported to result in enhanced polyspecificity and leveraged therapeutic effects in animal models of inflammation. Here, we observed that IVIG modification by ferrous ions, heme or low pH exposure, shifted the repertoires of specificities in different directions. Ferrous ions exposed Fe(II)-IVIG, but not heme or low pH exposed IVIG, showed increased pro-apoptotic effects on neutrophil granulocytes that relied on a FAS-dependent mechanism. These effects were also observed in human neutrophils primed by inflammatory mediators or rheumatoid arthritis joint fluid in vitro, or patient neutrophils ex vivo from acute Crohn's disease. These observations indicate that IVIG-mediated effects on cells can be enhanced by IVIG modification, yet specific modification conditions may be required to target specific molecular pathways and eventually to enhance the therapeutic potential.
Subject(s)
Apoptosis/drug effects , Ferrous Compounds/chemistry , Immunoglobulins, Intravenous/chemistry , Immunoglobulins, Intravenous/pharmacology , Neutrophils/drug effects , Arthritis, Rheumatoid/immunology , Crohn Disease/immunology , Humans , Hydrogen-Ion ConcentrationABSTRACT
B cells contribute to immune responses through the production of immunoglobulins, antigen presentation, and cytokine production. Several B cell subsets with distinct functions and polarized cytokine profiles have been reported. In this study, we used transcriptomics analysis of immortalized B cell clones to identify an IgG4+ B cell subset with a unique function. These B cells are characterized by simultaneous expression of proangiogenic cytokines including VEGF, CYR61, ADM, FGF2, PDGFA, and MDK. Consequently, supernatants from these clones efficiently promote endothelial cell tube formation. We identified CD49b and CD73 as surface markers identifying proangiogenic B cells. Circulating CD49b+CD73+ B cells showed significantly increased frequency in patients with melanoma and eosinophilic esophagitis (EoE), two diseases associated with angiogenesis. In addition, tissue-infiltrating IgG4+CD49b+CD73+ B cells expressing proangiogenic cytokines were detected in patients with EoE and melanoma. Our results demonstrate a previously unidentified proangiogenic B cell subset characterized by expression of CD49b, CD73, and proangiogenic cytokines.
Subject(s)
B-Lymphocyte Subsets , Eosinophilic Esophagitis , Melanoma , B-Lymphocyte Subsets/metabolism , Cytokines/metabolism , Humans , Immunoglobulin G , Inflammation , Integrin alpha2 , Melanoma/geneticsABSTRACT
Over the last decades, an increasing appearance of allergies and atopic disorders, such as asthma, dermatitis, and rhinitis, has been observed. The mechanisms of these disorders remain unclear, and therefore the development of novel therapies is limited. Current treatments are often symptomatic, nonspecific, or may have severe side effects. Further insights into the mechanisms of the underlying disease pathogenesis could reveal novel targets for treatment. In this review, we provide an update on recent basic and translational studies that offer novel insights and opportunities for the treatment of patients with atopic disorders.
