Intravenous immunoglobulin attenuates airway inflammation through induction of forkhead box protein 3-positive regulatory T cells.

BACKGROUND: Intravenous immunoglobulin (IVIG) is a frequently used disease-modifying therapy for a large spectrum of autoimmune and inflammatory conditions, yet its mechanisms of action are incompletely understood. Using a robust murine model of antigen-driven allergic airways disease, we have demonstrated that IVIG markedly improves ovalbumin (OVA)-induced airway hyperresponsiveness characterized by 4- to 6-fold enhancement in regulatory T (Treg) cells in pulmonary and associated lymphoid tissues. OBJECTIVE: We sought to determine whether IVIG induces antigen-specific Treg cells and to address cellular interactions that lead to induction of Treg cells by IVIG. METHODS: C57Bl/6 mice were sensitized and challenged by means of intranasal OVA exposure. IVIG or albumin control was administered 24 hours before challenge. Treg cells were tracked by using green fluorescent protein (GFP)-forkhead box protein 3 (Foxp3) knock-in reporter mice (Foxp3(GFP)), and Treg cell and dendritic cell (DC) phenotypes and activities were elucidated by using coculture and flow cytometry. RESULTS: IVIG therapy of OVA-sensitized and OVA-challenged mice induced antigen-specific forkhead box protein 3 (Foxp3)-positive Treg cells from non-Treg cell precursors. The induced Treg cells home specifically to the lungs and draining lymph nodes and have greatly potentiated suppressive activity compared with that seen in Treg cells purified from control mice. Induction of Treg cells is mediated by tolerogenic DCs generated after IVIG exposure. Compared with albumin-treated, OVA-exposed mice, IVIG-primed DCs express altered Notch ligands, including increased Delta-4 and reduced Jagged-1 levels, reflecting decreased T(H)2 polarization. Furthermore, IVIG-primed DCs can stimulate Treg cell differentiation from uncommitted Foxp3(-)CD4(+) T cells ex vivo, and adoptive transfer of IVIG-primed DCs abrogates airway hyperresponsiveness and induces Treg cells. CONCLUSION: The anti-inflammatory effects of IVIG therapy can be mediated by the immunomodulation of DCs, creating a bridge that induces antigen-specific, highly suppressive Treg cells.

Regulation of IL-13 receptor alpha 1 expression and signaling on human tonsillar B-lymphocyte subsets.

BACKGROUND: T(H)2 cytokines play crucial roles in driving human B lymphocytes to produce IgE. However, it is unclear whether IL-4 and IL-13 have parallel or sequential roles in the development of B lymphocytes. OBJECTIVE: We investigated IL-13 receptor (IL-13R) expression and regulation in mature and immature human B cells. METHODS: Purified B cells were isolated from human tonsils. We evaluated IL-13Ralpha1 mRNA expression using real-time PCR and IL-13Ralpha1 and IL-4 receptor (IL-4R) alpha expression using flow cytometry and microscopy. Signal transduction was assessed on the basis of signal transducer and activator of transcription 6 phosphorylation. RESULTS: IL13Ralpha1 mRNA was induced after stimulation with anti-CD40 antibodies, anti-CD40 plus IL-4, or anti-IgM/IgG. Baseline surface IL13Ralpha1 levels were low in unstimulated B cells but increased significantly at 24 hours and were sustained for 5 to 14 days. In contrast, IL4R alpha was constitutively expressed on tonsillar B cells, and levels did not significantly vary after stimulation. B cells activated by CD40 ligation or B-cell receptor cross-linking, but not resting B cells, showed significant increases in signal transducer and activator of transcription 6 phosphorylation in response to IL-13. IL-13Ralpha1 expression was induced on mature and memory B cells, as well as on naive subsets. CONCLUSIONS: There is lower constitutive expression and signaling of IL13Ralpha1 in resting tonsillar B lymphocytes compared with that of IL4R alpha. IL-13 is induced on both immature and mature B lymphocytes. CLINICAL IMPLICATIONS: This implies different roles for IL-4 and IL-13 in B-cell development, which would allow for specific targeting of IL-13 in IgE-mediated diseases.

The era of sport concussion: Evolution of knowledge, practice, and the role of psychology.

The topic of sport concussion has gained significant prominence over the last 20 years, resulting in dramatic growth in research funding, widespread media coverage, and increased public awareness. Although the knowledge base has greatly expanded, there is still much that is unknown or controversial about the long-term effects of sports-related head injury. Because of the high stakes of mismanaging these injuries, professional sports organizations, federal/state government, and various health-related disciplines have responded with efforts to educate the public and improve treatment and management of this injury. This has resulted in changes to laws, game rules and policies, and recovery management protocols. The field of psychology has also made significant contributions to research on sports concussions, resulting in the development of new assessment and treatment protocols. This article summarizes the latest research findings on sport concussion, highlights areas that require more research before consensus can be reached, and discusses the ways that multiple disciplines within psychology (clinical, neuropsychology, school) can continue to play a critical role in enhancing patient care. (PsycINFO Database Record

5-oxo-ETE is a major oxidative stress-induced arachidonate metabolite in B lymphocytes.

B lymphocytes convert arachidonic acid (AA) to the 5-lipoxygenase products leukotriene B4 (LTB4) and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) when subjected to oxidative stress. 5-HETE has little biological activity, but can be oxidized by a selective dehydrogenase in some cells to 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), a potent eosinophil chemoattractant. We found that CESS cells, a B lymphocyte cell line, convert AA to 5-oxo-ETE and this is selectively stimulated by oxidative stress. In the presence of H2O2, 5-oxo-ETE is a major AA metabolite in these cells (5-oxo-ETE≈5-HETE>LTB4). The cyclooxygenase product 12-hydroxy-5,8,10-heptadecatrienoic acid is also formed, but is not affected by H2O2. Diamide had effects similar to those of H2O2 and both substances had similar effects on human tonsillar B cells. H2O2 also stimulated 5-oxo-ETE formation from its direct precursor 5-HETE in tonsillar B and CESS cells, and this was inhibited by the glutathione reductase inhibitor carmustine. H2O2 concomitantly induced rapid increases in GSSG and NADP+ and reductions in GSH and NADPH. We conclude that oxidative stress stimulates 5-oxo-ETE synthesis in B lymphocytes by two mechanisms: activation of 5-lipoxygenase and increased oxidation of 5-HETE by NADP+-dependent 5-hydroxyeicosanoid dehydrogenase. B lymphocyte-derived 5-oxo-ETE could contribute to eosinophilic inflammation in asthma and other allergic diseases.