TY - JOUR
AB - Dlg1 restricts B-cell proliferation and antibody production Dlg1 (Disc large homolog 1) is a scaffold protein that regulates cell polarity and asymmetric cell division and may play a role as a tumor suppressor; it also regulates signaling in T cells and B cells, with variable importance in antigen-inexperienced versus antigen-experienced lymphocytes and in different subsets. Using mice with Dlg1 conditionally knocked out of B cells, Dong et al. show that B-cell subset development, homeostasis and marker expression appear unaffected in such Dlg1-KO mice. Activation of the immunological synapse, recruitment of signaling molecules and calcium mobilization in B cells are unaffected but Dlg1 deficiency does lead to exaggerated antibody (both IgM and IgG) production after immunization with NP33KLH, especially in recall responses. Mechanistically, there is an increased differentiation to plasma cells and an enhanced germinal center reaction; B-cell hyper-proliferation is associated with the down-regulation of an important transcription factor and tumor suppressor, FoxO1. Dlg1 is thus shown to function as a negative regulator of humoral responses, suppressing the proliferation of primary B cells. Memory B cells protect against heterologous influenza infection Humoral memory is enacted by long-lived plasma cells (LLPCs), which constitutively produce antibody that is thus immediately available, and by memory B cells, which must be re-stimulated by antigen before differentiating into antibody-producing plasmablasts (PBs). In this paper, Leach et al. confirm that antibodies (presumably from LLPCs) that are generated after a primary infection of mice with Narita or PR8 strains of H1N1 influenza A virus completely protect from re-infection with homotypic virus; however, serum from primary Narita-infected mice does not protect naive mice from primary PR8 infection. If primary Narita infection is followed by PR8 infection, all mice are protected by hemagglutinin (HA) stem-specific antibodies (recognizing multiple strains) that are derived not from naive B cells but from re-activated germinal center (GC)-derived memory B cells that rapidly differentiate into PBs. Naive PR8-infected mice produce stem-specific antibodies relatively slowly and with relatively low avidity and breadth of reactivity. GC-derived memory B cells are thus uniquely equipped to protect against subsequent infection by antigenically distinct influenza. HIF-1 induces LDH to decrease pyruvate in Mtb-infected macrophages Mycobacterium tuberculosis (Mtb) can persist and multiply within host macrophages, which involves complex interactions between the bacteria and the host immune and metabolic pathways. Hypoxia-inducible factor 1 (HIF-1) is a heterodimer of HIF-1β (constitutively expressed) and HIF-1α (induced by, e.g., hypoxia or infection). Glucose metabolism can utilize oxidative phosphorylation or instead pyruvate can be converted to lactate; lactate dehydrogenase (LDH) catalyzes the inter-conversion of pyruvate and lactate. Concentrating on IFN-γ-independent effects, Osada-Oka et al. first found that HIF-1α induction co-localizes with Mtb bacilli in pulmonary Mtb granuloma. They then show that HIF-1α is induced in mouse bone marrow-derived macrophages (BMDMs) by infection with Mtb. Myeloid-specific HIF-1α conditional knockout (HIF-1 CKO) increases the lethality of Mtb infection in vivo. In HIF-1 CKO BMDMs, replication of Mtb is increased and glycolysis-related genes, including that for LDH-A, are suppressed. LDH inhibition increases pyruvate availability for Mtb. Thus, HIF-1 induces LDH to decrease pyruvate levels as a source of energy or carbon for Mtb, thereby inhibiting bacterial growth. Dysbiosis contributes to the development of autoimmune pancreatitis Autoimmune pancreatitis (AIP) is a chronic inflammatory disease that has two sub-types. Type 1 is an ‘IgG4-related disease’ that features increased serum IgG4 production plus storiform fibrosis and the varying involvement of multiple organs. This features both adaptive immune responses and innate responses such as IFN-α and IL-33 production by plasmacytoid dendritic cells (pDCs). In this paper, Kamata et al. characterize the role of microbial diversity in a model of severe AIP induced by 100 μg poly (I:C). Oral broad-spectrum antibiotics inhibit all features of AIP, including pDC numbers and IFN-α/IL-33 production. The diversity of the intestinal/fecal microbiota is reduced in AIP. Co-housing mice that received lower-dose poly (I:C) with mice that received 100 μg poly (I:C) induced severe AIP in the former (see figure), as did fecal microbiota transplantation from mice that had received 100 μg poly (I:C). Pancreatic pDCs accumulate in these mice and produce IFN-α and IL-33. Thus, dysbiosis increases sensitivity to AIP, which develops via pDC activation. Plant-derived endornavirus dsRNA enhances a variety of immune responses Recognition of double-stranded RNA (dsRNA) in the cytoplasm is an important trigger for innate immune responses, especially anti-virus immunity. Several cultivated and wild plant species host endornaviruses, which are transmitted vertically. Rice-bran dsRNA is known to enhance immune responses against respiratory viruses such as influenza following signaling via MDA5, TLR3, type I interferons (IFNs) and IFN-stimulated genes (ISGs). Studying effects in mice, Hajake et al. show that high-molecular-weight endornavirus dsRNA derived from green bell peppers (Kyosuzu strain) induces IFN-β1 and ISGs in vitro. In vivo, intra-nasal dsRNA induces ISGs systemically. Intra-peritoneal dsRNA limits, via NK cell activation, the incidence and growth of melanoma derived from subcutaneously injected B16-F10 cells. The dsRNA also increases host survival after infection with the highly virulent H5N1 influenza A and from encephalomyocarditis virus. Intra-nasal dsRNA also acts as an adjuvant for a vaccine that contains inactivated H5N1. Thus plant-derived nucleic acids, administered at various sites, modulate several clinically important immune responses without apparent harmful effects. © The Japanese Society for Immunology. 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - In This Issue
JO - International Immunology
DO - 10.1093/intimm/dxz072
DA - 2019-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/in-this-issue-YM9sQrN2Dc
SP - 757
EP - 758
VL - 31
IS - 12
DP - DeepDyve
ER -