ABSTRACT
Endogenous retroviruses (ERVs) are an integral part of the mammalian genome. The role of immune control of ERVs in general is poorly defined as is their function as anti-cancer immune targets or drivers of autoimmune disease. Here, we generate mouse-strains where Moloney-Murine Leukemia Virus tagged with GFP (ERV-GFP) infected the mouse germline. This enables us to analyze the role of genetic, epigenetic and cell intrinsic restriction factors in ERV activation and control. We identify an autoreactive B cell response against the neo-self/ERV antigen GFP as a key mechanism of ERV control. Hallmarks of this response are spontaneous ERV-GFP+ germinal center formation, elevated serum IFN-γ levels and a dependency on Age-associated B cells (ABCs) a subclass of T-bet+ memory B cells. Impairment of IgM B cell receptor-signal in nucleic-acid sensing TLR-deficient mice contributes to defective ERV control. Although ERVs are a part of the genome they break immune tolerance, induce immune surveillance against ERV-derived self-antigens and shape the host immune response.
Subject(s)
B-Lymphocytes , Endogenous Retroviruses , Animals , Mice , Autoimmune Diseases/genetics , B-Lymphocytes/immunology , Endogenous Retroviruses/genetics , Mammals/geneticsABSTRACT
Airway epithelial cells contribute to a variety of lung diseases including allergic asthma, where IL-4 and IL-13 promote activation of the transcription factor STAT6. This leads to goblet cell hyperplasia and the secretion of effector molecules by epithelial cells. However, the specific effect of activated STAT6 in lung epithelial cells is only partially understood. Here, we created a mouse strain to selectively investigate the role of constitutively active STAT6 in Club cells, a subpopulation of airway epithelial cells. CCSP-Cre_STAT6vt mice and bronchiolar organoids derived from these show an enhanced expression of the chitinase-like protein Chil4 (Ym2) and resistin-like molecules (Relm-α, -ß, -γ). In addition, goblet cells of these mice spontaneously secrete mucus into the bronchi. However, the activated epithelium resulted neither in impaired lung function nor conferred a protective effect against the migrating helminth Nippostrongylus brasiliensis. Moreover, CCSP-Cre_STAT6vt mice showed similar allergic airway inflammation induced by live conidia of the fungus Aspergillus fumigatus and similar recovery after influenza A virus infection compared to control mice. Together these results highlight that STAT6 signaling in Club cells induces the secretion of Relm proteins and mucus without impairing lung function, but this is not sufficient to confer protection against helminth or viral infections.
Subject(s)
Asthma , Resistin , Animals , Mice , Asthma/metabolism , Epithelial Cells/metabolism , Lung , Mucus/metabolism , Resistin/metabolism , STAT6 Transcription Factor/genetics , STAT6 Transcription Factor/metabolismABSTRACT
Alveolar macrophages (alvMs) play an important role for maintenance of lung function by constant removal of cellular debris in the alveolar space. They further contribute to defense against microbial or viral infections and limit tissue damage during acute lung injury. alvMs arise from embryonic progenitor cells, seed the alveoli before birth, and have life-long self-renewing capacity. However, recruited monocytes may also help to restore the alvM population after depletion caused by toxins or influenza virus infection. At present, the population dynamics and cellular plasticity of alvMs during allergic lung inflammation is poorly defined. To address this point, we used a mouse model of Aspergillus fumigatus-induced allergic lung inflammation and observed that Th2-derived IL-4 and IL-13 caused almost complete disappearance of alvMs. This effect required STAT6 expression in alvMs and also occurred in various other settings of type 2 immunity-mediated lung inflammation or administration of IL-4 complexes to the lung. In addition, Th2 cells promoted conversion of alvMs to alternatively activated macrophages and multinucleated giant cells. Given the well-established role of alvMs for maintenance of lung function, this process may have implications for resolution of inflammation and tissue homeostasis in allergic asthma.
Subject(s)
Asthma , Pneumonia , Pulmonary Eosinophilia , Mice , Animals , Macrophages, Alveolar , Interleukin-4/metabolism , Lung/metabolism , Asthma/metabolism , Inflammation/metabolism , Pneumonia/metabolismABSTRACT
PURPOSE OF REVIEW: Epigenetic mechanisms are known to play a crucial role in the pathogenesis of asthma, allergic rhinitis, atopic dermatitis, food allergy, and other allergic disorders, especially through mediating the effects of the environmental factors, well recognized allergy-risk modifiers. The aim of this work was to provide a concise but comprehensive review of the recent progress in the epigenetics of allergic diseases. RECENT FINDINGS: Recent few years have substantially expanded our knowledge on the role of epigenetics in the pathogenesis and clinical picture of allergies. Specifically, it has been shown that epigenetic marks, especially DNA methylation, possess a diagnostic potential for atopic sensitization, asthma, allergic rhinitis, and food allergy. DNA methylation can be a predictor of clinical responses in controlled allergen challenges, including oral food challenges. Furthermore, direct or indirect targeting epigenetic mechanisms, this time especially histone modifications, was able to favorably affect expression of the genes underlying allergies and generally improve airway biology in allergic diseases or their animal models. SUMMARY: Further studies are needed to explore the diagnostic and therapeutic potential of epigenetic modifications in allergies and to develop respective clinical tools.
