Bronchus-associated Lymphoid Tissue Research Articles

Vaccination against H9N2 avian influenza virus reduces bronchus-associated lymphoid tissue formation in cynomolgus macaques after intranasal virus challenge infection.

H9N2 avian influenza virus causes sporadic human infection. Since humans do not possess acquired immunity specific to this virus, we examined the pathogenicity of an H9N2 virus isolated from a human and then analyzed protective effects of a vaccine in cynomolgus macaques. After intranasal challenge with A/Hong Kong/1073/1999 (H9N2) (HK1073) isolated from a human patient, viruses were isolated from nasal and tracheal swabs in unvaccinated macaques with mild fever and body weight loss. A formalin-inactivated H9N2 whole particle vaccine derived from our virus library was subcutaneously inoculated to macaques. Vaccination induced viral antigen-specific IgG and neutralization activity in sera. After intranasal challenge with H9N2, the virus was detected only the day after inoculation in the vaccinated macaques. Without vaccination, many bronchus-associated lymphoid tissues (BALTs) were formed in the lungs after infection, whereas the numbers of BALTs were smaller and the cytokine responses were weaker in the vaccinated macaques than those in the unvaccinated macaques. These findings indicate that the H9N2 avian influenza virus HK1073 is pathogenic in primates but seems to cause milder symptoms than does H7N9 influenza virus as found in our previous studies and that a formalin-inactivated H9N2 whole particle vaccine induces protective immunity against H9N2 virus.

びまん性汎細気管支炎に合併し, 自然消退した気管支原発悪性リンパ腫の 1 例

びまん性汎細気管支炎に合併し, 自然消退した気管支原発悪性リンパ腫の 1 例

Bronchus-Associated Lymphoid Tissue Lymphoma Associated with Gain of MALT1

Bronchus-Associated Lymphoid Tissue Lymphoma Associated with Gain of MALT1

Early IL-1 Signaling Promotes iBALT Induction after Influenza Virus Infection

Inducible bronchus-associated lymphoid tissue (iBALT) is a long lasting tertiary lymphoid tissue that can be induced following influenza A virus (IAV) infection. Previous studies have shown that iBALT structures containing germinal center (GC) B cells protect against repeated infection by contributing locally to the cellular and humoral immune response. If we are to exploit this in vaccination strategies, we need a better understanding on how iBALT structures are induced. One hypothesis is that the strength of the initial innate response dictates induction of iBALT. In the present study, we investigated the role of interleukin (IL)-1 and IL-1R signaling on iBALT formation. Mice lacking the IL-1R had a delayed viral clearance and, thus, a prolonged exposure to viral replication, leading to increased disease severity, compared to wild-type mice. Contradictorily, iBALT formation following clearance of the virus was heavily compromised in Il1r1−/− mice. Quantification of gene induction after IAV infection demonstrated induction of IL-1α and to a much lesser extent of IL-1β. Administration of recombinant IL-1α to the lungs of wild-type mice, early but not late, after IAV infection led to more pronounced iBALT formation and an increased amount of GC B cells in the lungs. Bone marrow chimeric mice identified the stromal compartment as the crucial IL-1 responsive cell for iBALT induction. Mechanistically, Q-PCR analysis of lung homogenates revealed a strongly diminished production of CXCL13, a B cell-attracting chemokine, in Il1r−/− mice during the early innate phase of IAV infection. These experiments demonstrate that appropriate innate IL-1α–IL-1R signaling is necessary for IAV clearance and at the same time instructs the formation of organized tertiary lymphoid tissues through induction of CXCL13 early after infection. These findings are discussed in the light of recent insights on the pathogenesis of tertiary lymphoid organ formation in the lung in various diseases where the IL-1 axis is hyperactive, such as rheumatoid arthritis and COPD.

Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung.

Following pulmonary inflammation, leukocytes that infiltrate the lung often assemble into structures known as inducible Bronchus-Associated Lymphoid Tissue (iBALT). Like conventional lymphoid organs, areas of iBALT have segregated B and T cell areas, specialized stromal cells, high endothelial venules, and lymphatic vessels. After inflammation is resolved, iBALT is maintained for months, independently of inflammation. Once iBALT is formed, it participates in immune responses to pulmonary antigens, including those that are unrelated to the iBALT-initiating antigen, and often alters the clinical course of disease. However, the mechanisms that govern immune responses in iBALT and determine how iBALT impacts local and systemic immunity are poorly understood. Here, we review our current understanding of iBALT formation and discuss how iBALT participates in pulmonary immunity.

Evaluation of oxidative response and tissular damage in rat lungs exposed to silica-coated gold nanoparticles under static magnetic fields.

The purpose of our study was the evaluation of toxicological effects of silica-coated gold nanoparticles (GNPs) and static magnetic fields (SMFs; 128 mT) exposure in rat lungs. Animals received a single injection of GNPs (1,100 µg/kg, 100 nm, intraperitoneally) and were exposed to SMFs, over 14 days (1 h/day). Results showed that GNPs treatment induced a hyperplasia of bronchus-associated lymphoid tissue. Fluorescence microscopy images showed that red fluorescence signal was detected in rat lungs after 2 weeks from the single injection of GNPs. Oxidative response study showed that GNPs exposure increased malondialdehyde level and decreased CuZn-superoxide dismutase, catalase, and glutathione peroxidase activities in rat lungs. Furthermore, the histopathological study showed that combined effects of GNPs and SMFs led to more tissular damages in rat lungs in comparison with GNPs-treated rats. Interestingly, intensity of red fluorescence signal was enhanced after exposure to SMFs indicating a higher accumulation of GNPs in rat lungs under magnetic environment. Moreover, rats coexposed to GNPs and SMFs showed an increased malondialdehyde level, a fall of CuZn-superoxide dismutase, catalase, and glutathione peroxidase activities in comparison with GNPs-treated group. Hence, SMFs exposure increased the accumulation of GNPs in rat lungs and led to more toxic effects of these nanocomplexes.

Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation

Memory CD4(+) T helper (Th) cells are central to long-term protection against pathogens, but they can also be pathogenic and drive chronic inflammatory disorders. How these pathogenic memory Th cells are maintained, particularly at sites of local inflammation, remains unclear. We found that ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue (iBALT) are formed during chronic allergic inflammation in the lung, and that memory-type pathogenic Th2 (Tpath2) cells capable of driving allergic inflammation are maintained within the iBALT structures. The maintenance of memory Th2 cells within iBALT is supported by Thy1(+)IL-7-producing lymphatic endothelial cells (LECs). The Thy1(+)IL-7-producing LECs express IL-33 and T-cell-attracting chemokines CCL21 and CCL19. Moreover, ectopic lymphoid structures consisting of memory CD4(+) T cells and IL-7(+)IL-33(+) LECs were found in nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, Thy1(+)IL-7-producing LECs control chronic allergic airway inflammation by providing a survival niche for memory-type Tpath2 cells.

Inducible Bronchus-Associated Lymphoid Tissue (iBALT) attenuates pulmonary Th2 responses

Abstract Inducible bronchus-associated lymphoid tissue (iBALT) is an ectopic lymphoid tissue formed in the lung after pulmonary infection or inflammation. This local lymphoid tissue is structurally similar to conventional secondary lymphoid organs (SLOs), with separated B and T cell areas, specialized stromal cells and lymphoid dendritic cells (DCs). The presence of iBALT is typically associated with pulmonary pathology and advanced lung disease, particularly in patients with chronic obstructive pulmonary disease (COPD), rheumatoid lung disease, pulmonary fibrosis and chronic infections, suggesting that iBALT functions to exacerbate local immune responses and pathology. Here, we tested whether the presence of iBALT affected the pulmonary immune responses to allergens. We induced iBALT formation in neonatal mice by pulmonary administration of lipopolysaccharide (LPS), and when the mice were adults, sensitized and challenged them intranasally with ovalbumin (OVA). We found that mice with iBALT exhibited reduced Th2 responses, reduced eosinophil recruitment, reduced goblet cell hyperplasia and reduced mucus production. The presence of iBALT delayed the accumulation of Th2 cells and eosinophils in the lung following challenge and altered the spatial distribution of T cells in the lung. We also found that the more organized iBALT structure was, the fewer eosinophil infiltrates were observed in house dust mite (HDM)-induced allergic inflammation. Although Th2 cells are generated in mice with iBALT, they are concentrated in iBALT area and more dilute in lung parenchyma. Overall, our studies expanded the field of iBALT from observation of what happens in pulmonary diseases to determining the machinery involved in the responses.

Inducible bronchus-associated lymphoid tissue plays an important role in the induction of antigen-specific immune response by Ag85B-hPIV2-based anti-tuberculosis vaccine in mice

Abstract Mycobacterium bovis bacilli Calmette-Guerin is the only licensed tuberculosis vaccine, which has been considered to be insufficient against adult pulmonary tuberculosis. As most of pathogens, including Mycobacterium tuberculosis, naturally enter the host through respiratory surface, nasal vaccine is an ideal method to prevent the diseases by inducing antigen-specific immune responses at respiratory sites as well as systemic compartments. Our group recently developed Ag85B-expressing human parainfluenza type 2 virus (Ag85B-hPIV2) as a nasal vaccine against tuberculosis. In this study, we aimed to elucidate the mechanisms underlying the induction of antigen-specific immune responses by Ag85B-hPIV2. We found that inducible bronchus-associated lymphoid tissue (iBALT) played an important role in the induction of antigen-specific immune responses. Intranasal administration of hPIV2 vector induced iBALT formation with induction of Th17 cells and CD11b+CD11c+ cells both of which are known to require for the formation and maintenance of iBALT structure, respectively. When iBALT structure was disrupted by depletion of CD11b+ cells in CD11b-diphtheria toxin receptor transgenic mice, Ag85B-specific immune response was diminished in the lung. These findings indicate that iBALT genesis is an essential process required in Ag85B-hPIV2 anti-tuberculosis mucosal vaccine.

Redistribution of T follicular helper cells to the lungs of neonatal mice infected with influenza

Abstract The infant immune system responds poorly to both infection and vaccination, however the mechanisms responsible for impaired immune responses in neonates are incompletely understood. Here we analyzed T and B cell responses to influenza infection in neonatal mice. We found that neonatal mice were much more susceptible to primary influenza infection and cleared virus with delayed kinetics. Although CD8 T cell responses were slightly delayed in neonates compared to adults, neonates ultimately generated robust CD8 T cell responses. Following resolution of infection, however, the accumulation of tissue-resident memory (Trm) CD8 T cell responses was impaired in mice infected as neonates. In contrast, the appearance of influenza-specific CD4 T cells, including T follicular helper (Tfh) cells, was not delayed. Surprisingly, Tfh cells appeared in the lungs of neonatal mice, but not the lungs of adult mice. Tfh cells in the lungs of neonates correlated with the appearance of germinal center (GC) B cells and the formation of inducible bronchus-associated lymphoid tissue (iBALT) in the lungs. However, despite the appearance of local Tfh and GC B cells, the production of influenza-specific antibody was severely impaired in neonatal mice. Thus, despite the differentiation of influenza-specific Tfh in both lymphoid organs and lungs of neonatal mice, B cell-mediated immunity was still profoundly impaired. Nevertheless, while mice given a primary influenza infection as neonates had diminished Trm CD8 T cell responses and impaired B cell-mediated immunity, they were able to survive lethal rechallenge as adults, indicating that protective immunity could be generated in neonates.

Serpine2 deficiency results in lung lymphocyte accumulation and bronchus-associated lymphoid tissue formation.

Serine proteinase inhibitor, clade E, member 2 (SERPINE2), is a cell- and extracellular matrix-associated inhibitor of thrombin. Although SERPINE2 is a candidate susceptibility gene for chronic obstructive pulmonary disease, the physiologic role of this protease inhibitor in lung development and homeostasis is unknown. We observed spontaneous monocytic-cell infiltration in the lungs of Serpine2-deficient (SE2(-/-)) mice, beginning at or before the time of lung maturity, which resulted in lesions that resembled bronchus-associated lymphoid tissue (BALT). The initiation of lymphocyte accumulation in the lungs of SE2(-/-) mice involved the excessive expression of chemokines, cytokines, and adhesion molecules that are essential for BALT induction, organization, and maintenance. BALT-like lesion formation in the lungs of SE2(-/-) mice was also associated with a significant increase in the activation of thrombin, a recognized target of SE2, and excess stimulation of NF-κB, a major regulator of chemokine expression and inflammation. Finally, systemic delivery of thrombin rapidly stimulated lung chemokine expression in vivo These data uncover a novel mechanism whereby loss of serine protease inhibition leads to lung lymphocyte accumulation.-Solleti, S. K., Srisuma, S., Bhattacharya, S., Rangel-Moreno, J., Bijli, K. M., Randall, T. D., Rahman, A., Mariani, T. J. Serpine2 deficiency results in lung lymphocyte accumulation and bronchus-associated lymphoid tissue formation.

Characterization of Th2 Induced Bronchial Associated Lymphoid Tissue (BALT) in a Mouse Model of Asthma

Characterization of Th2 Induced Bronchial Associated Lymphoid Tissue (BALT) in a Mouse Model of Asthma

Relationship Between Expression of Interleukin-5 and Interleukin-13 by Epithelial Cells and Bronchiolar Changes in Pigs Infected with Mycoplasma hyopneumoniae

Mycoplasma hyopneumoniae (Mh) is a bacterium that specifically infects the surface of bronchi and bronchioles of pigs without invading the host cells,and it is considered to be the primary agent of porcine enzootic pneumonia (PEN). The present study investigates the morphological and immunohistological changes induced in bronchiolar epithelium by Mh infection. Lungs from 20 pigs with naturally occurring Mh pneumonia were compared with those from 10 uninfected controls. Bronchiolar epithelial height, inflammatory infiltration, hyperplasia of bronchus-associated lymphoid tissue (BALT) and mucin subtype MUC5AC-producing cells significantly increased in all infected animals. Mh antigen was detected in association with the cilia of the bronchial and bronchiolar epithelium. Interleukin (IL)-5 and IL-13 were expressed consistently by epithelial and mononuclear cells of the airways of infected animals. The expression of these cytokines in the bronchial and bronchiolar tissues is related to the histological changes of PEN.

Case Report: Bronchial associated lymphoid tissue lymphoma and Mycobacterium chelonae

Bronchial-associated lymphoid tissue (BALT) lymphoma is a rare condition that accounts for only 0.5-1% of all malignant lung tumours. We present the case of a 66-year-old man admitted with pneumonia for further study and therapy. Initially the sputum was positive for Mycobacterium tuberculosis complex using polymerase chain reaction technology and antituberculous therapy was initiated. Due to the lack of imagiological improvement, the patient underwent a pulmonary transthoracic biopsy that revealed BALT lymphoma. Months later, Mycobacterium chelonae was identified and specific therapy was started with clarithromycin and tobramycin, before initiating BALT treatment with cyclophosphamide. There are only a few documented cases of BALT lymphoma associated with Mycobacterium. In this case M. chelonae might have been present before BALT lymphoma, contributing as an immunologic stimulus, or appeared afterwards, in the neoplastic context. BALT has an indolent evolution with a good prognosis and that is the reason why some experts favour a “watchful waiting” option.

Primary Pulmonary Lymphoid Lesions: Radiologic and Pathologic Findings.

The pulmonary lymphoid system is complex and is composed of two compartments: the pulmonary lymphatics and the bronchus-associated lymphoid tissue (BALT). Additional important cells that function in the pulmonary lymphoid system include dendritic cells, Langherhans cells, macrophages, and plasma cells. An appreciation of the normal lymphoid anatomy of the lung as well as its immunology is helpful in understanding the radiologic and pathologic findings of the primary pulmonary lymphoid lesions. Primary lymphoid lesions of the lung arise from the BALT and are uncommon. However, they are increasingly recognized within the growing number of posttransplant patients as well as other patients who are receiving immunosuppressive therapies. Primary lymphoid lesions encompass a wide range of benign and malignant lesions. Benign lymphoid lesions of the lung include reactive lymphoid hyperplasia, follicular bronchiolitis, lymphoid interstitial pneumonia, and nodular lymphoid hyperplasia. Malignant lymphoid lesions of the lung include low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), other non-Hodgkin lymphomas, and Hodgkin lymphoma. Last, a miscellaneous group of primary lymphoid lesions includes lymphomatoid granulomatosis, posttransplant lymphoproliferative disorders, acquired immunodeficiency syndrome (AIDS)-related lymphoma, and intravascular lymphoma/lymphomatosis. These lesions are best evaluated with multidetector chest computed tomography. The radiologic findings of the primary lymphoid lesions are often nonspecific and are best interpreted in correlation with clinical data and pathologic findings. The purpose of this article is to review pulmonary lymphoid anatomy as well as the most common primary pulmonary lymphoid disorders.

Bronchus-associated lymphoid tissue in kabuki syndrome with associated hyper-IgM syndrome/common variable immunodeficiency

Bronchus-associated lymphoid tissue in kabuki syndrome with associated hyper-IgM syndrome/common variable immunodeficiency

A case of disseminated bronchus-associated lymphoid tissue lymphoma masquerading as nonresolving pneumonia.

A case of disseminated bronchus-associated lymphoid tissue lymphoma masquerading as nonresolving pneumonia.

Mesenchymal stem cells require the peripheral immune system for immunomodulating effects in animal models of multiple sclerosis.

Mesenchymal stem cells require the peripheral immune system for immunomodulating effects in animal models of multiple sclerosis.

Noncytopathic bovine viral diarrhea virus 2 impairs virus control in a mouse model.

Bovine viral diarrhea virus (BVDV) is an economically important pathogen that causes development of mild to severe clinical signs in wild and domesticated ruminants. We previously showed that mice could be infected by BVDV. In the present study, we infected mice intraperitoneally with non-cytopathic (ncp) BVDV1 or ncp BVDV2, harvested the blood and organs of the infected mice at days 4, 7, 10 and 14 postinfection (pi), and performed immunohistochemical analyses to confirm BVDV infection. Viral antigens were detected in the spleens of all infected mice from days 4 through 14 and were also found in the mesenteric lymph nodes, gut-associated lymphoid tissue (GALT), heart, kidney, intestine, and bronchus-associated lymphoid tissue (BALT) of some infected mice. In ncp BVDV2-infected mice, flow cytometric analysis revealed markedly fewer CD4(+) and CD8(+) T lymphocytes and lower expression of costimulatory molecules CD80 (B7-1) and CD86 (B7-2) and major histocompatibility complex (MHC) class II (I-A/I-E) than those in ncp BVDV1-infected mice. Production of the cytokines interleukin (IL)-6 and monocyte chemotactic protein (MCP)-1 was higher in the plasma of ncp BVDV2-infected mice than that in that of ncp BVDV1-infected mice. Our results demonstrate that ncp BVDV1 and ncp BVDV2 interact differently with the host innate immune response in vivo. These findings highlight an important distinction between ncp BVDV1 and ncp BVDV2 and suggest that ncp BVDV2 impairs the host's ability to control the infection and enhances virus dissemination.

Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis.

Tuberculosis (TB) is a global pandaemic, partially due to the failure of vaccination approaches. Novel anti-TB vaccines are therefore urgently required. Here we show that aerosol immunization of macaques with the Mtb mutant in SigH (MtbΔsigH) results in significant recruitment of inducible bronchus-associated lymphoid tissue (iBALT) as well as CD4+ and CD8+ T cells expressing activation and proliferation markers to the lungs. Further, the findings indicate that pulmonary vaccination with MtbΔsigH elicited strong central memory CD4+ and CD8+ T-cell responses in the lung. Vaccination with MtbΔsigH results in significant protection against a lethal TB challenge, as evidenced by an approximately three log reduction in bacterial burdens, significantly diminished clinical manifestations and granulomatous pathology and characterized by the presence of profound iBALT. This highly protective response is virtually absent in unvaccinated and BCG-vaccinated animals after challenge. These results suggest that future TB vaccine candidates can be developed on the basis of MtbΔsigH.