Search

Background: Repeated inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently approved in Japan as a treatment for autoimmune pulmonary alveolar proteinosis. However, the detailed physiological and pathological effects of repeated inhalation in the long term, especially at increasing doses, remain unclear. Methods: In this chronic safety study, we administered 24 cynomolgus monkeys (Macaca fascicularis) aged 2–3 years with aerosolized sargramostim (a yeast-derived recombinant human GM-CSF [rhGM-CSF]) biweekly for 26 weeks across four dosing groups (0, 5, 100, and 500 µg/kg/day). We measured the serum GM-CSF antibody (GM-Ab) concentration by an ELISA and assessed the neutralizing capacity of GM-Ab using the GM-CSF-dependent cell line TF-1. We subjected lung tissue samples taken from all monkeys at 27 weeks to histopathological assessment using a sargramostim-specific monoclonal antibody to detect localization of residual sargramostim. Results: All the animals maintained good body condition and showed steady weight gain throughout the study. The pathological analyses of the lung revealed the formation of induced bronchus-associated lymphoid tissue (iBALT) in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day. There was a relationship between the number or size of BALT and sargramostim dose or the serum GM-Ab levels. Immunohistochemical analyses revealed GM-Ab–producing cells in the follicular region of iBALT, with residual sargramostim in the follicles. Leucocyte counts were inversely correlated with GM-Ab levels in the high-dose groups. Additionally, serum GM-Ab from the treated animals significantly suppressed the alveolar macrophage proliferation activity of both Cynomolgus recombinant and rhGM-CSF in vitro. Conclusion: Long-term repeated inhalation of sargramostim led to iBALT formation in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day, with the extent of iBALT formation increasing in a dose-dependent manner. Inhaled sargramostim was localized to the follicular region of iBALT nodules, which may induce the production of GM-Ab. [ABSTRACT FROM AUTHOR]

Bronchus-associated lymphoid tissue (BALT) is a rare cause of extranodal marginal zone lymphoma (MZL). Although most patients with BALT lymphoma (BALToma) show an indolent clinical course and are monitored without treatment, there are limited real-world data on the long-term outcome of "watch-and-wait' strategy in comparison with other treatments. The survival outcomes of patients newly diagnosed with BALToma at three tertiary hospitals in Korea undergoing two treatment strategies were analyzed: group A, patients who were monitored without any treatment or received only radiotherapy after diagnosis; and group B, patients receiving any kind of systemic chemotherapy after diagnosis, regardless of their history of any local treatment such as surgery or radiotherapy. Of the 67 patients included in our analysis, the 10-year progression-free survival (PFS) and 10-year overall survival (OS) rates were 65.3% and 83.2%, respectively. The 10-year PFS rates for observation or localized treatment and systemic chemotherapy were 78.7% and 56.9%, respectively (p = 0.044). Ten-year OS rates for observation or localized treatment and systemic chemotherapy were 100% and 71.7%, respectively (p = 0.016). Multivariate analysis showed that bilateral lung (HR 2.462, p = 0.047) and extrapulmonary organ (HR 4.485, p = 0.004) involvement were the only significant factors associated with poor PFS. Prognostic factor analysis for OS did not yield significant results. Patients with BALToma show a favorable prognosis, suggesting that observation or localized therapy alone may be effective for patient management. However, patients with bilateral lung or extrapulmonary involvement may require careful monitoring for disease progression and more aggressive treatment approaches. [ABSTRACT FROM AUTHOR]

Abstract Background Repeated inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently approved in Japan as a treatment for autoimmune pulmonary alveolar proteinosis. However, the detailed physiological and pathological effects of repeated inhalation in the long term, especially at increasing doses, remain unclear. Methods In this chronic safety study, we administered 24 cynomolgus monkeys (Macaca fascicularis) aged 2–3 years with aerosolized sargramostim (a yeast-derived recombinant human GM-CSF [rhGM-CSF]) biweekly for 26 weeks across four dosing groups (0, 5, 100, and 500 µg/kg/day). We measured the serum GM-CSF antibody (GM-Ab) concentration by an ELISA and assessed the neutralizing capacity of GM-Ab using the GM-CSF-dependent cell line TF-1. We subjected lung tissue samples taken from all monkeys at 27 weeks to histopathological assessment using a sargramostim-specific monoclonal antibody to detect localization of residual sargramostim. Results All the animals maintained good body condition and showed steady weight gain throughout the study. The pathological analyses of the lung revealed the formation of induced bronchus-associated lymphoid tissue (iBALT) in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day. There was a relationship between the number or size of BALT and sargramostim dose or the serum GM-Ab levels. Immunohistochemical analyses revealed GM-Ab–producing cells in the follicular region of iBALT, with residual sargramostim in the follicles. Leucocyte counts were inversely correlated with GM-Ab levels in the high-dose groups. Additionally, serum GM-Ab from the treated animals significantly suppressed the alveolar macrophage proliferation activity of both Cynomolgus recombinant and rhGM-CSF in vitro. Conclusion Long-term repeated inhalation of sargramostim led to iBALT formation in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day, with the extent of iBALT formation increasing in a dose-dependent manner. Inhaled sargramostim was localized to the follicular region of iBALT nodules, which may induce the production of GM-Ab.

(1) Background: We sought to investigate the baseline lung and heart biology of the Dp16 mouse model of Down syndrome (DS) as a prelude to the investigation of recurrent respiratory tract infection. (2) Methods: In controls vs. Dp16 mice, we compared peripheral blood cell and plasma analytes. We examined baseline gene expression in lungs and hearts for key parameters related to susceptibility of lung infection. We investigated lung and heart protein expression and performed lung morphometry. Finally, and for the first time each in a model of DS, we performed pulmonary function testing and a hemodynamic assessment of cardiac function. (3) Results: Dp16 mice circulate unique blood plasma cytokines and chemokines. Dp16 mouse lungs over-express the mRNA of triplicated genes, but not necessarily corresponding proteins. We found a sex-specific decrease in the protein expression of interferon α receptors, yet an increased signal transducer and activator of transcription (STAT)-3 and phospho-STAT3. Platelet-activating factor receptor protein was not elevated in Dp16 mice. The lungs of Dp16 mice showed increased stiffness and mean linear intercept and contained bronchus-associated lymphoid tissue. The heart ventricles of Dp16 mice displayed hypotonicity. Finally, Dp16 mice required more ketamine to achieve an anesthetized state. (4) Conclusions: The Dp16 mouse model of DS displays key aspects of lung heart biology akin to people with DS. As such, it has the potential to be an extremely valuable model of recurrent severe respiratory tract infection in DS. [ABSTRACT FROM AUTHOR]

Aspergillus nodules (AN) are an unusual form of chronic pulmonary aspergillosis. On the other hand, pulmonary nodular lymphoid hyperplasia (PNLH) is classified as a reactive pulmonary lymphoproliferative disorder. A 65-year-old male was referred to our hospital due to a nodule in the left upper lobe. Histologically, a mixture of prominent lymphoid follicular formation, and hyaline necrosis were observed. Grocott staining revealed morphological forms of Aspergillus spp. in the necrosis. The final clinical diagnosis was suspected AN histologically consistent with PNLH. This case suggests that there may be PNLH cases in which local infection with Aspergillus contributes to its pathophysiology. [ABSTRACT FROM AUTHOR]

The presence of bronchus-associated lymphoid tissue (BALT) and its size in humans largely depends upon age. It is detected in 35% of children less than 2 years of age, but absent in the healthy adult lung. Environmental gases or allergens may have an effect on the number of BALT. Lungs of rhesus macaque monkeys were screened by histology for the presence, size, and location of BALT after exposure to filtered air for 2, 6, 12, or 36 months or 12 and 36 months to ozone or 2, 12, or 36 months of house dust mite or a combination of ozone and house dust mite for 12 months. In the lungs of monkeys housed in filtered air for 2 months, no BALT was identified. After 6, 12, or 36 months, the number of BALT showed a significantly increased correlation with age in monkeys housed in filtered air. After 2 months of episodic house dust mite (HDM) exposure, no BALT was found. Monkeys exposed to HDM or HDM + ozone did not show a significant increase in BALT compared to monkeys housed in filtered air. However, monkeys exposed to ozone alone did show significant increases in BALT compared to all other groups. In particular, there were frequent accumulations of lymphocytes in the periarterial space of ozone exposed animals. In conclusion, BALT in rhesus monkeys housed under filtered air conditions is age-dependent. BALT significantly increased in monkeys exposed to ozone in comparison with monkeys exposed to HDM.

IntroductionPrimary Sjögren’s syndrome (pSS) is a systemic autoimmune disease that affects the function of exocrine glands, such as the lacrimal and the salivary glands. Extraglandular lesions and malignant lymphoma also occur during the progressive stage of pSS. We have, herein, focused on the pulmonary lesions of pSS and have aimed clarifying their pathophysiological mechanism by comparing the glandular with the extraglandular lesions observed in a mouse model of pSS.ResultsThe histopathological analysis of lung tissues obtained from NFS/sld mice that have undergone neonatal thymectomy was performed. Moreover, in vivo and in vitro experiments were conducted along with immunological analyses in order to characterize the unique phenotypes of the pulmonary lesions identified in these pSS model mice. Inflammatory lesions with a bronchus-associated lymphoid tissue-like structure were identified in the lungs of pSS model mice. In addition, relative to salivary gland lesions, pulmonary lesions showed increased CD23+ follicular B (FB) cells. In vitro and pulmonary B cells were more readily driven to CD23+ FB cell phenotype than salivary gland B cells in pSS model mice. Furthermore, the CD23+ FB cell differentiation was found to be enhanced in a CD4+ T-cell-dependent manner under a Th2-type condition in the lungs of herein examined pSS model mice.DiscussionA Th2-type response in the pSS lung may promote the progression of autoimmune lesions through an enhanced abnormal differentiation of B cells.

Bronchus-associated lymphoid tissue (BALT) lymphomas of the lung are uncommon, and diagnosis is often delayed due to the indolent clinical course. Often, adequate samples are difficult to obtain by bronchoscopy with transbronchial biopsy alone. This retrospective study reviewed the diagnosis and treatment of BALT lymphoma cases at our institution over the course of 19 years. Most patients were white, women, and >50 years old; the mean Charlson Comorbidity Index at the time of diagnosis was 6. Seven of 12 patients presented with solitary nodules or multiple nodules. For six cases, initial modalities were nondiagnostic; four subsequently underwent surgical biopsy, one underwent computed tomography–guided biopsy, and one underwent navigational bronchoscopy for final diagnosis of BALT lymphoma. Ultimately, 55% of cases were diagnosed with nonsurgical biopsy. One patient suffered a pneumothorax related to the initial diagnostic attempt. Ten patients received chemotherapy, radiation, and/or surgery, and 11 of the 12 are still alive. Our data confirm the previously described indolent behavior of BALT lymphomas and the challenges related to diagnosis. While previous studies have suggested surgical biopsy as the primary modality for obtaining histopathology, navigational bronchoscopy could serve as a safer alternative. [ABSTRACT FROM AUTHOR]

Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we use a conditional knockin (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of STING-associated vasculopathy with onset in infancy (SAVI) patients or patients afflicted with other ILD-related disorders. [Display omitted] • STING gain of function (GOF) in endothelial cells promotes BALT formation • Immune cell, epithelial, or fibroblast STING GOF is not sufficient for lung disease • Endothelial STING GOF drives chemokine expression • Ubiquitously targeted STING GOF further exacerbates lung inflammation Patients with STING gain-of-function (GOF) mutations develop a life-threatening lung autoinflammatory disease known as SAVI. In this study, Gao et al. utilize a mouse model of conditional STING GOF to demonstrate the key role of endothelial cells in initiating immune cell recruitment to the lungs of SAVI mice. [ABSTRACT FROM AUTHOR]

Mycoplasma pneumoniae (Mp) is a leading cause of human community-acquired pneumonia. To investigate the pathogenesis of the infection, 36 gerbils were intranasally inoculated with Mp culture (30 animals) or sterile mycoplasma broth (6 animals) and euthanized from 1 to 5 weeks post infection. A morphological and immunohistochemical study was carried out in all animals to determine the cellular populations present in lung parenchyma. Polyclonal and monoclonal antibodies were used to detect antigens of Mp and CD3, CD4, CD8 and CD79 lymphocytes, as well as cells containing S100 and major histocompatibility complex class II (MHC-II) antigens. There was progressive infiltration of mononuclear cells in the lamina propria of bronchi and bronchioles, and hyperplasia of the bronchus-associated lymphoid tissue (BALT) in the infected animals. BALT contained dendritic cells immunopositive to S100 and MHC-II and numerous CD3, CD4 and CD79 lymphocytes. The immunohistochemical results showed that T lymphocytes, particularly CD4 and CD79 cells, may play a role in the immune response of gerbils against Mp. This experimental model is valuable for investigation of the pathogenesis of Mp infection and may assist in the development of therapeutic strategies. [ABSTRACT FROM AUTHOR]

Bordetella spp. are respiratory pathogens equipped with immune evasion mechanisms. We previously characterized a Bordetella bronchiseptica mutant (RB50Δ btrS) that fails to suppress host responses, leading to rapid clearance and long-lasting immunity against reinfection. This work revealed eosinophils as an exclusive requirement for RB50Δ btrS clearance. We also show that RB50Δ btrS promotes eosinophil-mediated B/T cell recruitment and inducible bronchus-associated lymphoid tissue (iBALT) formation, with eosinophils being present throughout iBALT for Th17 and immunoglobulin A (IgA) responses. Finally, we provide evidence that XCL1 is critical for iBALT formation but not maintenance, proposing a novel role for eosinophils as facilitators of adaptive immunity against B. bronchiseptica. RB50Δ btrS being incapable of suppressing eosinophil effector functions illuminates active, bacterial targeting of eosinophils to achieve successful persistence and reinfection. Overall, our discoveries contribute to understanding cellular mechanisms for use in future vaccines and therapies against Bordetella spp. and extension to other mucosal pathogens. [Display omitted] • Eosinophils are required for clearance of B. bronchiseptica Δ btrS but not wild type • B. bronchiseptica suppresses eosinophil functions via btrS to promote persistence • Eosinophils facilitate the induction of iBALT, IL-17, and IgA • Eosinophils mediate iBALT formation via XCL1 secretion First et al. elucidate a btrS -mediated mechanism utilized by B. bronchiseptica to hinder eosinophil effector functions. Eosinophils drive iBALT formation within 7 days following btrS -null infection, fostering Th1/Th17 cellular responses and IgA-mediated humoral immunity. These findings introduce a potential role of eosinophils in shaping adaptive mucosal immune responses during respiratory infections. [ABSTRACT FROM AUTHOR]

Highlights • BPA exposure affect the plasma cytokine levels even at lower doses. • BPA exposure change distribution of CD8+ and CD4+ T lymphocytes in immune organs. • Disruption of immune cells and cytokine levels can result in immune system related diseases. Abstract The effects of bisphenol A on the some plasma cytokine levels and distribution of CD8+ and CD4+ T lymphocytes in spleen, ilealPeyer's patch and bronchus-associated lymphoid tissue in rats were investigated. A total of fourty male Wistar Albino rats were divided into five groups including 8 rats in each one: control, vehicle, BPA 5, BPA 50 and BPA 500 groups. Doses of 5, 50 and 500 μg/kg BPA were dissolved in ethanol, then mixed with corn oil. The control group received no treatment. The vehicle group was given the ethanol-corn oil mixture. BPA 5, BPA 50 and BPA 500 groups were given, respectively, 5, 50, and 500 μg/kg/day orally. In blood samples, IL-4, IL-6, IL-10 and TNF-α plasma levels were determined with ELISA. Tissue samples (spleen, ileal Peyer's patches and lung) were processed by means of routine histological techniques. CD4 and CD8 were stained immunohistochemically. Data obtained from this study showed that, BPA causes the alteration on immune parameters including cytokine profile, distribution of CD8+ and CD4+ T lymhpocytes in spleen and ileal Peyer's patches. Present study indicated that BPA may affect immune systems even at lower doses.Disruption of immun system cells and cytokine levels can result in harmful outcomes triggering autoimmune diseases and immunodeficiencies. [ABSTRACT FROM AUTHOR]

Introduction: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that affects the function of exocrine glands, such as the lacrimal and the salivary glands. Extraglandular lesions and malignant lymphoma also occur during the progressive stage of pSS. We have, herein, focused on the pulmonary lesions of pSS and have aimed clarifying their pathophysiological mechanism by comparing the glandular with the extraglandular lesions observed in a mouse model of pSS., Results: The histopathological analysis of lung tissues obtained from NFS/ sld mice that have undergone neonatal thymectomy was performed. Moreover, in vivo and in vitro experiments were conducted along with immunological analyses in order to characterize the unique phenotypes of the pulmonary lesions identified in these pSS model mice. Inflammatory lesions with a bronchus-associated lymphoid tissue-like structure were identified in the lungs of pSS model mice. In addition, relative to salivary gland lesions, pulmonary lesions showed increased CD23 + follicular B (FB) cells. In vitro and pulmonary B cells were more readily driven to CD23 + FB cell phenotype than salivary gland B cells in pSS model mice. Furthermore, the CD23 + FB cell differentiation was found to be enhanced in a CD4 + T-cell-dependent manner under a Th2-type condition in the lungs of herein examined pSS model mice., Discussion: A Th2-type response in the pSS lung may promote the progression of autoimmune lesions through an enhanced abnormal differentiation of B cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sato-Fukuba, Arakaki, Ushio, Otsuka, Nagao, Matsuzawa, Tawara, Tsunematsu and Ishimaru.)

Introduction: Marginal zone B-cell lymphoma is a rare disease which can be considerably difficult to recognize and diagnose when signs of systemic involvement are absent. Case Presentation: We report the case of a 57-year-old woman with initial olfactory disturbance, followed by psychosis, diabetes insipidus and hypothalamic eating disorder as an uncommon clinical presentation of marginal zone B-cell lymphoma. Conclusion: Marginal zone B-cell lymphoma should be considered as a potential differential diagnosis in patients with hypothalamic disturbances.

Aspergillus nodules (AN) are an unusual form of chronic pulmonary aspergillosis. On the other hand, pulmonary nodular lymphoid hyperplasia (PNLH) is classified as a reactive pulmonary lymphoproliferative disorder. A 65-year-old male was referred to our hospital due to a nodule in the left upper lobe. Histologically, a mixture of prominent lymphoid follicular formation, and hyaline necrosis were observed. Grocott staining revealed morphological forms of Aspergillus spp. in the necrosis. The final clinical diagnosis was suspected AN histologically consistent with PNLH. This case suggests that there may be PNLH cases in which local infection with Aspergillus contributes to its pathophysiology. J. Med. Invest. 70 : 499-502, August, 2023.

Sjögren's syndrome (SS) is primarily defined by its impact on the oral and ocular system resulting in xerostomia and xerophthalmia. However, SS can also manifest throughout the respiratory system. Subclinical pulmonary involvement is common. Clinically significant involvement can result in a 4-fold increased risk of death. Thus, recognizing the many potential presentations of SS in the lung is critical in caring for patients with SS. Additionally, SS should be included in the differential diagnosis of a number of forms of interstitial lung disease. [ABSTRACT FROM AUTHOR]

In order to dissect the histopathological changes produced by the infection of avian infectious bronchitis virus in previously vaccinated egg-laying hens from a poultry farming unit, 35 White Leghorn egg-laying hens that had been in production for 9 to 10 months (twenty seven of which had clinical symptoms corresponding to respiratory disease and eight apparently healthy individuals) were selected for further study. After clinical examination and necropsy, they were classified into apparently healthy, mild, moderate or severe according to the severity of the clinical-pathological process. Samples were taken from paranasal sinuses, trachea and lungs for histopathological study, and trachealung pools were prepared from four individuals for virus isolation and molecular biology assays. The presence of mucus was evidenced with Schiff's non-enzymatic histochemical staining, and histomorphometric analyses were used to estimate the number of glands in the tracheal mucosa. The proportions of histopathological lesions were compared, using one-way Anova to determine gland loss at the tracheae with a signifi cance level of p < 0.05 in both cases. Histopathological analysis of the epithelia of paranasal sinuses, trachea and bronchia revealed the presence of epithelial erosion, mucous exudate and hyperplasia of mucosa-associated lymphoid tissue. Glandular cysts were observed at the paranasal sinuses, and epithelial metaplasia was detected in the trachea. It was possible to isolate and identify infectious bronchitis coronavirus from the original samples and from samples passaged in chicken embryos. [ABSTRACT FROM AUTHOR]

In order to dissect the histopathological changes produced by the infection of avian infectious bronchitis virus in previously vaccinated egg-laying hens from a poultry farming unit, 35 White Leghorn egg-laying hens that had been in production for 9 to 10 months (twenty seven of which had clinical symptoms corresponding to respiratory disease and eight apparently healthy individuals) were selected for further study. After clinical examination and necropsy, they were classified into apparently healthy, mild, moderate or severe according to the severity of the clinical-pathological process. Samples were taken from paranasal sinuses, trachea and lungs for histopathological study, and trachea-lung pools were prepared from four individuals for virus isolation and molecular biology assays. The presence of mucus was evidenced with Schiff's non-enzymatic histochemical staining, and histomorphometric analyses were used to estimate the number of glands in the tracheal mucosa. The proportions of histopathological lesions were compared, using one-way Anova to determine gland loss at the tracheae with a significance level of p < 0.05 in both cases. Histopathological analysis of the epithelia of paranasal sinuses, trachea and bronchia revealed the presence of epithelial erosion, mucous exudate and hyperplasia of mucosa-associated lymphoid tissue. Glandular cysts were observed at the paranasal sinuses, and epithelial metaplasia was detected in the trachea. It was possible to isolate and identify infectious bronchitis coronavirus from the original samples and from samples passaged in chicken embryos. [ABSTRACT FROM AUTHOR]

Sphingosine-1-phosphate (S1P) is an immunomodulatory lipid mediator that plays an important role in lymphocyte trafficking. Elevated levels of S1P are found in bronchoalveolar lavage (BAL) fluid of patients with asthma; however, its role in disease is not known. FTY720, a synthetic analog of S1P, has been shown to abrogate allergic inflammation and airway hyperresponsiveness following acute allergen challenge. However, its effects on asthmatic airway remodeling induced by repeated allergen exposure are unknown. Ovalbumin (OVA)-sensitized rats were challenged on days 14, 19, and 24 after sensitization. FTY720 or vehicle (PBS) therapy was administered 1 h prior to each challenge. BAL fluid and quantitative histological analysis were performed 48 h after the last challenge. FTY720 inhibited OVA-induced features of airway remodeling including increased airway smooth muscle mass and bronchial neovascularization, without affecting lymphocyte numbers in secondary lymphoid organs. Furthermore, CD3+ cells adjacent to airway smooth muscle bundles were increased in OVA-challenged rats but the increase was inhibited by FTY720. There was an expansion of bronchus-associated lymphoid tissue following FTY720 treatment of OVA-challenged animals. Real-time quantitative PCR revealed that Th2-associated transcription factors were inhibited following FTY720 therapy. Airway remodeling is a cardinal feature of severe asthma. These results demonstrate that allergen-driven airway remodeling can be inhibited by FTY720, offering potential new therapies for the treatment of severe asthma. [ABSTRACT FROM AUTHOR]

The article presents a study which describes the five cases of Bronchus-associated lymphoid tissue (BALT) lymphomas. The study uses a cohort of patients who were managed with chemotherapy, immunotherapy and chemo-immunotherapy. The result shows that the BALT lymphomas are asymptomatic and are linked with chronic inflammation with an excellent survival outcome which is superior to other primary pulmonary non-Hodgkin lymphoma.

The composition of lymphocyte subsets in the lung has been found to be compartment-specific. To characterize the effect of age, weanling, young adult and adult rats were studied in control conditions and after a single intratracheal dose of the Toll-like receptor 2/6 (TLR2/6) agonist macrophage activating lipopeptide-2 (MALP-2). In all age groups, T, B and natural killer (NK) cells increased dramatically in the epithelium and lamina propria of the bronchi. Male adult rats were found to have responded to MALP-2 to a much greater extent than females when lymphocyte subsets were counted in the epithelium and the lamina propria. In a second series of experiments the time kinetics of regulatory T-cell (Treg) subsets and dendritic cells (DCs) in the lung was studied after local stimulation with MALP-2. Different time-dependent patterns were found in the Treg subsets CD4+ CD25+, CD4+ CD25+ neuropilin 1+ and CD4+ CD25+ Foxp3+ cells. Neutrophils and DCs also showed different patterns. Thus, the local application of a TLR agonist increased the number of lymphocyte subsets in a compartment-specific pattern. However, data should not be generalized or extrapolated from one age group, sex or lymphocyte subpopulation to another. [ABSTRACT FROM AUTHOR]

Summary: Background: Primary Sjögren''s syndrome (pSs) is an autoimmune rheumatic disease that may express in a small number of patients a spectrum of lymphoproliferative diseases. The aim of this study was to describe clinical, imaging and pathology features of the extranodal marginal zone B-cell lymphoma (MZCL) of the lung of mucosa-associated lymphoid tissue (MALT) type in patients with pSs. Methods: All patients () with biopsy proven MZCL of the lung of MALT type diagnosed in a tertiary teaching hospital during the last 7 years were studied. Results: Seven patients had pSs. Almost all patients presented an indolent clinical course, contrasting strongly with the spectacular radiological findings in both chest roentgenograms and computed tomography. Pathology infiltration patterns observed were either nodular, peribronchial–perivascular, alveolar, or interstitial. Immunohistochemical study in all cases showed B cell phenotypes. Immunoglobulin light chain restriction was demonstrated in all patients. Monoclonal IgM(κ) was evident in 5/7, IgM(λ) in 1/7 and IgG (κ) in 1/7 of patients. Conclusions: Lung MZCL associated with pSs are characterized by an important dissociation between clinical expression and radiological pattern. Clinical presentation and imaging features are not specific. Therefore, histologic documentation is mandatory to ensure diagnosis. Various chemotherapeutic agents in combination with rituximab lead to partial or complete remission in the majority of patients. [Copyright &y& Elsevier]

Ersch J, Tschernig T, Stallmach T. Frequency and potential cause of bronchus-associated lymphoid tissue in fetal lungs.Pediatr Allergy Immunol 2005: 16: 295–298.© 2005 Blackwell MunksgaardBronchus-associated lymphoid tissue consists of lymphoid follicles with or without a germinal center within the bronchial wall. Bronchus-associated lymphoid tissue is part of the integrated mucosal immune system and present in about 50% of healthy infants. We examined a series of 141 fetal and neonatal lungs and detected bronchus-associated lymphoid tissue in 100% of cases with amniotic infection while postpartum perinatal pneumonia did not elicit bronchus-associated lymphoid tissue formation. Only rarely and in low density, bronchus-associated lymphoid tissue was present in non-infected fetuses. Thein uteroformation of bronchus-associated lymphoid tissue seems to be a reactive phenomenon and– as has been shown in another study– does not portend an adverse prognosis. [ABSTRACT FROM AUTHOR]

Exposure to silica is associated with the development of chronic airflow obstruction as well as pulmonary fibrosis, probably mediated in part by silica-induced small airway disease. To elucidate the mechanism of mucosal immune responses in the small airways, we analyzed the roles of interferon-γ (IFN-γ) using mice deficient of this cytokine in silicotic lung. IFN-γ knockout mice (−/−) and wild-type C57BL/6 mice were treated with either a single fibrogenic dose of silica or an equivalent volume of saline and euthanized 21 days after intratracheal instillation. Total cell counts in bronchoalveolar lavage fluids increased in silica-instilled mice compared to saline-instilled mice, but there were no significant differences between IFN-γ knockout mice and wild-type mice treated with silica. Morphometric estimation for fibrotic lesions within the lung did not show any differences between these mice. However, bronchus-associated lymphoid tissues (BALT), which are known to be involved in the mucosal immune responses, were significantly larger in the lungs of IFN-γ knockout mice than in those of wild-type mice treated with silica. In addition, we evaluated the development of BALT in interleukin 4 (IL-4) knockout mice in order to clarify the effect of Th2 cytokine. Morphometric estimation for BALT did not show any differences between IL-4 knockout mice and wild-type mice in silicotic lung. These results suggest that IFN-γ has an inhibitory effect on the development of BALT and may be involved in small airway disease in silicotic lung. [Copyright &y& Elsevier]

Previous findings indicate that severe protein deficiency at weaning, even after casein refeeding (R21), alters the seeding of BALT lamina propria (LP) with IgA+ B-lymphocytes and CD5+ T-lymphocytes. Aim of the present study was to determine which T-lymphocyte subsets remain altered in refed (R21) rats compared to age-matched rats receiving commercial diet (C). The number of CD4+, CD8α/α+ and α/βTCR T-lymphocytes were significantly decreased in the BALT LP of R21 rats; the CD8α/α+ T-lymphocyte subpopulation was also significantly decreased in the intraepithelium (IE). The y/§TCR T-lymphocytes found in the BALT LP and in the IE were significantly increased in R21 rats compared to C fed rats. In summary: The decreased number of CD4+ T-lymphocytes in the LP and CD8α/α+ T-lymphocytes in LP and IE tissues may indicate alterations in some effector functions in refed protein deficient rats. The finding of an increase in the number of y/§+ T-lymphocytes in R21 rats, altering the relationship of T-lymphocytes expressing y/§ and α/ß TCR, indicates an impairment in BALT lymphocyte differentiation. [ABSTRACT FROM PUBLISHER]

Objective:Bronchus-associated lymphoid tissue (BALT) plays an important role in the immunological defence of airways. However, the mechanisms of BALT development, antigen sampling, and subsequent cell kinetics remain unclear. To clarify these chronological processes, we used a Pseudomonas aeruginosa-exposed mouse model. Methodology: In BALB/c and C57BL/6 mice, BALT development was induced by inhalation of heat-killed P. aeruginosa after sensitization with subcutaneous injection of P. aeruginosa in the presence of Freund’s complete adjuvant. Subsequently, we chronologically killed these mice who had inhaled PKH26-labelled P. aeruginosa and examined bacterial transport using fluorescence microscopy. The distribution of interleukin-4-positive cells and interferon-γ-positive cells was studied immunohistochemically. Results: The degree of BALT hyperplasia was greater in sensitized mice than in non-sensitized mice and in BALB/c mice than in C57BL/6 mice. PKH26-labelled bacteria were found in BALT earlier in sensitized mice than in non-sensitized mice. Immunohistochemical studies revealed that interleukin-4-positive cells predominated over interferon-γ-positive cells in the peripheral areas of lymphoid follicles. Conclusion: These results indicate that administered antigens are actively transported into BALT and that sensitized Th2 lymphocytes play an important role in forming and maintaining BALT. [ABSTRACT FROM AUTHOR]

Development of bronchus-associated lymphoid tissue (BALT) was studied in clinically healthy and diseased Assam local goats. Animals were sacrificed before term as well as at different postnatal periods to screen lung sections for the presence of BALT. In a retrospective study sections prepared from pneumonic lungs were examined for any alteration of BALT. No BALT-like structure was found in neonatal goats. Bronchial lymphoid structures appeared in half of the animals from 1 month of age onward. The frequency of the BALT/4.5 cm of lung section ranged from one to two in 1-month-old and three to six in 1-year-old goats. In pneumonic lungs BALT became hyperplastic, and the size was also increased. The incidence of BALT was increased in lungs with fibrotic pneumonia. The number of BALT/section was high (five to eight/4.5-cm area) in mesenchymal cell proliferation. The present study shows that BALT did not develop in prenatal periods. But in the presence of potent antigens lymphoid aggregates appeared in the bronchial lamina propria of normal and diseased lungs. [ABSTRACT FROM AUTHOR]

Changes in the expression of calcitonin gene-related peptide (CGRP) and polyneural protein gene product 9.5 (PGP) in hilar peribronchial innervation was investigated by immunohistochemistry in specific pathogen-free rats chronically infected with Mycoplasma pulmonis. Image analysis of immunostained sections revealed a reduction of approximately 62% in the amount of CGRP- and PGP-immunoreactive innervation of the peribronchial area in the infected animals. The portion of the total bronchial perimeter occupied by bronchus-associated lymphoid tissue was increased six-fold. The decrease in the CGRP-immunoreactive area could be the result either of an enhanced CGRP release or of a loss of nerve fibres. The decrease in the PGP-immunoreactive fibres indicates a degenerative loss of nerves. Increased bronchus-associated lymphoid tissue and decreased bronchial innervation by neurons releasing the immunomodulatory neuropeptide CGRP might both contribute to the pathophysiology and symptoms of mycoplasmosis in the rat. [ABSTRACT FROM AUTHOR]

The health hazards associated with grain dust exposure have been recognized as a cause of lung diseases. In the present study, we used germ-free rats exposed to Aspergillus versicolor to elucidate the mechanism for the lung damage induced by grain dust exposure. One month after exposure to the mold, remarkable proliferation of bronchus-associated lymphoid tissues with germinal centres was induced by aspiration of mold spores. After 1 month, alveolar macrophages increased, becoming foamy macrophages by ingestion and digestion of mold spores. They expressed interleukin (IL)-1, Ia antigens and intercellular adhesion molecule-1 intensely and occasionally bound lymphocytes. Numerous lymphocytes infiltrated the granulomatous lesions which consisted of accumulated foamy macrophages and some T lymphocytes which carried IL-2 receptor. Granulomatous lesions were identified in the entire lung, especially around bronchioles. They extended from alveolar ducts to alveolar spaces for 6 months after exposure to the mold. The macrophage appears to be a key effector cell in granulomatous reactions to inhaled molds. [ABSTRACT FROM AUTHOR]

Bronchus-associated lymphoid tissue (BALT) lymphomas of the lung are uncommon, and diagnosis is often delayed due to the indolent clinical course. Often, adequate samples are difficult to obtain by bronchoscopy with transbronchial biopsy alone. This retrospective study reviewed the diagnosis and treatment of BALT lymphoma cases at our institution over the course of 19 years. Most patients were white, women, and >50 years old; the mean Charlson Comorbidity Index at the time of diagnosis was 6. Seven of 12 patients presented with solitary nodules or multiple nodules. For six cases, initial modalities were nondiagnostic; four subsequently underwent surgical biopsy, one underwent computed tomography-guided biopsy, and one underwent navigational bronchoscopy for final diagnosis of BALT lymphoma. Ultimately, 55% of cases were diagnosed with nonsurgical biopsy. One patient suffered a pneumothorax related to the initial diagnostic attempt. Ten patients received chemotherapy, radiation, and/or surgery, and 11 of the 12 are still alive. Our data confirm the previously described indolent behavior of BALT lymphomas and the challenges related to diagnosis. While previous studies have suggested surgical biopsy as the primary modality for obtaining histopathology, navigational bronchoscopy could serve as a safer alternative., (Copyright © 2021 Baylor University Medical Center.)