Structure and function of bronchus-associated lymphoid tissue (BALT)

This article deals with the ontogeny, morphology, and function of bronchus-associated lymphoid tissue (BALT). The surface epithelium of the respiratory tract, including the lymphoepithelium of BALT, is described, with emphasis on infiltrated nonepithelial cells (lymphocytes, macrophages). Special attention is given to antigen handling by the lymphoepithelium and the interaction with BALT and lung macrophages. The structure and function of the diverse types of BALT nonlymphoid cells are discussed. The local immune responses (cellular and humoral reactions), the relationships between local and systemic immune reactions, and the role of BALT in the common mucosal immune system are reviewed. The BALT is compared with Peyer's patches in terms of antigen processing, local immune responses, cell populations, and migration of lymphoid and nonlymphoid cells.     

A morphologic study of bronchus-associated lymphoid tissue in turkeys

Bronchus-associated lymphoid tissue (BALT) in normal turkeys of ages 1 day and 1, 2, 3, 4, 8, and 18 weeks was examined by light microscopy and by scanning and transmission electron microscopy. Turkey BALT resembled other mucosa-associated lymphoid tissues; it was made up of a population of lymphocytes covered by a specialized epithelium different from typical pseudostratified ciliated columnar bronchial epithelium. There were distinct age-related differences in BALT structure. Bronchus-associated lymphoid nodules were larger and more numerous in older turkeys. In 1-day- to 2-week-old turkeys, the primary cell type of BALT epithelium was nonciliated cuboidal; in 2-week old turkeys it was squamous; and in turkeys older than 4-weeks of age, the epithelium was primarily ciliated columnar. In 1- to 4-week old turkeys, large numbers of intraepithelial lymphocytes disrupted the normal organization of the epithelium. In older turkeys, epithelial and lymphoid cells were in discrete compartments separated by connective tissue. Lymphocytes in 1-day-old turkeys were found in loose aggregates around venules and within the epithelium. In 1-week old turkeys, lymphocytes were organized into compartments of morphologically similar cells. By 3-weeks of age, lymphocytes were present in distinct germinal centers. Epithelial cells of BALT did not have large numbers of apical vesicles and thus were not structurally specialized for antigen uptake by endocytosis. However, the epithelial barrier appeared to be disrupted over lymphoid nodules, suggesting that antigen would be readily available to lymphocytes and phagocytes in BALT. Age-related differences in turkey BALT structure may have functional consequences with respect to the respiratory immune response.     

Mucosa-associated lymphoid tissue lymphoma of the esophagus coexistent with bronchus-associated lymphoid tissue lymphoma of the lung

Non-Hodgkin's lymphoma very rarely involves the esophagus, occurring in less than 1% of patients with gastrointestinal lymphoma. A few cases of mucosa-associated lymphoid tissue (MALT) lymphoma of the esophagus have been reported in the English literature. To our knowledge, there has been no report of MALT lymphoma of the esophagus coexistent with bronchus-associated lymphoid tissue lymphoma (BALT) of the lung. This report details the radiological and clinical findings of this first concurrent case.     

Depletion of bronchus-associated lymphoid tissue associated with lung allograft rejection.

Pulmonary infections remain one of the major complications of lung transplantation. The bronchus-associated lymphoid tissue (BALT) forms a local immune system that normally protects the lung from infection. The effects of lung transplantation and lung allograft rejection on the BALT were examined using immunoperoxidase techniques. The BALT was evaluated by quantifying the number of immunoglobulin-bearing plasma cells in the lamina propria of sections of trachea and mainstem bronchus. Sections of donor mainstem bronchus from 2 patients with allograft rejection were compared with sections of native trachea from these same patients, and with sections of mainstem bronchus from 2 transplanted lungs without rejection and 20 controls. Lung allografts from the 2 patients with rejection had a marked depletion of submucosal IgA-bearing and IgG-bearing plasma cells. Two sets of transplanted lungs without evidence of rejection showed only a mild reduction of the BALT. The depletion of BALT associated with allograft rejection may contribute to the increased incidence of pulmonary infections seen in these patients.     

The response of rat bronchus-associated lymphoid tissue to local antigenic challenge

Single doses of antigen suspension (alum-precipitated canine serum proteins) were administered intratracheally to SPF rats. After periods of 1, 2 and 3 weeks rats were killed and their lungs examined histologically. After an initial macrophage and perivascular lymphoid reaction, dose-related increases were found in the amount of bronchus-associated lymphoid tissue (BALT) and in the amount of DNA within BALT cells, indicating increased cell division. Immunoglobulin-containing cells were demonstrated within BALT 3 weeks after the exposure to antigen. A prominent and extensive bronchial lympho-epithelium was seen overlying BALT follicles in antigen-treated rats, while in control animals the respiratory epithelium overlying BALT was predominantly normal ciliated epithelium. The significance of these findings is discussed in the light of the possible defensive role of BALT in cases of respiratory disease of man and animals.     

The development of inducible bronchus-associated lymphoid tissue depends on IL-17

Ectopic or tertiary lymphoid tissues, such as inducible bronchus-associated lymphoid tissue (iBALT), form in nonlymphoid organs after local infection or inflammation. However, the initial events that promote this process remain unknown. Here we show that iBALT formed in mouse lungs as a consequence of pulmonary inflammation during the neonatal period. Although we found CD4(+)CD3(-) lymphoid tissue-inducer cells (LTi cells) in neonatal lungs, particularly after inflammation, iBALT was formed in mice that lacked LTi cells. Instead, we found that interleukin 17 (IL-17) produced by CD4(+) T cells was essential for the formation of iBALT. IL-17 acted by promoting lymphotoxin-α-independent expression of the chemokine CXCL13, which was important for follicle formation. Our results suggest that IL-17-producing T cells are critical for the development of ectopic lymphoid tissues.     

Subpopulations of lymphoid and non-lymphoid cells in bronchus-associated lymphoid tissue (BALT) of the mouse

Lymphoid and non-lymphoid subpopulations were investigated in the lung of the mouse with immunocyto-, immunohisto- and enzyme-histochemical methods. Special attention was paid to the cell populations in bronchus-associated lymphoid tissue (BALT), which is positioned between a bronchus and an artery. In BALT, discrete T- and B-cell areas can be found. The majority of the T cells belong to the L3T4+ (T-helper) subpopulation. In the T-cell area interdigitating cells can be recognized by anti-class II antibodies as well as by specific monoclonal antibodies, NLDC-145 and MIDC-8. Macrophage subpopulations can be discriminated by location, enzyme reactivity and various macrophage-specific monoclonal antibody markers. On the outer rim of BALT macrophages are recognized by the MOMA-1 and ERTR9 antibody. Macrophages dispersed in BALT can only be discriminated with the MOMA-2 antibody. The macrophage markers F4/80 and Mac-1 show no reactivity in BALT. In lung, tissue macrophages around bronchi and blood vessels are predominantly recognized by the MOMA-1 and MOMA-2 antibody, and a minor population by the ERTR9 antibody. Alveolar macrophages show heterogeneity with the MOMA-1, MOMA-2 and NLDC-145 antibody. The relationship between alveolar macrophages and antigen-presenting cells is discussed here.     

The response of rat bronchus-associated lymphoid tissue to local antigenic challenge.

Single doses of antigen suspension (alum-precipitated canine serum proteins) were administered intratracheally to SPF rats. After periods of 1, 2 and 3 weeks rats were killed and their lungs examined histologically. After an initial macrophage and perivascular lymphoid reaction, dose-related increases were found in the amount of bronchus-associated lymphoid tissue (BALT) and in the amount of DNA within BALT cells, indicating increased cell division. Immunoglobulin-containing cells were demonstrated within BALT 3 weeks after the exposure to antigen. A prominent and extensive bronchial lympho-epithelium was seen overlying BALT follicles in antigen-treated rats, while in control animals the respiratory epithelium overlying BALT was predominantly normal ciliated epithelium. The significance of these findings is discussed in the light of the possible defensive role of BALT in cases of respiratory disease of man and animals.     

Malignant lymphoma of bronchus-associated lymphoid tissue (BALT) coexistent with pulmonary tuberculosis

A case in which malignant lymphoma occurred in association with a tuberculosis focus in a 70-year-old man is reported. Surrounding the epithelioid cell granulomas with caseous necrosis was a dense and diffuse monotonous infiltration of atypical lymphoid cells. Acid-fast bacilli were found in the granulomas and pulmonary tuberculosis was diagnosed. The infiltrating atypical lymphoid cells occasionally invaded the respiratory epithelium producing lymphoepithelial lesions. Immunohistochemically, the lymphoid cells were positive for CD20, and clonal rearrangement of the immunoglobulin heavy chain gene was demonstrated by polymerase chain reaction (PCR). We diagnosed the lesion as a pulmonary malignant lymphoma of bronchus-associated lymphoid tissue (BALT) occurring in the background of tuberculosis. This is the first reported case of pulmonary BALT lymphoma coexistent with pulmonary tuberculosis.     

Developmental study of immunocompetent cells in the bronchus-associated lymphoid tissue (BALT) from Wistar rats

The aim of the present report was to study in growing Wistar rats the development of immunocompetent cells in the bronchus-associated lymphoid tissue (BALT). We found at day 4 postpartum, a high number of TCRgamma/delta+ T cells and very few CD8alpha+, CD8beta+, CD5+, TCRalpha/beta+ T cells in BALT. The latter cells and CD4+ T cells increase with age. Even though T cells expressing TCRgamma/delta outnumber those expressing TCRalpha/beta early in development, until 45 days of age, alpha/beta+ predominate over gamma/delta+ T cells only in adult rats (60 days of age). Moreover, a predominance of suppressor/cytotoxic T cells over T-helper cells was found in 60 days old rats. Surprisingly, more CD8alpha+ than CD8beta+ T cells in BALT are observed. The number of IgA+ B and CD4+ T cells found in the BALT increases with age. The early appearance - 4 days of age - of all T-cell phenotypes in BALT especially of gamma/delta+ T cells may imply a benefit to respond to inhaled antigen soon after birth.     

诱导性支气管相关淋巴组织(iBALT)相关细胞因子CXCL13在AECOPD患者肺泡灌洗液中的变化及临床意义

目的:分析诱导性支气管相关淋巴组织(iBALT)相关细胞因子CXCL13在慢性阻塞性肺疾病急性加重期慢性阻塞性肺疾病患者(AECOPD)肺泡灌洗液(BALF)中的变化及临床意义.方法:选取14例因细菌感染诱发AECOPD的患者为AECOPD组,并选取同期24例急性细菌性肺炎患者为单纯感染组.采用支气管镜采集两组患者BA...     

Stimulation of bronchus-associated lymphoid tissue in rats by repeated inhalation of aerosolized lipopeptide MALP-2.

OBJECTIVE: Bronchus-associated lymphoid tissue (BALT) is a part of the integrated mucosal immune system. It may play an important functional role for antigen uptake and induction of specific immune reactions. The aim of this study was to investigate whether it is possible to induce or modulate BALT by the repetitive inhalation of the synthetic lipopeptide MALP-2. METHODS: Female Lewis rats (245 +/- 19 g) inhaled 25 microg of MALP-2 six times at intervals of 1 week. One week after the last inhalation, they were sacrificed. Cells of the bronchoalveolar lavage and the left lung were investigated by flow cytometry. The middle lobe of the right lung was embedded in paraffin. BALT was semiquantitatively measured in 15 serial cross sections per animal. RESULTS: After repetitive inhalation of the diluent as well as MALP-2, BALT was found. The total area was increased after repetitive treatment with MALP-2. In addition, the preferential incidence of BALT was higher after MALP-2 application, in association with a bronchial diameter of 0.6-1 mm. The cellular analysis revealed no differences in the number of leukocyte subsets between the control and MALP-2 group. CONCLUSION: MALP-2 is a potent local stimulator and can be used to modulate BALT by repetitive inhalant treatment. The functional significance of enlarged or activated BALT has to be elucidated in future studies.     

The presence of specialized epithelial cells on the bronchus-associated lymphoid tissue (BALT) in the mouse

The aggregation of lymphoid cells in the bronchial mucosa has been named the bronchus-associated lymphoid tissue (BALT) and investigated in comparison with the gut-associated lymphoid tissue (GALT). To elucidate precisely the structure and function of the BALT, the present study examined the age-related change in the mouse BALT by light microscopy. We also observed the characteristics of the overlying epithelium, especially the lectin-binding properties of the epithelial cells, by the combined use of light microscopy (LM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). By LM, lymphoid aggregates were not recognizable in the bronchial mucosa of young (8-10 week-old) mice, while they were commonly found at the second to fourth branching portions of the bronchial tree in older (32-40 week-old) mice. The epithelium overlying the lymphoid aggregates of the mature mice often contained a large number of mononuclear cells. Lectin cytochemistry revealed that UEA1 (Ulex europaeus agglutinin 1) positive cells were not only restricted to the overlying epithelium of the BALT in the older mice but also found in a cell group in the mucous epithelium at the branching portions in the young mice. Comparison between the LM and SEM images of the UEA1-stained whole mount specimens clarified the surface morphology of the lectin-stained epithelial cells, showing them to be non-ciliated cells with a large number of short microvillous projections on the apical surface. TEM studies further demonstrated that the UEA1 reaction products appeared on the plasma membrane of the non-ciliated cells which often enfolded lymphocytes in the old mice. Latex microbeads, which were administrated intratracheally, were selectively taken up by the UEA1-positive cells of the BALT. These results indicate that the mouse BALT has specialized epithelial cells similar to the UEA1 positive M cells in the GALT and probably functions as a part of the mucosal immune system. This study also showed the possibility that the UEA1 positive cells appear in the mucous epithelium before the formation of the BALT.     

Lymphocyte subpopulations in high endothelial venules and lymphatic capillaries of bronchus-associated lymphoid tissue (BALT) in the rat

The subpopulations of lymphocytes and non-lymphoid cells in high endothelial venules (HEV) and in lymphatic capillaries surrounding lymphoid follicles in bronchus-associated lymphoid tissue (BALT) were examined by electron microscopy after preembedding the tissue and staining with an immunoperoxidase technique. The results were compared with those obtained in gut-associated lymphoid tissue (GALT) reported previously. Monoclonal mouse-anti-rat T cell, IgG, IgM, IgA, and Ia antisera were used. Plasma cells that were reactive to anti-IgG, anti-IgM, and anti-IgA were detected as cells in which the 3′, 3′ -diaminobenzidine tetrahydroxychloride reaction product was localized in rough endoplasmic reticulum and perinuclear spaces but not on plasma membranes. These plasma cells did not occur in either lymphatic capillaries or HEV in BALT as they did in GALT. Cells with surface Ig (sIg cells), T-cell antigen (T cells), and Ia antigen (Ia cells) were present in BALT. T cells were located predominantly in the follicular area opposite the bronchial epithelium; IgM- and IgG-reactive cells were found in the follicular area adjacent to the bronchial epithelium; and IgA-positive cells were found in the lateral part of the area where the T cells were localized (T-cell area). Ia cells were abundant throughout BALT and in moderate numbers in the epithelium. A striking observation was the presence of “nurse-cell”-like structures in the periphery of BALT. The percentages of T, sIgG, sIgM, and sIgA cells in the HEV were 54.7%, 2.4%, 28.9%, and 27.3%, respectively, and in the lymphatic capillaries, 41.2%, 3.8%, 38.2%, and 21.2%, respectively. Non-lymphoid cells with Ia antigen, presumably interdigitating cells (IDC), were often seen in the two types of vessels. The percentage was 4. 3% in the HEV and 5.6% in the lymphatic capillaries. The results indicate that the largest common lymphocyte subpopulation in the two types of vessels surrounding follicles in BALT is T cells, followed by sIgM or sIgA cells as seen in GALT; IDC may be one of the main migrating cells within BALT.     

Characterization of pulmonary macrophages and bronchus-associated lymphoid tissue (BALT) macrophages in the rat. An enzyme-cytochemical and immunocytochemical study

Three subpopulations of macrophages present in the lung, viz. pulmonary alveolar macrophages (PAM), pulmonary tissue macrophages (PTM), and macrophages in the bronchus-associated lymphoid tissue (BALT), were compared using enzyme-cytochemical and immunocytochemical methods. BALT macrophages can be distinguished from PAM and PTM on the basis of their enzyme reaction products. With three monoclonal antibodies, ED1, ED2, and ED3, that recognize different antigen determinants of rat macrophages, the three subpopulations could be clearly distinguished. PAM are ED1-positive and PTM are ED2-positive. The macrophage subpopulation scattered throughout BALT is ED1-positive; macrophages situated at the peripheral site of BALT, near artery and bronchus, are ED2-positive. No ED3-positive macrophages were observed either in the lung or in BALT. These results are discussed with respect to the possible relationship between the subpopulations of pulmonary macrophages.     

Is the bronchus-associated lymphoid tissue (BALT) an integral structure of the lung in normal mammals, including humans?

In the respiratory tract, lymphoid aggregates with a specialized epithelium have been called bronchus-associated lymphoid tissue (BALT) and compared to the organized lymphoid tissue of the gut (GALT), e.g., Peyer's patches. BALT might play a central role in antigen uptake, initiating immune responses and disseminating primed lymphoid cells in the respiratory tract. In the present study, lungs of mice, rats, guinea pigs, rabbits, pigs, cats, and humans have been studied with respect to the presence and number of BALT and the dependence of BALT on age and microbial stimulation. BALT is not a constitutive structure in all these species. Its frequency varies widely, from 100% in rabbits and rats, 50% in guinea pigs, 33% in pigs, to its absence in cats and all normal human lungs. BALT seems to be a lymphoid structure which is not present in all the species studied but can develop in the lung after stimulation. This is in contrast to lymphoid organs, such as lymph nodes or Peyer's patches, which can always be found. These species differences are of major importance in interpreting the clinical relevance of experiments in animal models on the lung immune system, e.g., antigen uptake, immunostimulation, or lung transplantation.     

Morphological and immunohistochemical studies of the lungs and bronchus-associated lymphoid tissue in a rat model of chronic pulmonary infection with Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the most frequently encountered bacterial pathogens in patients with chronic pulmonary infections, including cystic fibrosis and diffuse panbronchiolitis. Bronchus-associated lymphoid tissue (BALT), noted frequently in patients with cystic fibrosis and diffuse panbronchiolitis, is considered to play an important role in the local immunologic defense mechanisms in the respiratory tract. To investigate the role of BALT in chronic pulmonary infections, we developed an animal model for chronic pulmonary infection and studied the morphological and immunohistochemical characteristics of BALT. Experimental pneumonia was produced in rats by intratracheal inoculation of P. aeruginosa enmeshed in agar beads. The histological changes corresponded to those occurring in chronic bronchiolitis. Immunohistochemically, surface immunoglobulin M-positive (sIgM+) cells and sIgA+ cells were recognized in the inflamed bronchial walls from day 4, and sIgG+ cells were recognized from day 14, W3/25+ cells exceeded OX8+ cells in number until day 14. In the BALT, there was a massive accumulation of lymphocytes in the lymphatics and high endothelial venules. The development of germinal centers was accompanied by increased numbers of sIgM+ and sIgA+ cells. W3/25+ cells exceeded OX8+ cells in number in the BALT until day 14. On the other hand, OX8+ cells were predominant in comparison with W3/25+ cells at day 21, and then both sIgM+ and sIgA+ cells and inflammatory changes in the lung decreased at day 28. These findings suggest that BALT regulates the local immune responses against chronic pulmonary infection due to P. aeruginosa.     

Effects of microbial stimulation on the number, size and activity of bronchus-associated lymphoid tissue (BALT) structures in the pig.

The development of bronchus-associated lymphoid tissue (BALT) was investigated in the pig, which is a species in which BALT is not found constantly. Different routes of contact with a specifically lung-pathogen bacterium Actinobacillus (Haemophilus) pleuropneumoniae were tested. Pigs, selected by bacteriological screening methods and the number of granulocytes in the bronchoalveolar lavage (BAL), were infected by aerosol. They were compared to previously enterally immunized pigs using active and inactivated bacteria. The development of BALT after the infection was compared to that in pigs with a single enteral, or no, contact with the bacterium. BALT was less frequent in these groups than in the infected pigs. Previously immunized pigs developed the highest number and the largest BALT with the most prominent morphological signs of activation. Immunization with living or inactivated bacteria did not cause histological differences. BALT was preferentially located around bronchioli and small bronchi. Additional BALT predominantly occurred in the walls of larger bronchi. Definite compartments of T and B lymphocytes were not found in immunohistological studies of BALT. It was concluded that the development of BALT can be induced by different modes of microbial stimulation.