Aged human thymus hassall's corpuscles are immunoreactive for IGF-I and IGF-I receptor.

Although Hassall's corpuscles have been proposed to act in both maturation of developing thymocytes and removal of apoptotic cells, their function remains an enigma. The involvement of insulin-like growth factor I (IGF-I) in the local autocrine and paracrine control of T-cell development in human thymus is still unclear. In this study, we investigated the structure and distribution of IGF-I and IGF-I receptor (IGF-IR)-immunopositive Hassall's corpuscles in aged human thymus using bright-field immunohistochemistry and immunoelectron microscopy. We report new immunocytochemical data for the presence of IGF-I/IGF-IR double-immunopositive Hassall's corpuscles in structurally preserved regions of age-involuted thymus and discuss the involvement of these unique thymic components in the local regulation of T-cell development and thymus plasticity during aging by IGF-I/IGF-IR-mediated cell signaling pathway.

Differential expression of LAMPs and ubiquitin in human thymus.

Lysosome-associated membrane proteins 1 and 2 (LAMP-1 and LAMP-2) are implicated in a variety of normal and pathological processes. LAMP-2 is proposed to participate in chaperone-mediated autophagy.Autophagy regulates T-lymphocyte homeostasis by promoting both survival and proliferation. The biological importance of this process in the thymic gland and especially the involvement of LAMPs are far from being elucidated. The aim of the study was to examine the parallel expression of LAMPs and ubiquitin, a key molecule in autophagy, in normal human thymic glands and thymomas. The immunohistochemical expression of both markers was compared with that of cyclin D1--an important regulator of cell cycle progression. Novel evidence for differential expression of LAMPs and ubiquitin is presented. Most Hassal's corpuscules in thymoma were negative for LAMPs, but positive in normal thymus.Both lymphocytes and epithelial cells in pathological thymus showed higher intensity for LAMP-2 compared with LAMP-1. In thymoma, ubiquitin was more intensively positive in these cell types compared with the normal thymus, suggesting activated autophagy in the course of this pathological state. A deregulation in cyclin D1 expression in thymoma is also reported. The functional importance of these molecules in autophagy accompanying normal and pathological processes in the thymic gland is reviewed.

Thymic epithelial cells of human patients affected by myasthenia gravis overexpress IGF-I immunoreactivity.

Accumulating evidence shows that several kinds of thymic cells express insulin-like growth factor-I (IGF-I), which is known to play an important role in T cell ontogeny under both physiological and pathological conditions. Still, little is known about the mechanisms of IGF-I involvement in the pathological transformation of the thymocyte microenvironment. The present study focuses on a comparative analysis of the IGF-I immunoreactivity of thymic epithelial cells (EC) from human patients with hyperplasia-associated myasthenia gravis (MG) versus physiological thymic tissue from healthy controls using immunohistochemistry and immunoelectron microscopy. We show that myasthenic EC overexpress IGF-I in comparison to EC from control subjects. The IGF-I immunoreactivity in the medullary and cortical EC from MG patients was stronger than in the normal gland. The increased expression of IGF-I and more frequent distribution of IGF-I and IGF-I-receptor (IGF-IR) immunopositive EC correlated with modulation in the immunoreactivity of double (IGF-I/IGF-IR) positive EC. Our data provide new immunocytochemial evidence for alterations of IGF-I and IGF-IR immunoreactivity in EC from pathological thymi. The persisting expression of IGF-I and IGF-IR most likely indicates that the myasthenic thymus is still capable of governing IGF-I signaling pathways, which are involved in the local regulation of T cell development and plasticity.

Nerve growth factor immunoreactivity of mast cells in acute involuted human thymus.

The acute involution of the thymus is induced by either exogenous or endogenous factors, including some infections (infection type involution). The present study was focused on both detection and immunocytochemical analysis of NGF immunopositive mast cells in child thymus with acute infection-induced involution. Autopsy thymus specimens from children with infection diseases (Sepsis, Encephalomyelitis, Varicella) were examined at light and electron microscopic level and compared to normal infantile thymuses. We observed a redistribution of NGF immunopositive mast cells in infection-affected child thymus, which lobular architecture was collapsed. A positive correlation between the degree of the involutive changes, increased distribution and enhanced NGF immunoreactivity of mast cells was defined. The possible involvement of NGF immunopositive mast cells in the process of acute thymus involution is discussed.

Lysosomal membrane-associated glycoproteins are differentially expressed in acute and chronic human thymic involution.

The lysosomal membrane-associated glycoproteins LAMP-1 and LAMP-2 are the major constituents of lysosomal membranes with still undefined biological functions. As autophagy is an alternative model of programmed cell death in which lysosomes play a crucial role, we hypothesize that LAMPs might participate in this phenomenon in the involuting thymus. Thymic glands from cases with acute (infection induced) and chronic (senile) involution were examined immunohistochemically for the expression of LAMPs. In acute involution LAMP-1 was localized mainly in medullary epithelial cells, in single macrophages and lymphocytes. Hassall's corpuscules were stained less intensely as compared to control specimens. The quantitative analysis showed a significantly elevated LAMP-2 expression compared to LAMP-1. LAMPs were detected with very slight reactivity in the senile thymus. The enhanced expression of LAMPs, and mainly of LAMP-2, in epithelial cells of incidentally involuted thymus might be an indicator of acute cell injury requiring autophagic degradation of damaged structures. The diminished expression of LAMPs in age-involuted thymus could be a sign of the morphological reorganization and the functional disregulation of the gland. In conclusion, we present novel evidence for differential expression of LAMP-1 and LAMP-2 in thymic involution suggesting their possible involvement in the process of accidental involution of the thymic gland.

Modulation of ABH histo-blood group antigen expression in normal and myasthenic human thymus.

The role of ABH histo-blood group antigens (HBGA) in intercellular communication during normal and pathological processes is still uncertain. The present work investigates the expression of ABH HBGA in epithelial cells and lymphocytes in normal thymus, and characterizes the modulation of their immunoreactivity during myasthenic transformation. Immunohistochemistry and immunoelectron microscopy were applied on normal young thymus and on myasthenia gravis-associated thymomas and thymic hyperplasias. The Hassall's corpuscules in the thymus of young individuals were homogeneously stained for HBGA, while in hyperplastic glands only their central part was positive. Stromal epithelial cells permanently expressed HBGA in all tissue samples. In thymomas, mainly the lymphocytes in close proximity to antigen expressing epithelial cells were positive, while in the hyperplastic gland the most intensely stained lymphocytes were those within Hassall's corpuscules. Novel evidence for modulation of ABH antigen reactivity in normal and myasthenic human thymus is presented. It suggests that HBGA might participate in the regulation of the cross-talk in the thymocyte microenvironment throughout the ontogeny, as well as during the myasthenic transformation.

ABH histo-blood group antigens in human thymus involution.

BACKGROUND: Human histo-blood group antigens (HBGA) are genetically determined glycoproteins supposed to participate in cell differentiation, adhesion, cancer metastasis and angiogenesis. In tissues, HBGA are mostly expressed in epithelial cells (EC). The EC comprising the thymocyte microenvironment play an important role in the ontogeny of the thymus. The aim of the present work is to investigate ABH HBGA in senile thymus and to characterize their expression pattern related to the process of aging. METHODS: Routine histology and immunohistochemical techniques were applied on thymus glands from senile and young individuals. RESULTS: Involuted thymus exhibited large areas of adipose tissue containing scattered EC, all positive for HBGA. Stromal EC revealed different morphology and intrathymic localization but uniform cytoplasmic staining for ABH antigens. Endothelial cells of blood vessels and red blood cells were intensely stained for HBGA. Only single scattered lymphocytes possessed HBGA. In contrast with senile thymus, most lymphocyte populations in the gland of young individuals, as well as the Hassall's corpuscules, expressed HBGA. CONCLUSIONS: The epithelial framework reorganization during age-related thymus involution involves modulation in ABH antigen expression in EC. These molecules are required by thymic EC to maintain the reduced but important crosstalk with lymphocytes during involution. The diminished reactivity for ABH antigens in the lymphocytes of aged thymus might reflect the impaired communication between these two cell types. We present novel evidence for permanent presence and modulation of ABH antigen reactivity in senile thymus, supporting the view that these molecules might be developmentally regulated.

Epithelial framework reorganization during human thymus involution.

BACKGROUND: The thymus undergoes age-related (physiological) involution in the course of normal ontogenetic development. In addition to this chronic involution, the thymus can also undergo an acute (age-independent) regression, defined as spontaneous, transient involution. This process is induced by either exogenous or endogenous factors, including some infections (infection-type involution). OBJECTIVE: The purpose of the present work was to undertake a comparative study of the epithelial framework organization and cytokeratin immunoreactivity of human thymic epithelial cells during age-related and infection-induced involution. METHODS: Routine methods for light and transmission electron microscopy, as well as indirect immunoperoxidase staining and immunogold electron microscopy, were applied. RESULTS: The epithelial thymocyte microenvironment was of a generally similar cellular composition in both chronically and acutely involuted thymus. Structurally, aged thymus glands and infection-affected thymus glands displayed a large mass of adipose tissue containing scattered islands composed of epithelial cells, lymphocytes and reticular connective tissue. Correlation between thymus involution and regional peculiarities in the presence and distribution of cytokeratin-immunopositive cells and their intermediate filaments was investigated. CONCLUSION: The epithelial framework of the thymus undergoes reorganization during both age-related and infection-induced thymus involution. The involutionary processes demonstrated essential regional and intracellular (structural and immunocytochemical) differences. The epithelial cell rearrangement and cytokeratin modulation that we observed might be involved in thymic microenvironment plasticity and reorganization in the course of these processes.

Altered levels of nerve growth factor in the thymus of subjects with myasthenia gravis.

We have previously reported that nerve growth factor (NGF), a polypeptide known for its neurotrophic activities, is also involved in the differentiation and survival of immune cells, and that NGF and its high-affinity receptor are present in the thymus. We here demonstrate that the thymus of humans affected by myasthenia gravis (MG) contains significant concentrations of NGF. These observations support our hypothesis of a role for NGF in the thymus and suggest that the changes observed in the thymus of subject with MG may have functional significance.

Structural and ultrastructural localization of NGF and NGF receptors in the thymus of subjects affected by myasthenia gravis.

We have previously reported that the thymus of patients affected by myasthenia gravis (MG) is characterized by an elevated level of nerve growth factor (NGF), an endogenous polypeptide which plays a marked role in the cell biology of nervous and immune system. A consistent number of studies has shown altered expression of NGF in diseases associated with inflammatory and/or autoimmune responses. To evaluate the biochemical and molecular mechanisms implicated in NGF action in human myasthenic thymus, it is important to identify the cellular and structural organization of NGF receptors. To address this question, we investigated, both at light and electron microscopic levels, the cellular distribution of immunoreactivity for NGF and its low-affinity receptors, (p75) and its high-affinity receptor (TrkA) in the thymus of patients with MG. The present investigation shows that NGF and NGF receptors are overexpressed in the thymic cells of patients with MG compared to control subjects.