Macrophages in endocrine glands, with emphasis on pancreatic islets

ABSTRACT We review here the macrophages found in endocrine tissues, placing emphasis on those residing in the islets of Langerhans of the pancreas. The islets represent the endocrine organ where macrophages have been examined in great detail and where our own studies and experience have been directed.</jats:p

Processing of proteins in autophagy vesicles of antigen-presenting cells generates citrullinated peptides recognized by the immune system

Our laboratory has been investigating for some time the nature of the response of T lymphocytes in autoimmunity in the reactions against self-proteins that result in a number of diseases, such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis (RA) and others. T cells recognize peptides generated from proteins that are processed by antigen-presenting cells (APC). The peptides may derive from exogenous proteins or from the normal catabolism of self-proteins. The peptides complexed to major histocompatibility complex (MHC) molecules constitute the chemical entity that is engaged by the antigen-receptor of T cells. An important hypothesis postulates that self-peptides that suffer post-translational modifications in the APC may form neo-antigens that are recognized by the immune system and form the target of autoimmunity. Our interest in citrullination in the context of antigen processing and presentation stemmed from studies suggesting that an immune response to citrullinated self-peptides may be involved in autoimmunity. In a first publication, we found T cells that specifically recognized citrullinated peptides after immunization of inbred mice with standard foreign proteins. We used the small protein hen-egg white lysozyme. These T cells only recognized the citrullinated peptide and not the unmodified one, thus proving that a neo-epitope had been created by this modification. But how this modification took place was not known. Our recent report describes a central role for autophagy in citrullination of peptides by APC

PERSISTENCE OF IMMUNOGENICITY OF ANTIGEN AFTER UPTAKE BY MACROPHAGES

Peritoneal macrophages were cultured for several hours after uptake of 131I-hemocyanin. The cells degraded most of the 131I-labeled protein within 2–5 hr. Their ability to prime lymphocytes of syngeneic mice for a secondary immune challenge remained unchanged for long periods of time despite the loss of more than 90% of the original content of antigen. The persistence of immunogenicity was associated with a small percentage of antigen retained by the cell in a form which was protected from rapid breakdown and elimination

LIGAND-INDUCED MOVEMENT OF LYMPHOCYTE MEMBRANE MACROMOLECULES : V. Capping, Cell Movement, and Microtubular Function in Normal and Lectin-Treated Lymphocytes

Capping of surface Ig by anti-Ig antibodies involves a membrane perturbation requiring an energy-dependent step. Lymphocytes treated with anti-Ig are stimulated to move. Previously, we had shown that movement was not essential for capping, although it influenced the localization of the cap. We have investigated the role of cell movement and of microtubular proteins in this phenomenon. Treatment of B lymphocytes with colchicine does not affect capping of Ig nor does it affect the increase in translational movement produced by anti-Ig antibodies. Treatment of lymphocytes with cytochalasin B stops translational movement and may affect capping to some degree under appropriate circumstances. Lymphocytes treated with both drugs are impaired in capping. We surmise that there may be two cytoplasmic events regulating directly or indirectly capping: one associated with the process of translational movement, the other associated with the activity of microtubules. Lymphocytes treated with concanavalin A do not cap Ig. Colchicine reverses this inhibition. Certain experimental procedures antagonize the colchicine effect, the most striking of which is the use of cytochalasin B. Colchicine appears to increase movement of the Con A-treated lymphocyte, and this increased movement appears responsible for the accumulation of complexes to the posterior part of the cell. Con A inhibits patching of Ig by anti-Ig, and this is not reversed by colchicine

THE IMMUNOGENICITY OF ANTIGEN BOUND TO THE PLASMA MEMBRANE OF MACROPHAGES

Macrophages were cultured for several hours after a brief exposure to radio-iodinated keyhole limpet hemocyanin. Most of the hemocyanin taken up by the macrophages was rapidly catabolized and eliminated from the cell. A few molecules were retained on the plasma membrane of the cells for prolonged periods and were not subject to endocytosis and catabolism. These few molecules of hemocyanin bound to the plasma membrane were identified by observing the fixation of antibody fragments to macrophages at low temperature. The membrane-bound antigen, which could be removed by trypsin or EDTA, was of large molecular size, though heterogeneous. A great part of the immune responses of mice to hemocyanin bound to live macrophages could be abrogated by treatment of the macrophages in vitro with antibody or trypsin. Hence, most of the immunogenicity of hemocyanin bound to macrophages was attributed to the few molecules of antigen bound to the plasma membrane

EVENTS AFTER THE BINDING OF ANTIGEN TO LYMPHOCYTES : REMOVAL AND REGENERATION OF THE ANTIGEN RECEPTOR

The behavior of the immunoglobulin antigen receptor on lymphocytes was studied using both fluorescent antiimmunoglobulin antibody to detect B cells and autoradiography with radiolabeled antigens to detect antigen-binding cells. It was shown that after binding of antiimmunoglobulin antibody to the lymphocyte there was a rapid loss of surface immunoglobulin and then a progressive reappearance over 18 h. This could be quantitated using an inhibition assay for surface immunoglobulin. Similarly, after binding various dinitrophenyl-conjugated proteins or keyhole limpet hemocyanin to their specific antigen-binding cells, there was a loss of the antigen receptor from the surface and then a progressive reappearance of the receptor. The reappearance of surface immunoglobulin and of the antigen receptor proceeded at about the same rate. Repeated exposure to antibody or prolonged exposure to antigen did not diminish the capacity of the lymphocyte to re-express its receptor. These events, which follow the interaction of antigen and its receptor, are of possible importance in understanding the mechanism of triggering of the immune response and of tolerance

Type I Interferon Sensitizes Lymphocytes to Apoptosis and Reduces Resistance to Listeria Infection

Infection with Listeria monocytogenes causes lymphocyte apoptosis that is mediated by the actions of the pore-forming virulence factor listeriolysin O (LLO). Previous work showed that activated lymphocytes were highly sensitive to LLO-induced apoptosis, whereas resting lymphocytes were less susceptible. We now show that mice deficient in the type I interferon (IFN) receptor were more resistant to Listeria infection and had less apoptotic lesions than wild-type counterparts. Furthermore, treatment of resting splenic lymphocytes with recombinant IFN-αA enhanced their susceptibility to LLO-induced apoptosis. Together, these data suggest that type I IFN signaling is detrimental to handling of a bacterial pathogen and may enhance the susceptibility of lymphocytes undergoing apoptosis in response to bacterial pore-forming toxins

LIGAND-INDUCED MOVEMENT OF LYMPHOCYTE MEMBRANE MACROMOLECULES : III. RELATIONSHIP BETWEEN THE FORMATION AND FATE OF ANTI-IG-SURFACE IG COMPLEXES AND CELL METABOLISM

Spleen lymphocytes were studied for the movement and interiorization of complexes of anti-Ig-surface Ig. The movement of the complex into a small, compact zone of the cell membrane (forming a cap) was inhibited by drugs that inhibited glycolysis and oxidative phosphorylation, but not by drugs that affected protein synthesis. Dead lymphocytes did not form caps. Freeze-etching techniques revealed that inhibited lymphocytes showed formation of multiple small complexes over the entire cell surface. Inhibitors of glycolysis and of oxidative phosphorylation also inhibited the interiorization and catabolism of radioiodinated anti-Ig. We hypothesize that cross-linking of all the surface Ig triggers the membrane movements that are required to pull the lattice into one zone of the cell