The present review draws attention to the diversity of islet lesions seen in human type 1 and type 2 diabetes. This heterogeneity of islet changes is best demonstrated by immunocytochemistry. In type 1 diabetes the endocrine pancreas is characterized by selective loss of B cells, which most likely results from a slowly acting autoimmune process depending on the presence of both genetic and environmental factors. The process starts years before overt diabetes develops and manifests when the B-cell volume is reduced by about 80%. In type 2 diabetes B cells are always present, regardless of the duration and severity of the disease, but lack any signs of functional activity. This reflects a secretory defect of the B cells which obviously becomes evident under the conditions of obesity, hyperinsulinism and insulin resistance. Obese but non-diabetic subjects show, in parallel to their hyperinsulinism, an increased B cell volume, suggesting that under prediabetic conditions the B cells have still the capacity to respond to increased functional demands by enhanced proliferation. In manifest diabetes the B cells have lost their proliferative potential. Whether this is due to an inherent defect or the consequence of a functional disturbance, is not clear. The development of islet amyloidosis most likely represents an associated functional abnormality of the B cell.
The nephropathy observed in rats after administration of mercuric chloride can be used to clarify the mechanisms underlying renal autoimmunity induced by chemicals. As a necessary preliminary step in the study of this animal model, we have investigated the kinetics and species-specificity of autoimmune responses to renal antigens. By a recently developed enzyme-linked immunosorbent assay (ELISA), circulating autoantibodies to the glomerular basement membrane of the kidney (anti-GBM) have been detected within 8 days after the initiation of mercuric chloride treatment. Anti-GBM antibodies reach a peak by 15 days and then decrease rapidly in the following 2 weeks. Extensive cross-reactions between rat and human GBM antigens have been detected by ELISA, indicating a high degree of conservation of some renal autoantigens and suggesting certain similarities between the autoimmune response induced in rats by mercuric chloride and that observed in human glomerulonephritis caused by anti-GBM. Dose-response studies have been performed to ascertain whether anti-GBM responses are correlated with massive kidney damage and release of renal antigens. We have noted that a wide range of levels of mercuric chloride are capable of stimulating the production of anti-GBM and that animals receiving this chemical in as low a concentration as 0.02 mg/100 g body weight (i.e. a dose ten times lower than those causing massive nephrotoxic effects) still have anti-GBM specifically bound to their kidneys. Thus, it is possible that the administration of mercury compounds to BN rats results in kidney autoimmunity not only because of the release of renal autoantigens, but also through the activation of specific lymphocytes and/or disruption of regulatory networks. Finally, we have observed that both BN and MAXX rats produce anti-GBM after mercuric chloride treatment, while M520 rats do not. Since the MAXX strain was initially obtained from a cross of BN and Lewis rats and shares antigens of the major histocompatibility complex with the BN strain, our findings stress the importance of genetic factors in chemical-induced autoimmunity and suggest that a similar situation may occur in human subjects exposed to environmental chemicals.
The repeated administration of mercuric chloride to BN rats induces the production of anti-GBM. In the present paper, we describe the immunohistopathology and histopathology of the kidneys from mercuricchloride-treated rats. Direct immunofluorescence demonstrated bright linear deposits of immunoglobulins at the level of the GBM of the kidney. Light microscopy failed to reveal substantial glomerular changes, but electron microscopy demonstrated a spectrum of ultrastructural alterations of the glomeruli (including the detachment of endothelial cells from the GBM and the presence of electron-opaque deposits). In the aggregate, these findings are suggestive of membranous glomerulonephritis. We also investigated whether treatment with low doses of PG had any effect on the course of this experimental model of autoimmune renal disease. Two groups of mercuric-chloride-treated BN rats received different doses of DMPGE2. This resulted in significantly lower levels of circulating autoantibodies to the GBM, as well as a decrease in the amounts of rat immunoglobulins bound to the kidneys and an increase in proteinuria. On the other hand, there were no major differences in renal histopathology between rats treated with DMPGE2 and controls.
In considering the pathology associated with infectious diseases, the most common host response to such infection is inflammation. The mechanism(s) whereby inflammation is initiated and the cell types involved will dictate the kinds of acute phase plasma changes that can be seen associated with the infection. Bacteria seem to initiate the classical type of inflammatory response and plasma protein changes similar to those seen in experimental inflammation induced by chemical means. Viruses, on the other hand, in the absence of cytopathology do not appear to induce the same kind of inflammatory changes and avoid the induction of the acute phase protein response since they may not initiate activation of monocytes and/or macrophages. Those viruses that do cause macrophage activation would be expected to have acute phase protein changes associated with that activation. Parasites, however, appear to initiate the acute phase plasma response only when their migration leads to tissue destruction and local inflammation such as caused by parasitemia with Trypanosoma cruzi in the mouse or with migration of Nippostrongylus brasiliensis in the rodent. Human parasitic diseases require much more investigation in order to clarify the role played by acute phase proteins in the subsequent establishment of the host-parasite relationship. We postulate that the macrophage or monocyte on interaction with the infectious pathogen becomes activated and secretes a number of factors, including interleukin 1 and hepatocyte-stimulating factor, which have a marked effect on the total acute phase reaction. In addition to an effect on phagocytic and immune systems, the mediators cause hepatocytes to markedly increase the secretion of plasma acute phase proteins. Some of these proteins return to the site of inflammation and interact with the infectious pathogen and/or cells and proteins of the host, thereby affecting the final outcome of inflammation. We also propose that the initial interaction of an organism such as a parasite and the mammalian host involves early recognition by the macrophage, thereby initiating both the humoral and cellular acute phase reactions and subsequently affects the immune response against the parasite. Variations in the acute phase reaction may help to explain differences in susceptibility to infectious organisms and the presence or lack of host killing mechanisms for the parasite.
It appears then that the F-actin microfilaments and the centrosome and associated microtubules of the endothelial cytoskeleton are important in the repair of endothelial denudation. These dynamic cytoskeletal systems are able to act rapidly and can be regulated by a variety of factors including neighboring cells, extracellular matrix, and soluble factors in the environment. One testable hypothesis is that atherogenic agents which have been shown to enhance atherosclerosis may in fact act by perturbation of the endothelial cytoskeleton resulting in abnormal repair of the endothelial monolayer.
This review has emphasized several recent advances in our understanding of human lymphocyte biology made possible by mAbs that recognize specific functional subpopulations of lymphocytes, coupled with multiparameter flow-cytometric analysis. In the last 3 years, both the T4+ and T8+ subsets of T cells have been further divided according to function and appearance of specific cell surface antigens. In addition, subpopulations of NK cells with different maturation states and B cells with distinct functional abilities have been discovered. Multiparameter flow-cytometric analysis of lymphocyte subpopulations can provide clues to the pathogenetic mechanisms of immune disorders, as has been demonstrated in AIDS patients and children with JRA. The use of multiparameter flow-cytometric analysis to study human immune responses in vitro has enabled a clearer understanding of the complex lymphoid interactions and, as we believe, may play an important role in the analysis of immune-associated disease processes.
Investigations into mechanisms by which macrophages distinguish mature from senescent self cells revealed that a approximately 62,000 Mr glycoprotein, the senescent cell antigen, a terminal differentiation antigen, appears on the surface of senescent and damaged cells. It is recognized by the antigen-binding Fab region of a specific IgG autoantibody in serum which attaches to cells carrying the senescent cell antigen and initiates their removal by macrophages. The senescent cell antigen was first observed on the surface of senescent human erythrocytes, but has since been demonstrated on the surface of lymphocytes, polymorphonuclear leukocytes, platelets, embryonic kidney cells and adult liver cells.
HPVs are associated with a variety of proliferative squamous lesions. 27 different types of HPV have been identified by DNA molecular hybridization studies. Genus- and type-specific HPV structural antigens can be detected in approximately half of benign warts and condylomata by immunocytochemistry; positive lesions are considered infectious. Genus- and type-specific putative HPV DNA sequences replicating as episomes can be recovered from the majority of benign (exophytic and flat condylomata) and malignant squamous lesions of the cervix and anogenital area. The type of HPV determines, in part, the anatomic site, clinical appearance, and natural history (including potential malignant conversion) of the lesion.
A recurrent conclusion of studies on margination and emigration of leucocytes into acute inflammatory lesions has been that these two processes are the result of different stimuli. The recent description of tachyphylaxis of skin lesions to neutrophil chemotaxins is compared with the purported regulation of acute inflammation by deactivation of neutrophils, inactivation of chemotaxins and inhibition of cell migration. It is concluded that tachyphylaxis might regulate the intensity of the peak neutrophil influx whereas chemotaxin inactivators and migration inhibition factors might regulate the subsequent low grade neutrophil influx into lesions. It is suggested that the chemotaxin receptors which manifest tachyphylaxis may be located on endothelial cells of post-capillary venules. The literature indicates that an alteration in endothelium provides a sufficient stimulus for margination to occur. It is emphasised that attention should be directed towards determining the minimal changes in endothelium necessary to permit or induce margination to proceed. Emigration of marginated neutrophils might then occur in response to chemotaxin diffusing to the vessel wall or by locomotion along a gradient of substratum-bound chemotaxin. The selectivity of the leucocyte infiltration of tissues that occurs in some types of inflammation could be exerted by the stimulus for margination or the stimulus for emigration. It is noted that selective margination of lymphocytes occurs in post-capillary venules of lymphoid tissues. The role of a lymphocyte chemotaxin as the stimulus for emigration in this location is unknown. To encompass the known phenomena, a general theory of leucocyte margination and emigration would predict that leucocytes selectively marginate onto acceptor molecules expressed by endothelium and extravasate in response to a chemotactic stimulus. Endothelium-bound chemotaxins may function as acceptor molecules. A bipartisan model of leucocyte migration to extravascular locations is proposed which contends that leucocyte can be recruited non-specifically as inflammatory cells or they can be recruited specifically as effector cells of immune reactions. It is suggested that tachyphylaxis is a characteristic of inflammatory cell recruitment but not of immunologically driven cell recruitment. The binding of chemotaxins to endothelial cells in vivo, the selectivity of margination, the status of margination in desensitised tissues and the role of chemotaxins in lymphocyte recirculation through lymph nodes are identified as critical questions to resolve the mechanisms of leucocyte margination and emigration.
