Cellular Autoimmunity Research Articles

Intractable vasculitis, resorptive osteolysis, and immunity to type i collagen in type viii ehlers‐danlos syndrome

A unique patient with type VIII Ehlers-Danlos syndrome and cutaneous vasculitis, resorptive osteolysis, and cardiac valvular disease is described. Collagen analyses identified morphologic and physical abnormalities of type I collagen. The patient's T lymphocytes could be propagated in vitro with type I collagen and produced a 60-kd lymphokine that bound this protein. Cellular autoimmunity to type I collagen may be responsible for this patient's intractable clinical condition.

Initial role of macrophage in the development of anti-β-cell cellular autoimmunity in multiple low-dose streptozotocin-induced diabetes in mice

Multiple injections of low doses of streptozotocin to susceptible strains of mice produce an experimental autoimmune diabetes mellitus. To investigate the possible initial role of macrophages in the development of insulitis, we studied the effect of macrophage-toxic silica administration on the development of in vitro cellular cytotoxic immune response against pancreatic β-cells. Multiple streptozotocin-treated mice developed hyperglycemia at day 12 and their splenocytes showed cytotoxicity against cultured rat insulinoma cells. Mice given silica and streptozotocin together remained normoglycemic and their splenocytes showed no cytotoxicity. In contrast, in vitro depletion of macrophages from the splenocytes of mice given multiple streptozotocin alone did not abolish the cytotoxicity. These reslts show that macrophages themselves contribute little to the cellular cytotoxicity, but are necessary for the development of cytotoxic cells. From these results we suggest that there are at least two different steps in the development of insulitis; the presentation of β-cell autoantigen by macrophages to helper-T cells, followed by the development of β-cell-specific cytotoxic cells.

A new view of the beta cell as an antigen-presenting cell and immunogenic target

Cellular autoimmunity is thought to be primarily responsible for the selective destruction of islet beta cells in Type I diabetes. Why the T lymphocyte reacts to self and recognizes the beta cell as foreign, as against the other endocrine islet cells, is unknown. One key issue is whether the beta cell itself is capable of presenting autoantigen(s) and thereby breaking T lymphocyte tolerance. In this paper we discuss current concepts of antigen presentation and relate these to recent findings from our laboratory, suggesting that the beta cell can be induced to display many of the phenotypic properties of classical antigen-presenting cells, including induction of MHC and ICAM-1 expression and production of IL-6. Finally, a model is presented which provides a new view of the initiation and perpetuation of autoimmune beta-cell destruction in Type I diabetes.

Immunopathogenesis and Immunotherapy of Type 1 Diabetes

Research in recent years has elucidated more clearly the genetic and immunopathogenic basis as well as the natural history of Type 1 diabetes mellitus. The development of Type 1 diabetes can be conceptually divided into stages, beginning in part with a human leukocyte antigen (HLA)-restricted genetic susceptibility. In some genetically susceptible subjects, a triggering event activates both cellular and humoral autoimmunity. Glucose-stimulated insulin secretion and beta cell mass diminish as anti-islet autoimmunity progresses. This process culminates in overt diabetes when only residual beta cell mass (estimated to be less than 10%) remains. Complete beta cell destruction follows within months to years of diagnosis. Most attempts at interrupting beta cell destruction have taken the form of broad immunosuppressive therapy begun at diagnosis when beta cell destruction is nearly complete. Greater understanding of early immune mediators and refinement of techniques to identify subjects at risk for Type 1 diabetes have set the stage for more specific immunomodulation targeted earlier in the course of the disease. We will review these recent advances in understanding the immunopathogenesis of Type 1 diabetes as they pertain to current and future trials of immunotherapy.

The neurobiology of human immunodeficiency virus infections.

A variety of diseases of the central and peripheral nervous systems evolves during the course of human immunodeficiency virus (HIV) infections. Most are not related to documented opportunistic infections and may be the direct result of HIV infections, as large proportions of healthy and ill HIV-infected persons show evidence of nervous system infection. These diseases occur at different times during the infection and have diverse inflammatory, demyelinating, or degenerative pathological features that suggest different pathogenetic mechanisms. The route and determinants of HIV invasion of the nervous system are unknown. Within the brain, viral antigen and RNA are found predominantly in macrophages, but the reason why profound dementia and cortical atrophy result from this infection remains a mystery. By analogy to other lentivirus infections, particularly visna virus in sheep, neuropathological changes may be mediated by cytokines. Other possible pathogenetic mechanisms include toxicity of viral polypeptides, transactivation of viral or cellular genes, autoimmunity, or other opportunistic infections. Clarification of the pathogenesis of HIV-related diseases is critical to the design of rational therapies.

Cellular autoimmunity in psoriasis and lichen planus

The objective of this investigation was to determine whether specific cellular recognition of the epidermis is associated with the human skin diseases, psoriasis and lichen planus. Epidermal cells (EC) obtained from biopsies of involved and uninvolved skin of patients with these diseases were used as stimulators and targets for autologous peripheral blood mononuclear cells (PBMC) in assays of three conventional manifestations of cellular immunity: lymphocyte transformation, leukocyte migration-inhibition and cell-mediated cytotoxicity. Parallel tests were conducted with autologous PBMC as stimulators to ascertain the tissue specificity of the reactions evoked by autologous EC. Similar assays were conducted with EC and PBMC from a large group of normal subjects, and the results were compared to those of the dermatology patients by rigorous statistical analyses. No evidence of lymphocyte-mediated cytotoxicity towards autologous EC was obtained with any of the subject groups, but autologous EC, and to a lesser extent PBMC, of the psoriasis patients, but not of the other two groups, evoked significant lymphocyte transformation. These results were obtained only with patients on Goeckerman therapy, raising the possibility that they were a manifestation of the treatment (topical coal-tar and ultraviolet light irradiation) rather than of the disease, although reasons are presented why this is unlikely. Clearer evidence of disease-associated autoimmunity was obtained in the leukocyte migration-inhibition assays, where autologous EC, and to a lesser extent, PBMC, of the psoriasis patients in general, not just those on Goeckerman therapy, and not those of the lichen planus patients or of the normal subjects, stimulated the release of a leukocyte migration-inhibition factor. These results support the concept of a central role for T-cell mediated autoimmunity in the pathogenesis of psoriasis.

Current molecular approaches to experimental thyroid autoimmunity.

Autoimmune thyroiditis is characterized by mononuclear cell infiltration of the thyroid gland, with accompanying tissue damage, and associated cellular and humoral autoimmunity to thyroid antigens such as thyroglobulin (Tg) and microsomal antigen (for reviews see Bigazzi and Rose, 1985; Rose et al., 1981; Weetman and McGregor, 1984; Weigle, 1980; Wick et al., 1985). Since the seminal studies by Rose and Witebsky (1956) demonstrating the experimental induction of autoimmune thyroiditis, animal models have been used extensively, both in the search for clues to the etiology of human autoimmune thyroiditis and to investigate basic mechanisms in the regulation of autoimmunity. Thyroid autoimmunity arises spontaneously in a number of species (Bigazzi and Rose, 1975), but most work has concentrated on the obese strain chicken (Wick et al., 1982, 1985), buffalo rats (Bigazzi and Rose, 1975), and the diabetes-prone BB/W rat (Sternthal et al., 1981). Thyroiditis may also be induced experimentally in many species by injecting Tg and an appropriate adjuvant (Weigle, 1980). A different model of thyroiditis can be induced in rats by a combination of thymectomy and irradiation (Penhaie et al., 1973, 1975). Studies of these various models have provided valuable information regarding the mechanisms involved in thyroid autoimmunity. More recently, we and others have begun to use a variety of in vitro techniques to gain insight into the molecular basis of thyroid autoimmunity.

Exercise induced augmentation of cellular and humoral autoimmunity associated with increased cardiac dilatation in experimental autoimmune myocarditis.

To determine the effects of exercise in experimental autoimmune myocarditis, guinea pigs immunised with heterologous heart protein (rat heart), Freund's complete adjuvant, and pertussis vaccine (treated group) were exercised on a treadmill for a total of 11 weeks and compared with non-exercise treated animals. In vivo heart rates and pressures, in vitro left ventricular pressure-volume relations, myocardial histology, circulating antiheart antibody, and in vitro lymphocyte stimulation were determined. Exercise resulted in increased cardiac dilatation in treated animals as assessed by in vitro left ventricular pressure-volume relations compared with non-exercise treated animals (at 8 mmHg 1.41(0.17) ml.kg-1 vs 1.20(0.17) ml.kg-1 respectively, p less than 0.005). Exercise also resulted in increased concentrations of circulating antiheart antibody as assessed by radioimmunoassay (0.14(0.04) microgram vs 0.10(0.03) microgram respectively, p = 0.01), and increased lymphocyte activation to specific antigen (stimulation index 3.7(0.07) vs 2.4(1.0) respectively, p less than 0.001). Despite the associated augmentation of autoimmunity with cardiac dilatation, there were no differences in the histopathological findings between the exercised treated and the non-exercised treated animals either qualitatively or quantitatively (number of inflammatory cell microaggregates). This finding suggests that, although the immune system is important in experimental autoimmune myocarditis, the amount of inflammation and necrosis does not appear to correlate with the degree of left ventricular dilatation and presumed dysfunction.

Immunoregulatory T-lymphocyte subset deficiency in newly diagnosed type 1 (insulin-dependent) diabetes mellitus.

Humoral and cell-mediated disorders in Type 1 (insulin-dependent) diabetes suggest that an imbalance of immunoregulatory T-cell subsets exists. In 23 newly diagnosed (onset less than 3 months) and 21 long-standing Type 1 diabetic patients, T lymphocyte subsets were analyzed using monoclonal antibodies (OKT3, OKT4, OKT8, OKM1). The newly diagnosed patients showed a reduction with a significant difference from healthy controls in total T cells (OKT3+: 58.1 +/- 8.5% versus 70.7 +/- 8.0%), helper/inducer cells (OKT4+: 33.8 +/- 7.0% versus 47.1 +/- 8.3%), suppressor/cytotoxic cells (OKT8+: 18.5 +/- 7.3% versus 32 +/- 6.8%) and monocytes (OKM1+: 11.5 +/- 3.8% versus 19.9 +/- 5.2%) (p less than 0.001). The long-standing diabetic patients also revealed a low number of immunoregulatory T cells compared with control subjects, although to a lesser extent (p less than 0.01-0.05). The helper/suppressor ratio (OKT4+/OKT8+) was higher in newly diagnosed patients than in control subjects (2.2 +/- 1.3 versus 1.5 +/- 0.3; p less than 0.02). When compared with 95% tolerance limits in the control subjects, the reduction of OKT8+ cells in the newly diagnosed diabetic patients appeared more marked: the mean (18.5%) coincided with the lower limit of normal subjects (18.3%). Ten of the newly diagnosed Type 1 diabetic patients had a value below the normal lower limit. Out data point to the occurrence of different immunoregulatory abnormalities in newly diagnosed Type 1 diabetic patients, especially in OKT8+ and OKT4+ cells. The imbalance in T lymphocyte subsets is further proof of the role of cellular autoimmunity in the pathogenesis of the early phases of Type 1 diabetes.

The Use of Immunologic Mutations as Probes of Cellular Interactions and Autoimmunity in New Zealand Mice

The Use of Immunologic Mutations as Probes of Cellular Interactions and Autoimmunity in New Zealand Mice

Tamm-horsfall protein: structure and biological properties

Tamm-Horsfall protein (THP), which is a prominent component of urinary casts, is a glycoprotein with a molecular weight of 7×10⁶ composed of subunits of 10⁵ daltons and contains approximately 23% carbohydrate. Electron microscopic studies after adsorption with horseradish peroxidase reveal a zig-zag pattern of periodicity 21 nm, and a flattened helical structure is proposed. Biologically some THP preparations stimulate cell division in normal human lymphocytes. Recent work suggests this may reflect the presence of glucose in stimulatory preparations. This mitogenic property must be taken into account in evaluating cellular autoimmunity against THP in patients with renal disease. As THP is secreted by cells in the ascending limb of the loop of Henle and distal convoluted tubule, its detection in Bowman's space may prove to be a useful sign of intrarenal urinary reflux.

Spleen Cell Cytotoxicity in New Zealand Black Mice (NZB) with Autoimmune Disease

Abstract New Zealand black mice (NZB)2 develop disease spontaneously which is similar in many ways to human systemic lupus erythematosis (SLE) and is characterized by autoantibodies, nephritis, (1, 2) and perivascular cellular infiltration. These mice have also shown a decreased capacity with ageing to reject tumors induced by Moloney sarcoma virus (3). Cantor and co-workers (4) have demonstrated that the capacity of spleen cells from NZB mice to mount a graft-vs-host reaction also decreases with age. Both of these observations indicate reduced efficacy of the thymus-dependent immune system or thymus-dependent lymphocytes (T cells), but do not show whether programmed T cells are responsible for some of the cellular autoimmunity in this disease. We have investigated the ability of spleen cells from diseased NZB mice to elicit a cytotoxic effect against fetal target cells, in vitro, by a modified form of the colony inhibition, or lymphocyte cytotoxicity system (5, 6).

Thyroid, gastric and adrenal auto-immunity in diabetes mellitus.

ABSTRACT The clinical association between diabetes mellitus and auto-immune diseases of the thyroid, the adrenals and the gastric mucosa occurs more frequently than could be expected by chance. Sera from 133 patients with diabetes mellitus and 128 controls were therefore investigated for the presence of organ-specific auto-antibodies. Thyroid microsomal antibody and gastric-parietal-cell antibody were demonstrated with significantly increased frequency – 20% and 16% respectively – in sera from patients with diabetes mellitus. Antibodies reacting specifically with tissue components of the endocrine pancreas could not be demonstrated. From the data presented and from a review of the literature it is concluded that evidence is accumulating pointing to a disorder of the immunological system in patients with diabetes mellitus with regard to the formation of organ-specific humoral and cellular auto-immunity, and the occurrence of organ-specific auto-immune diseases.

Chronic Lymphocytic Leukemia—an Accumulative Disease of Immunologically Incompetent Lymphocytes

Abstract Chronic lymphocytic leukemia, far from being simply a very chronic, very dull disease, has many facets which may help to illuminate the pathogenesis of a variety of immunologic aberrations. It appears likely that this is an accumulative disease of lymphocytes rather than one which is due to rapid proliferation, as was originally thought. The abnormal lymphocytes of the disease—with their various indications of metabolic but, more particularly, immunologic incompetency and their reduced ability to transform with both PNA and antigenic stimulation—eventually accumulate in large masses throughout the body. In the course of time, a host of disorders develop, including reduced immunity of both humoral and cellular varieties, autoimmunity, and extreme reactions to viruses and insects, numerous infections and wasting, finally leading to death. A striking response to corticosteroids is characteristic of the disease. On the other hand, large doses of x-ray or alkylating agents may result in violent and often fatal autoimmune reactions. Many future studies are indicated to demonstrate the nature of the metabolic defect in the lymphocyte and its pathogenesis, whether genetic or on some other basis. The possibility of modifying the tendency of the abnormal lymphocyte to accumulate, perhaps with the judicious use of corticosteroids, in association with other methods deserves intensive study.