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N R Rose

Publications and source records attributed to N R Rose.

At least 127 records · Page 7Linked to original sources
PubMed1990

Circulating heart-reactive antibodies in patients with myocarditis or cardiomyopathy.

Heart-reactive antibodies are commonly observed in patients with myocarditis or cardiomyopathy. Such antibodies may be important in the pathogenesis of these disorders, yet the specific antigens recognized have not been studied systematically. This report characterizes circulating heart autoantibodies from patients with myocarditis (n = 17) or idiopathic cardiomyopathy (n = 71) and from healthy volunteers (n = 15). Indirect immunofluorescence demonstrated that high titer (greater than or equal to 1:20) immunoglobulin G (IgG) antibody activity occurred in 59% of the myocarditis samples, 20% of the cardiomyopathy samples and none of the normal samples. All samples were tested by Western immunoblotting for IgG activity against a normal human heart extract. The number of antigens recognized by each sample was enumerated and the molecular weight of each antigen estimated; the prevalence of reactivity against antigens in selected molecular weight classes was determined. There was no difference in the mean number of heart antigens recognized by serum from each group. For most weight classes, prevalence either did not differ significantly among the various groups or subgroups or was greatest among samples from healthy volunteers. Prevalence of reactivity with 190 to 199 kilodalton (kd) antigens was greatest (p less than 0.05) among low titer serum samples from patients with myocarditis. High titer cardiomyopathy serum differed from normal serum by an increased (p less than 0.05) prevalence of antibodies to 40 to 49 and 100 to 109 kd antigens. These results suggest that western immunostaining may ultimately contribute substantively to identifying patients with myocarditis or cardiomyopathy.

Adolescent↗
PubMed1990

Thyroid autoantibodies in black and in white children and adolescents with type 1 diabetes mellitus and their first degree relatives.

Genetic susceptibility is an important issue in understanding the mechanism of the autoimmune endocrinopathies and in assessing the risk of these conditions in pediatric patients. To this end, we evaluated autoantibodies to thyroid antigens, thyroglobulin (TgA) and microsomal antigen (TMA), in white and in American black juvenile patients with Type I diabetes mellitus (DM) to determine the predictive value of thyroid autoantibodies for the development of autoimmune thyroid disease. Sera from 159 patients (77 black and 82 white) with Type I DM were evaluated. A greater number of whites (41/82 or 50%) than blacks (12/72 or 16%) had thyroid autoantibodies (p less than 0.01). Fourteen patients (4 black and 10 white) exhibited hypothyroidism, and all had both TgA and TMA. Three patients (all black) had Graves' disease, one of whom had both TgA and TMA. Families of each racial group that had a diabetic child (proband) with thyroid autoantibodies (seropositive) or without thyroid autoantibodies (seronegative) were assessed for TgA and TMA as well as autoimmune thyroid disease. The prevalence of thyroid autoantibodies among siblings of seropositive probands was significantly greater than among the siblings of seronegative probands (p less than 0.01). The white sibling population showed a closer association of thyroid autoantibody prevalence with increasing age (p less than 0.05) than the blacks. Significantly more parents of probands than control parents exhibited thyroid autoantibodies (p less than 0.01). The general pattern of inheritance of either racial group showed that if one or both parents had thyroid autoantibodies, their progeny developed a significantly higher prevalence of thyroid autoantibodies than those of the seronegative parents. While there was no increase in overt thyroid disease among siblings of seropositive probands, a risk of developing autoimmune thyroid disease is probably imparted to these siblings by virtue of the thyroid autoantibodies.

Adolescent↗
PubMed1990

Mapping the autoepitopes of thyroglobulin.

Chronic thyroiditis is currently the best available model of an organ-restricted autoimmune disease, because the principle antigen Tg is a well-characterized protein and the disease can be reproduced by experimental immunization. The pattern of autoantigenic determinants of Tg that is recognized by sera from subjects without detectable thyroid disease is clearly different from that seen with thyroiditis patients. Both sets of sera react with the evolutionary conserved portions, the hormonogenic regions containing the T3 and T4 moieties. Sera of thyroiditis patients, however, also react with the evolutionary variable, species-specific portions of the Tg molecule. Mice immunized with human Tg respond to the same, immunodominant sites. Mice injected with mouse Tg preferentially recognize the analogous, mouse-specific sites of Tg. Mice are not restricted, however, in their use of V-(D)-J genes for Ig production, even when the same antigenic determinant is involved.

Animals↗
PubMed1989

Pathogenic mechanisms in autoimmune diseases.

Autoimmunity may be initiated by a variety of mechanisms involving changes in autologous antigens or alterations in immune regulation. Autoimmune disease, the pathological consequence of an autoimmune response, depends principally upon the stimulation of helper/inducer T cells reactive with self-antigens. Such T cells direct the quantity and quality of the immune response by influencing the mixture of interleukins produced. Autoantibodies react with accessible cells and mediate injury directly or indirectly. Delayed hypersensitivity reactions indirectly damage tissues through the agency of lymphokines. Cytotoxic T cells penetrate tissue spaces and attack cells bearing requisite surface antigens complexed with the appropriate major histocompatibility complex product. Macrophages and NK cells, activated by lymphokines, have potential to augment tissue damage. These several mechanisms do not operate in isolation; rather, multiple processes act in unison in most autoimmune diseases.

Animals↗
PubMed1988

The induction of antigen-specific thymic regulatory cells in the mouse.

Regulatory T cells are known to play a role in the termination of the immune response. In this investigation, we bring evidence in support of the induction of antigen-specific regulatory cells in the thymus of the mouse. These thymus-derived regulatory cells depend upon injection with a high dose of antigen for their induction, appear in the thymus early after primary immunization (Days 7-12), are H-2- and strain-restricted in their action, and can by themselves suppress directly the secretion of antibodies from syngeneic antibody-forming cells in vitro. These regulatory cells, therefore, differ from previously reported murine suppressor T cells which exert their effect on antibody formation indirectly, generally by acting on helper T cells.

Animals↗
PubMed1988

The induction of organ-specific antibodies during the graft-vs.-host reaction.

During the parent (P) into F1 hybrid graft-vs.-host reaction (GVHR), nuclear, leukocyte and erythrocyte autoantibodies are commonly seen. The specificity of these autoantibodies is reminiscent of those found in systemic lupus erythematosus (SLE) patients and SLE-prone mice. Organ-specific antibodies, however, including thyro-globulin (Tg) antibodies do not arise spontaneously. There have been conflicting reports about the ability of exogenous Tg to induce an anti-Tg response during the GVHR. We have re-examined this question in greater detail. Using the murine P----F1 GVHR system, the results of this work demonstrate that mouse thyroglobulin (MTg)-specific antibodies can be induced during a GVHR. However, mice must both be undergoing a GVHR, and have received exogenous MTg. The highest autoantibody response occurs if mice are injected with mouse thyroid extract or purified MTg at the time of P----F1 cell transfer. The anti-MTg response is MTg dose dependent. The ability to induce anti-MTg antibody was not major histocompatibility complex restricted, for both the DBA/2----B6D2F1 (low responder H-2 haplotypes to MTg), and AKR or DBA/2----AKD2F1 (high/low responder----high responder haplotype) GVHR gave similar responses. The anti-MTg titers peaked between days 7-10 and declined thereafter. In contrast, antibodies to dsDNA were not present at this early time, but developed after several weeks. We conclude that organ-specific autoantibodies can be induced during a GVHR if the appropriate antigen(s) are presented near the time of GVHR induction.

Acute Disease↗
PubMed1988

The initiation and early development of autoimmune diseases.

Our understanding of autoimmunity has changed considerably over the past years as a consequence of the demonstration that self-reactive B cells and T cells are not necessarily deleted from the immunological vocabulary. The critical event in initiating (or avoiding) autoimmune responses is presentation to T cells of the self-peptide-MHC antigen complex. Based on the premise that quantitative aspects are of paramount importance, we suggest that T-cell activity, MHC expression, and self-peptide binding determine the initiation of autoimmune responses.

Animals↗
PubMed1988

Current concepts of autoimmune disease.

Our concepts of autoimmune disease have evolved with our changing understanding of the immune response. In recent years, clonal deletion theories have gradually given way to more dynamic views of the regulation of anti-self immune reactions. It is now clear that self-reactive B cells and some self-reactive T cells persist in the body, and there is every reason to believe that antigen-presenting cells are fully capable of presenting self-antigens in the same manner as foreign antigens. The critical event in the induction of autoimmune disease, therefore, is the quantitative balance of active suppression v the induction of self-reactive help. This help provided a helper T cell response requires that the self-antigens be presented in the context of self-MHC with sufficient affinity and avidity. The antireaction must be potent enough to overcome the totality of suppressive factors, including specific and non-specific suppressor T cells and anti-idiotypic or anti-T-cell-receptor responses.

Antigen-Presenting Cells↗
PubMed1987

Cardiac myosin induces myocarditis in genetically predisposed mice.

After infection with coxsackie virus B3 (CB3), H-2 congenic mice on an A- background develop immunologically mediated myocarditis associated with an increased titer of myosin autoantibody, part of which is specific for the cardiac myosin isoform. The present study demonstrates that cardiac myosin itself induces severe myocarditis and high titers of myosin autoantibodies in A/J, A.SW/SnJ, and A.CA/SnJ mice. As in CB3-induced myocarditis, one population of these autoantibodies was specific for cardiac myosin. A.BY/SnJ and B10.A/SgSnJ mice also developed the disease after immunization, but the prevalence and the myosin autoantibody titers were lower. In contrast, C57BL/6J and C57BL/10J mice were resistant to myocarditis induced by cardiac myosin and did not develop increased myosin autoantibodies or cardiac myosin-specific autoantibodies. Immunization with skeletal muscle myosin had no effect compared with controls injected with complete Freund's adjuvant, thereby suggesting that the immunogenic epitopes are unique to the cardiac myosin isoform. Furthermore, we found that susceptibility to myocarditis induced by cardiac myosin is influenced by the major histocompatibility complex and by genes not closely linked to the major histocompatibility complex. Because there are parallels between myocarditis induced by cardiac myosin and that induced by CB3, this new animal model can be used to analyze the pathologic mechanisms in autoimmune heart disease.

Animals↗
PubMed1987

Autoantibodies specific for the cardiac myosin isoform are found in mice susceptible to Coxsackievirus B3-induced myocarditis.

Several mouse strains are susceptible to immunopathic myocarditis after infection with Coxsackievirus B3 (CB3). This disease is associated with autoantibodies that are directed against myosin. In this study we characterized sera from CB3-infected mice for their reactivity with three different myosin isoforms (heart, skeletal muscle, and brain myosins) and for autoantibody isotype by using an ELISA. Competitive inhibition assays and absorption studies with various myosins demonstrated the presence of two autoantibody populations in sera of susceptible A.CA and A.SW mice. The first was specific for cardiac myosin and was mainly IgG. The second antibody population cross-reacted with heart, skeletal muscle, and brain myosin and was mainly IgM. B10.PL/SgSf and B10.A/SgSf mice, which do not develop immunopathic myocarditis, produced only the IgM autoantibody population cross-reactive with all three myosin isoforms. Because the heart-specific myosin autoantibodies were found exclusively in the mouse strains that developed immunopathic myocarditis, they can be considered a serologic marker for autoimmune heart disease.

Animals↗
PubMed1987

Cardiac myosin and autoimmune myocarditis.

Infection with type 3 of the group B Coxsackieviruses (CB3) sometimes leads to the development of myocarditis in humans. Circumstantial evidence in the form of heart-reactive antibodies in these cases of human myocarditis suggests that the later phases of the disease may be due to autoimmunization. Since human myocarditis is a relatively rare sequel to infection with CB3 virus, we propose that it reflects a genetic predisposition in some individuals. To investigate this possibility we established an experimental murine model of viral myocarditis. By testing a large number of strains of inbred mice infected with CB3 we found that a few strains developed an ongoing myocarditis characterized by diffuse interstitial mononuclear infiltration and by the production of heart-specific IgG autoantibodies. These antibodies reacted with myocardial sarcolemma and myofibrils as well as with muscle striations. The principal myocardial autoantigen, identified by means of postinfectious sera of mice with heart-specific autoantibodies, was found to be the cardiac isoform of myosin. Immunization of susceptible mice with cardiac myosin stimulated the production of heart-specific antibodies reactive with both cardiac muscle striations and sarcolemma, accompanied by mononuclear infiltration of the myocardium. From these results we infer that cardiac myosin is an autoantigen capable of inducing postinfectious myocarditis in genetically predisposed individuals.

Animals↗
PubMed1987

Heart-specific autoantibodies induced by Coxsackievirus B3: identification of heart autoantigens.

Postinfection sera from A.CA/SnJ A.SW/SnJ, B10.S/SgSf, and B10.PL/SgSf mouse strains which varied in their susceptibility to Coxsackievirus B3-induced immunopathology were suspected to contain autoantibodies against cardiac tissue. These sera were used to identify the target myocardial autoantigen(s). Sera pools were made during the peak of the early, virus-induced myocarditis at 5 and 7 days and during the peak of the late, immunopathic phase of myocarditis at Days 15 and 21 after infection. Only the A.CA/SnJ and A.SW/SnJ strains which develop the immunopathic heart disease had heart-specific autoantibodies as determined by indirect immunofluorescence. This panel of sera pools was then tested against solubilized extracts from whole heart and skeletal muscles. Results from Western immunoblotting analyses demonstrated that antibodies to myosin were a prominent feature in the sera of strains which developed immunopathic myocarditis. The immunopathic sera pools were subsequently assayed against low-salt, high-salt, and a number of detergent extracts of heart and skeletal muscle. Anti-myosin was still the most notable reactivity, even though other autoantigens were detected. Absorption with cardiac myosin removed the vast majority of heart reactivity from the pooled sera derived from the A.CA/SnJ and A.SW/SnJ strains as determined within the limitations of the immunofluorescent and immunochemical assays. Both sarcolemmal and A-band staining patterns were abolished by the cardiac myosin absorption. These studies suggest that myosin is one of the major autoantigens in Coxsackievirus B3-induced autoimmune myocarditis.

Animals↗
PubMed1987

Coxsackievirus B3 murine myocarditis: a pathologic spectrum of myocarditis in genetically defined inbred strains.

Group B coxsackieviruses are the most frequent causative agents in human viral myocarditis. Susceptibility to viral infections varies widely among individuals. In the mouse, coxsackievirus B3 also causes myocarditis. The differential susceptibility of different inbred strains of mice to coxsackie B3-induced myocarditis also appears to be under genetic control. This study details the histopathology of coxsackie B3 myocarditis in six different inbred strains of mice for the first 45 days after coxsackie B3 infection. These strains differ either in the haplotypes of their major histocompatibility complex or in their background genome. During the first 7 days after coxsackie B3 infection, there are dramatic differences among strains with respect to prevalence and severity of myocarditis. Focal zones of myocyte necrosis involving polymorphonuclear leukocytes as well as contraction band injury appear to be the early manifestations of direct viral injury. Four of the six strains, though, continue to show myocardial inflammation after day 9. This late phase myocarditis is characterized by the emergence of mononuclear cells within healing foci of myocyte necrosis as well as a distinctive diffuse interstitial pattern of myocarditis. The strains that develop this late ongoing myocardial inflammation frequently produce heart-specific autoantibodies. Thus the pathologic features of murine coxsackie B3 myocarditis change over the course of the illness, and genetic susceptibility to both early and late phase myocarditis differs markedly among various mouse strains.

Animals↗
PubMed1987

Natural killer cell activity of prostatic cancer patients.

Natural killer (NK) cell activity of prostatic cancer patients was compared with that of control groups by the radioactive indium (111In) release assay using the K562 and H494 cells as targets. Patients suffering from advanced prostatic cancer (clinical stages C and D) exhibited significantly lower NK activity against K562 cells (28 +/- 18%) than did the normal group (41 +/- 19%). The lower NK activity of these patients is not related to their age, since patients in the same age range with localized cancer (stage B) or benign prostatic hyperplasia did not show low NK activity (37% +/- 19%). This lower NK activity is not due to a depletion of the NK cell precursor population, since the NK activity of advanced cancer patients improves significantly after in vitro incubation with interferon. The NK activity of normal subjects or patient groups showed wide fluctuations during the 18-month observation period. Because of these interassay variations, it is necessary to use standard control subjects during long-term monitoring of the NK activity of the patients.

Age Factors↗