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Biomedical subjects

N R Rose

Publications and source records attributed to N R Rose.

At least 145 records · Page 8Linked to original sources
PubMed1987

Coxsackievirus induced myocarditis in mice: cardiac myosin autoantibodies do not cross-react with the virus.

After infection with Coxsackievirus B3 (CB3), H-2 congenic strains of mice on an A-background develop an immunologically mediated myocarditis associated with autoantibodies directed mainly against cardiac myosin. We tested these autoantibodies for cross-reactivity with the virus. Using immunoblotting and virus neutralizing assays with affinity purified antibodies and absorbed sera, we found that the autoantibodies to heart myosin did not cross react with CB3. In addition, myosin autoantibodies induced by immunization with cardiac myosin did not react with the virus. Western immunoblotting revealed that the anti-CB3 antibodies in the infected mice are directed against the capsid protein VP 2. We conclude that CB3 antigens do not stimulate an immune response that cross-reacts with cardiac myosin.

Animals↗
PubMed1986

Variations in the susceptibility to Coxsackievirus B3-induced myocarditis among different strains of mice.

This study was undertaken to examine the inherent predisposition of different inbred strains of mice to develop Coxsackievirus B3-induced myocarditis. A time course study established the pertinent, differential parameters of the disease and their corresponding genetic control. The A.BY/SnJ (H-2b), A.SW/SnJ (H-2s), A.CA/SnJ (H-2f), B10.S/SgSf (H-2s), B10.PL/SgSf (H-2u), and C3H.NB/SnJ (H-2p) strains were found to vary widely in the extent and duration of viremia, in the temporal appearance and titer of neutralizing antibody, and in the prevalence, severity, and duration of myocardial disease. The A.BY/SnJ (H-2b), A.SW/SnJ (H-2s), A.CA/SnJ (H-2f), and C3H.NB/SnJ (H-2p) mice developed continuing, chronic myocardial disease, whereas B10.S/SgSf (H-2s) and B10.PL/SgSf (H-2u) did not. The four strains that displayed prolonged myocarditis also produced heart-specific myocardial autoantibodies. Heart-specific autoantibodies were not found in the B10.S/SgSf and B10.PL/SgSf animals. Differences in prevalence and titer of these heart-specific autoantibodies were noted among the three A strain H-2 congenic lines. The influence of the major histocompatibility complex (MHC) on disease production was demonstrated by comparison of the three A strain and two B10 strain H-2 congenics. Differences between A.SW/SnJ (H-2s) and B10.S/SgSf (H-2s) suggested non-MHC control of disease. These studies additionally indicate that the genetic regulation of susceptibility to CB3 infection and the direct virus-induced inflammation differ from the later immunopathic myocarditis.

Animals↗
PubMed1986

Cell-mediated immunity in autoimmune thyroid disease.

The initiation of an autoimmune response requires the establishment of an appropriate microenvironment. This, in turn, involves several requirements, including antigen expression on the membrane surface of the target cells, class II antigen expression on the antigen-presenting cell or target cell, a relative systemic or local increase in the helper/inducer subset of T cells, and/or a relative decrease in the suppressor subset of T cells. All of these conditions have been described in the thyroid gland. Appropriate cellular interactions result in the appearance of activated T cells and the generation of cytotoxic T cells. The pathologic alterations may be produced by the local production of antibody and subsequent formation of immune complexes, by direct lymphocyte damage, or by lymphokine production. Autoimmune thyroid disease remains, to our minds, the most instructive paradigm of the organ-specific autoimmune endocrinopathies.

Animals↗
PubMed1985

Heart-specific autoantibodies following murine coxsackievirus B3 myocarditis.

The sera from A.SW/SnJ mice infected with Coxsackievirus B3 (CB3) were tested on normal mouse tissue by indirect immunofluorescence. Heart-reactive antibodies were found. Absorption studies with organ extracts showed some of these autoantibodies to be heart-specific. Additional antibodies were crossreactive with skeletal muscle and kidney. These findings suggest a role for autoimmunity in the pathogenesis of murine CB3-induced myocarditis. This study establishes an animal model for the study of the humoral autoimmune response in human viral myocarditis.

Absorption↗
PubMed1985

Effects of natural or synthetic microbial adjuvants on induction of autoimmune thyroiditis.

Natural and synthetic adjuvants of microbial origin were compared for their capacity to potentiate the induction of experimental autoimmune thyroiditis (EAT) with the autoantigen mouse thyroglobulin (MTg). Regardless of the immunomodulator used, severe thyroiditis was observed only in EAT-susceptible strains of the k haplotype and not in EAT-resistant strains of the d haplotype. Compared to phenol-extracted lipopolysaccharide, a potent adjuvant for enhancing EAT induction, phthalyl-substituted, detoxified lipopolysaccharide, even at doses 15- to 50-fold greater, led to only low anti-mouse thyroglobulin titers and mild thyroid infiltration. The synthetic adjuvant N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and three of its analogs, N-acetylmuramyl-L-alanyl-D-isoglutamine-L-alanyl-D-glycerol mycolate (MDP-L-Ala-Glyc-Myc), N-acetylmuramyl-L-alanyl-D-glutamyl-(decyl)methyl ester [MDP(decyl)methyl], and N-acetylmuramyl-L-alanyl-D-glutamine-alpha n-butyl ester [MDP-(Gln)-OnBu], designated murabutide, were tested in incomplete Freund adjuvant or in saline. In incomplete Freund adjuvant, MDP-L-Ala-Glyc-Myc was inefficient in inducing EAT, murabutide induced very mild involvement, and MDP and, more so, MDP(decyl)methyl were active but to a lesser degree than CFA. When saline was used, low levels of thyroid infiltration were observed in a few of the MDP-treated animals in only one experiment, whereas no lesions were observed when murabutide was used.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

The genetics of thyroiditis as a prototype of human autoimmune disease.

The predisposition to autoimmune disease has been termed an autoimmune diathesis. The genetic basis for this predisposition has been analyzed, using three different models: juvenile thyroiditis in humans, spontaneous thyroiditis in chickens, and experimental thyroiditis in mice. At least three different categories of genetic factors contribute to the development of autoimmunity. They include an increased immune response due to immunoregulatory genes associated with the major histocompatibility complex, the balance of thymus-derived lymphocyte population with helper/inducer vs suppressor properties, and intrinsic metabolic abnormalities of the target thyroid cells.

Adolescent↗
PubMed1984

AT-1.1: a thymus-specific alloantigen of chickens.

A thymocyte-specific alloantigen, designated AT (avian thymus)-1.1, has been detected in Cornell C strain (CS) and Obese strain (OS) chickens, the latter being a strain derived from CS which develops a spontaneous form of autoimmune thyroiditis (SAT). Antisera specific for this antigen were developed first in a turkey immunized with thymocytes from an OS chicken and, later, in AT-1.1-negative CS chickens immunized with AT-1.1-positive thymocytes. AT-1.1 was detected in 50-70% of cells in a thymus cell suspension, but was not seen on peripheral blood lymphocytes, erythrocytes, or cells from bursa, spleen, kidney, liver, or brain. It was present on thymocytes of chickens at all ages tested, from 1 day to 6 months of age. AT-1.1 was not detected in six chicken lymphoid tumor cell lines tested, and birds expressing it were found to be negative for the presence of Marek's disease viral antigens. Pedigree studies on 287 (OS X CS)F2 chickens demonstrated that AT-1.1 is expressed in a dominant or codominant manner, and the gene coding for this antigen was not linked to the beta (major histocompatibility) complex. The genetics and tissue distributions of AT-1.1 indicate that it differs from thymus cell surface antigens, avian or mammalian, previously described.

Animals↗
PubMed1984

T-cell subsets in the thyroids of mice developing autoimmune thyroiditis.

To examine the role of T-cell subsets in the development of thyroid lesions, female CBA/J mice were immunized with 60 micrograms mouse thyroglobulin (MTg) in 0.1 ml complete Freund's adjuvant in both hind footpads. The thyroids were removed 12-21 days later, pooled, and dispersed. The cell suspension was examined by membrane immunofluorescence for the distribution of Thy-1+, Lyt-1+, Lyt-2+, and sIg+ lymphocytes. For comparison, peripheral blood leukocytes (PBL) from the same animals were similarly examined. Throughout this 10-day interval, B cells in the thyroid were consistently below 5%, whereas B cells represented 19-24% of PBL. Thy-1+ cells in PBL ranged from 45 to 59%, whereas Thy-1+ cells in the thyroid were 37-50%. However, only thyroidal T cells showed a consistent decline with time and were replaced gradually by cells without T or B cell markers. In particular, there was a clear shift in the Lyt-1+:Lyt-2+ ratio from about 7 down to 2 in the thyroid as the early predominance of Lyt-1+ cells was followed by a relative increase in Lyt-2+ cells. Our results show that there is an accumulation of Lyt-1+ and Lyt-2+ cells in the infiltrated thyroid. These cells may include MTg-reactive, helper, and cytotoxic T cells which localize (or differentiate) in the thyroid and initiate the lesions.

Animals↗
PubMed1984

Genetics of carbon tetrachloride-induced liver injury in mice. II. Multigenic regulation.

Mice from many different congenic inbred strains were given an intramuscular injection of carbon tetrachloride (CCl4) in olive oil to determine the genetic influences on induction of, and recovery from, liver damage. Liver and blood samples were taken at days 1, 4 and 7. The degree of necrosis and lymphoid infiltration appeared to be controlled, qualitatively and quantitatively, by both H-2-linked and Ah-linked genes. Strain differences were noted in the patterns of hepatocellular necrosis and the proportions of lymphoid, monocytic and other inflammatory cells which characterized the infiltrating population. Kinetic studies of F1 hybrids from matings between the susceptible BALB/cJ male parent and the resistant SJL/J female parent suggested that two dominant genetic influences play a major role in CCl4-induced liver damage. The gene contributed from the BALB/cJ parent affects the extent of liver necrosis and a second gene from SJL/J augments recovery. These results suggest, therefore, that the CCl4-induced liver damage and subsequent recovery are under multigenic control by H-2, Ah and possibly other genes.

Animals↗
PubMed1984

Injection of mouse thyroglobulin and/or adult thymectomy do not break tolerance to thyroglobulin during the lupus like graft versus host disease in mice.

In a previous paper (Gleichmann, van Elven & van der Veen, 1982), it had been reported that, in contrast to lupus like autoantibodies such as anti-DNA, autoantibodies to mouse thyroglobulin (MTg) were not detectable in serum of F1 mice suffering from a lupus like graft versus host disease (GVHD) (GVH F1). In the present paper, possible explanations for this restricted autoantibody formation during the potent allogeneic stimulation were investigated. The main question was whether the natural level of circulating MTg was too low to induce the formation of anti-MTg antibodies in GVH F1 mice. Existence, in the F1 mice studied, of B cells capable of producing anti-MTg antibodies was demonstrated by injection of lipopolysaccharide (LPS) and exogeneous MTg. However, MTg injected into various F1 mice at the onset of the GVH reaction (GVHR) failed to overcome the lack of antibody formation to MTg even though the GVHR led to a severe lupus like disease. Furthermore, adult thymectomy (ATx) of either the recipients, the donors, or both also did not break tolerance to MTg during the GVHR, irrespective of administration of exogeneous MTg. Thus, neither intravenous injection of MTg nor ATx, designed to remove T suppressor (TS) cells, is adequate to enable an autoantibody response to MTg during lupus like GVHD. Hence, the non-specific T cell help that causes lupus like GVHD seems to be intrinsically insufficient to trigger the Tg reactive B cells. We suggest that globular proteins, such as Tg, require specific T cell help. In the presence of only non-specific T help, self-antigens such as DNA seem to be more apt than globular proteins to provide an effective signal 1 to the corresponding autoreactive B cells.

Animals↗
PubMed1983

Experimental autoimmune thyroiditis. In vitro cytotoxic effects of T lymphocytes on thyroid monolayers.

Effector mechanisms in experimental autoimmune thyroiditis (EAT) were studied in vitro by establishing a cytotoxicity system with thyroid target cells. Lymph node cells (LNC) from popliteal and inguinal lymph nodes were obtained from CBA/J mice (8-10 wk old) 12-18 d after immunization with 120 micrograms mouse thyroglobulin (MTg) in complete Freund's adjuvant (0.2 ml to both hind footpads and thighs) and were cultured with MTg (10-50 micrograms/ml). On day 5 of culture, viable LNC were added to labeled thyroid monolayers and their cytoxicity was assayed after 16 h. Functional thyroid target cells, as reflected by MTg production for up to 9 d, were prepared by adding 1 mM dibutyryl adenosine 3',5'-cyclic monophosphate and 60 microU thyroid-stimulating hormone/ml to the culture medium. On days 5-7, confluent monolayers were labeled with 111In and used as targets. Specific 111In-release ranged from 56 to 85%. The cytotoxic response is MTg specific and H-2 restricted. Pretreatment of thyroid target cells with rabbit antiserum to MTg completely inhibited cytotoxicity. Pretreatment with mouse antiserum to either Kk or Dk products resulted in approximately 50% inhibition, whereas the combined use of both antisera led to total inhibition. No cytotoxicity was observed when control BALB/c thyroid cultures were the target cells. The kinetics of the expansion of Thy-1+ cytotoxic cells by in vitro exposure to MTg were then studied. The cytotoxic response required 5 d to develop and was abolished by treating LNC on day 4 with monoclonal antibody to Lyt-1.1, but not to Lyt-2.1, plus complement. In contrast, by day 5, cytotoxicity was abrogated by similar treatment with antiserum to Lyt-2.1, but not to Lyt-1.1. We conclude that cytotoxic cells derived from MTg-immunized mice are Lyt-2-bearing cells but require the presence of Lyt-1-bearing cells for their generation and/or differentiation.

Animals↗
PubMed1983

The decreased growth rate of obese strain chicken thyroid cells provides in vitro evidence for a primary target organ abnormality in chickens susceptible to autoimmune thyroiditis.

The obese (OS) strain of chickens develops severe autoimmune thyroiditis, whereas its progenitor, the Cornell (CS) strain, rarely does. To detect possible developmental abnormalities in the OS thyroid, CS and OS embryonic thyroid epithelia were cultured in vitro and compared in several assays for growth and DNA metabolism. It was found that OS thyroid cells incorporated less tritiated thymidine, reached lower saturation densities, and possessed a significantly longer doubling time (26.1 hr) than CS cells (17.6 hr). The decreased growth rate of OS thyroid cells correlated with their inability to condition their own media. These abnormalities in the embryonic development of OS thyroid cells were discussed in the context of factors predisposing to autoimmune thyroiditis.

Animals↗
PubMed1983

Comparison of cultures of human lymphocytes obtained following NH4Cl induced red blood cell lysis and Ficoll-Hypaque density gradient centrifugation.

Lymphocyte thymidine uptake in leucocytes prepared by NH4Cl induced RBC lysis was compared with that of lymphocytes obtained following Ficoll-Hypaque centrifugation using polynomial regression dose response curves which adjusted for inherent subject variability. Eleven male subjects were studied. Heparinized blood was either layered in Ficoll-Hypaque or treated with 0.87% NH4Cl to induce RBC lysis. Phytohemagglutinin-P (PHA) dose response curves were determined for each subject using triplicate 5 day cultures. For each subject, at each Pha concentration ranging from 12.5 to 167micrograms/ml, triplicate mean cpm of Ficoll-Hypaque treated lymphocytes and NH4Cl treated lymphocytes were compared by the 2 tailed Student's T test. Responses of cultures of NH4Cl treated lymphocytes were significantly different (less than 0.05) from the responses of cultures of Ficoll-Hypaque treated lymphocytes for at least 2 PHA doses in 8 of the 11 subjects. The quadratic dose response curves were also significantly different (p less than 0.05) for 9 of the 11 subjects. A repeated measures quadratic regression was used to determine the best fit dose response curves for each of the experimental conditions. For Ficoll-Hypaque treated lymphocytes, mean cmp=44,977+1400.4 (PHA concentration)-5.90 (PHA concentration)2+ subject effect; s.e.=22,256; for NH4Cl treated lymphocytes, mean cpm=58,039+1022.8(Pha concentration)-5.32 (PHA concentration)2+ subject effect; s.e.=37,966. The p values from the F tests for significance of these quadratic regressions are different, F=1.91, d.f.=30,30; p less than 0.001. The lack of significance of the NH4Cl treated lymphocytes' does response quadratic regression and its larger s.e. indicates that the NH4Cl treated lymphocyte culture dose response curve is less predictable than that of Ficoll-Hypaque treated lymphocytes.

Ammonium Chloride↗