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K W Beisel

Publications and source records attributed to K W Beisel.

At least 55 records · Page 3Linked to original sources
PubMed1991

Susceptibility to Coxsackievirus B3-induced chronic myocarditis maps near the murine Tcr alpha and Myhc alpha loci on chromosome 14.

This study was undertaken to determine the genetic control of host susceptibility to coxsackievirus B3 (CVB3)-induced chronic myocarditis in a mouse model. An autosomal recessive autoimmune myocardial disease (amd) gene (possibly more than one gene), which determined susceptibility to CVB3-induced chronic myocarditis in the A/J and DBA/2J inbred mouse strains, was mapped to a segment of chromosome 14. Data from both the AXB/BXA recombinant inbred (RI) strains and the B10.D2(57N) H-8b congenic mice supported this linkage relationship. Analysis of the AXB/BXA RI strain distribution patterns suggested that amd maps distal to the Np-2, Tcr alpha, and Myhc alpha loci.

Animals↗
PubMed1990

A neutralizing monoclonal antibody against Coxsackievirus B4 cross-reacts with contractile muscle proteins.

A panel of Coxsackievirus B4 (CVB4) neutralizing monoclonal antibodies (mAbs) were tested against a panel of normal mouse tissues. One mAb, 356-1, reacted specifically with murine heart tissue. Immunohistochemical studies revealed an A band pattern of staining of the heart. Examination of sequential differential extracts of heart by Western immunoblotting showed that 356-1 predominantly reacted with the murine cardiac myosin heavy chain. A rather weak cross-reaction was found with actin. These observations were confirmed by the binding of 356-1 to purified cardiac myosin and actin. This antibody showed a higher affinity for murine cardiac muscle myosin than for skeletal muscle myosin. Examination of the reactivity of 356-1 with CVB4 polypeptides using Western immunoblotting revealed that 356-1 binds to the VP-1 capsid protein. These studies imply that molecular mimicry is one mechanism by which autoimmunity could develop during CVB4 induced myocarditis.

Animals↗
PubMed1990

Characterization of Epstein-Barr virus-induced lymphoproliferation derived from human peripheral blood mononuclear cells transferred to severe combined immunodeficient mice.

Mice with severe combined immunodeficiency (SCID) received 6 X 10(7) fresh human peripheral blood mononuclear cells (PBMC) intraperitoneally from Epstein-Barr virus (EBV)-seropositive and -seronegative donors. B95-8 EBV was inoculated intraperitoneally and intravenously to the mice 6 weeks after transfer of seronegative PBMC. Three of four mice transferred with PBMC from two EBV-seropositive donors and two of four mice from two EBV-seronegative donors inoculated with EBV developed fatal EBV-induced lymphoproliferative disease within 6 to 10 weeks. These tumors were oligoclonal or polyclonal by cytoplasmic immunoglobulin expression. Furthermore no consistent clonal chromosomal abnormalities were shown. Cell lines established from these tumors showed low cloning efficiency in soft agarose. In addition, latent membrane protein, B-lymphocyte activation antigen (CD23), and cell-adhesion molecules (ICAM-1, CD18) all were expressed in the EBV-positive infiltrating lymphoproliferative lesions in each mouse. These results suggest that lymphoid tumors are comparable to lymphoblastoid cell lines immortalized by EBV and are not malignant lymphomas such as Burkitt's lymphoma. This model may be useful for investigating mechanisms responsible for the growing numbers of lymphoproliferative diseases that are occurring in patients with inherited or acquired immunodeficiencies.

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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

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↗
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.

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