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(Circulation. 1997;95:655-661.)
© 1997 American Heart Association, Inc.

Articles

Low-Molecular-Weight Tumor Necrosis Factor Receptor p55 Controls Induction of Autoimmune Heart Disease

Kurt Bachmaier, MD; Christian Pummerer, MD; Ivona Kozieradzki, MSc; Klaus Pfeffer, MD; Tak W. Mak, PhD; Nikolaus Neu, MD; Josef M. Penninger, MD

the Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Canada; the Institute for Medical Microbiology and Hygiene, Technical University, Munich, Germany (K.P.); and the Department of Pediatrics, University of Innsbruck, Austria (C.P., N.N.).

Correspondence to Josef Penninger, Amgen Institute/Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Ave, Toronto, Ontario, M5G 2C1 Canada. E-mail jpenning@amgen.com.

	Abstract

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Background Tumor necrosis factor- (TNF-) is involved in the pathogenesis of myocarditis and can bind to either tumor necrosis factor receptor (TNF-R) p55 or TNF-Rp75. However, it is not known which TNF-R mediates the specific functions of TNF in disease. To determine the role of the TNF/TNF-R system in chronic heart disease, we used a murine model of cardiac myosin–induced myocarditis that closely resembles the chronic stages of virus-induced myocarditis in humans.

Methods and Results Mice lacking TNF-Rp55 expression after targeted disruption of the TNF-Rp55 gene were backcrossed into a genetic background susceptible to the induction of myocarditis with cardiac myosin. Here, we demonstrate that TNF-Rp55 gene–deficient mice did not develop any inflammatory infiltration into the heart after autoantigen injection, whereas control littermates showed autoimmune myocarditis at high prevalence and severity. Despite the absence of autoimmune heart disease, TNF-Rp55^-/- mice produced cardiac myosin–specific IgG autoantibodies, indicating that activation of autoaggressive T and B lymphocytes had occurred. However, heart interstitial cells failed to express major histocompatibility complex (MHC) class II molecules in TNF-Rp55^-/- animals, and adoptive transfer of autoreactive T cells resulted in heart disease only in TNF-Rp55^+/+ but not in TNF-Rp55^-/- littermates.

Conclusions Cardiac myosin–induced myocarditis is dependent on autoaggressive T cells and on autoantigen presentation in association with MHC class II molecules within the heart. Thus, lack of TNF-Rp55 expression could interfere with either lymphocyte activation or target organ susceptibility. The data presented here show that the TNF-Rp55 is a key regulator for the induction of autoimmune heart disease by its controlling target organ susceptibility.

Key Words: myocarditis • molecular biology • signal transduction • genetics

	Introduction

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Myocarditis and dilated cardiomyopathy are major healthcare problems.^{1 2} Myocarditis is caused by a wide variety of pathological conditions, in particular by viral infections,^{2 3} and often precedes the development of dilated cardiomyopathy, a condition that necessitates heart transplantation.^{4 5 6} Other treatment options for chronic heart disease are limited.^{7 8} Clinical and experimental studies have provided evidence that chronic stages of myocarditis leading to dilated cardiomyopathy are due to aberrant immune responses toward autoantigens. Therefore, the understanding of the induction phase of autoimmunity, ie, breakdown of immunological tolerance and target organ susceptibility, will be crucial for the successful prevention of these diseases.^{9 10 11}

The pathogenic involvement of cytokines in T cell–mediated immunity, ie, septic shock, malignancies, graft versus host disease, inflammatory immune responses, and autoimmune disorders, is well established.¹² The TNF/TNF-R system, in particular, is involved in murine autoimmune myocarditis,^{13 14 15} experimental allergic encephalomyelitis,^{16 17} collagen-induced arthritis,^{18 19 20} insulin-dependent diabetes mellitus,^{21 22} systemic lupus erythematosus,^{23 24} and multiple sclerosis.²⁵ The exact role of the TNF/TNF-R system in the development of autoimmunity is not fully understood. TNF- and TNF-ß can bind to either the low-molecular-weight TNF-Rp55 or the high-molecular-weight TNF-Rp75.^{26 27 28 29} The third distinct receptor to interact with TNF, TNF-Rrp, preferentially interacts with TNF-ß and appears to control the development of Peyer's patches and lymph nodes.³⁰ However, it is not known which TNF-R mediates the crucial effects of TNF during induction and maintenance of autoimmunity.

Mice lacking the TNF-Rp55 after homologous recombination have normal T- and B-cell development but succumb to Listeria monocytogenes infections. In addition, these mice are resistant to toxic shock syndrome induced by bacterial toxins.^{31 32} To determine the role of the TNF/TNF-R system in chronic heart disease, we introduced a TNF-Rp55 null mutation³¹ into a genetic background susceptible to cardiac myosin–induced autoimmune myocarditis.³³ Murine experimental myocarditis resembles the chronic phase of virus-induced heart disease in humans^{3 33 34 35} and is strictly organ-specific and dependent on CD4⁺ T cells and MHC class II expression in the autoimmune target organ.^{36 37 38} In this study, we provide genetic evidence that the low-molecular-weight TNF-Rp55 is a key regulator in the development of autoimmune heart disease.

	Methods

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Mice
To generate mice in an MHC haplotype susceptible to cardiac myosin–induced autoimmune disease,³³ TNF-Rp55–deficient mice³¹ were backcrossed into an A/J strain (H-2^k/k) for three generations. In all experiments, only littermate mice were used. Care of animals was in accordance with guidelines of the Canadian Research Council.

Immunization, Histopathology, and Serology
Cardiac myosin was purified from mice as described previously.³⁹ Eight-week-old mice were twice immunized subcutaneously at a 7-day interval with 150 µg of cardiac myosin emulsified in FCA or with FCA alone. Twenty-one days after the first immunization, mice were killed and analyzed histologically for infiltration of the heart muscle and serologically for the presence of cardiac myosin–specific IgG auto-Abs.^{39 40} For histological analysis, hearts were fixed in formaldehyde and processed for hematoxylin-eosin staining. Histological grading of severity was 0, no infiltration in heart muscle; 1, up to 5% of histological cross section infiltrated; 2, 6% to 10%; 3, 11% to 20%; and 4, >20% infiltrated. Specificity of myosin IgG auto-Abs against the cardiac isoform of myosin has been demonstrated previously.⁴⁰ IgG auto-Ab titers were determined by ELISA using the cardiac myosin isoform as test antigen.³⁹

Adoptive Transfer
Adoptive transfer was performed as previously described.⁴¹ Briefly, A/J donors were immunized twice with cardiac myosin on days 0 and 7. Spleen cells were obtained on day 14 and cultured in 2.5 µg ConA for 48 hours at 37°C. ConA-stimulated cells (5x10⁶) were injected intravenously into 6-week-old TNF-Rp55^+/+ or TNF-Rp55^-/- recipients treated with 25 µg LPS in 100 µL saline intraperitoneally 10 and 6 days before transfer.⁴¹ All recipients were killed 10 days after transfer. Prevalence and disease severity were determined histologically on hematoxylin-eosin–stained heart sections, and disease severity was scored as described above.

Immunohistochemistry
To determine induction and expression of MHC class II and cell adhesion molecules on heart interstitial cells, 6-week-old mice were injected intraperitoneally on day 0 and day 4 with LPS (25 µg/100 µL saline per mouse) or with saline alone, and hearts were removed on day 8 after the first injection. In addition, littermate mice were immunized with cardiac myosin or FCA alone as described above and killed 21 days after the initial immunization. Hearts from untreated controls, from LPS- or saline-injected animals, and from cardiac myosin–immunized animals or FCA-injected controls were processed for cryosections. For immunoperoxidase staining,³⁶ cryostat sections were fixed in acetone, and the endogenous peroxidase activity was blocked with 0.6% NaN₃ and 0.125% H₂O₂. Sections were incubated with the following MAbs: anti-IA^k (MHC class II) (biotinylated, dilution 1:20; Serotec, MCA46B); anti–ICAM-1 (supernatant, clone YN1/1.7.4; rat IgG2a); anti-CD45 (supernatant, clone M1/9.3.4; rat IgG2a); anti-CD11b (supernatant, clone Mac-1; rat IgG2a); and anti-CD3 (supernatant, clone KT3; rat IgG2a). The rat MAbs were derived from hybridomas obtained from American Type Culture Collection. The biotinylated MAb was detected with alkaline phosphatase–labeled streptavidin (dilution 1:200; Molecular Probes Inc, S-921), and the unlabeled culture supernatant MAbs were detected with peroxidase-conjugated rabbit anti–rat IgG antibodies (dilution 1:100; Dako, P-162). Antibody binding was visualized by conversion of substrates (Sigma fast red, F-4523 or Sigma fast DAB, D-0426). Finally, sections were counterstained with hematoxylin. For quantitative analysis of MHC class II CD3, CD45, and CD11b expression, the total numbers of positively stained cells were counted per visual field at a magnification of x100.⁴¹ In each heart, at least 10 different visual fields were counted by two independent observers. Interstitial cells were defined as CD45⁺/CD11b⁺/CD3^-cells.

	Results

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TNF-Rp55 Is Crucial for the Induction of Autoimmune Heart Disease in Knockout Mice
TNF is involved in the pathogenesis of myocarditis and dilated cardiomyopathy.¹⁵ Development of virus-induced autoimmune myocarditis is associated with local production and secretion of TNF,⁴² and administration of TNF- can promote myocarditis in experimental mouse models.¹³ However, it is not clear which receptor mediates the biological activities of TNF in disease. Therefore, TNF-Rp55^-/-, TNF-Rp55^+/-, and TNF-Rp55^+/+ littermate mice were injected with purified cardiac myosin emulsified in FCA.³³ Within 21 days after the initial injection, all immunized TNF-Rp55^+/+ mice and 80% of TNF-Rp55^+/- mice developed severe autoimmune myocarditis, as assessed by the extent of inflammatory infiltration (Table 1 and Fig 1A and 1B). However, TNF-Rp55^-/- littermates immunized with cardiac myosin were protected from autoimmune heart disease and did not show any inflammatory infiltration into the heart (Table 1 and Fig 1C). Neither TNF-Rp55^+/+ nor TNF-Rp55^-/- mice immunized with FCA alone developed myocarditis (Table 1 and Fig 1D). These results indicate that the TNF-Rp55 has a crucial role in the pathogenesis of autoimmune heart disease. Pathological manifestations of autoimmune diseases are dependent on the balance between activation of autoaggressive lymphocytes and target organ susceptibility.^{10 43} Thus, the lack of TNF-Rp55 expression could interfere with either lymphocyte activation or target organ susceptibility.

View this table: [in this window] [in a new window]   Table 1. Prevalence and Severity of Cardiac Myosin–Induced Myocarditis in TNF-Rp55-/-, TNF-Rp55+/-, and TNF-Rp55+/+ Mice

View larger version (628K): [in this window] [in a new window]   Figure 1. Hearts of TNF-Rp55+/+ (A), TNF-Rp55+/- (B), and TNF-Rp55-/- (C) mice injected with cardiac myosin and FCA. In TNF-Rp55+/+ (A) and in TNF-Rp55+/- mice (B), cellular infiltrates consisted mainly of mononuclear cells and were diffuse and interstitial. By contrast, cardiac myosin–immunized TNF-Rp55-/- littermates (C) showed no inflammatory infiltration and displayed the same normal morphology of a heart muscle as a TNF-Rp55-/- mouse injected with FCA alone (D). Immunization and analysis of cellular heart infiltrates were as described in "Methods." Hematoxylin-eosin, x160.

TNF-Rp55^-/- Mice Produce Cardiac Myosin–Specific Auto-Abs
Mice with autoimmune myocarditis develop high titers of anti-myosin IgG auto-Abs,^{33 39} and the production of IgG auto-Abs is strictly dependent on functional T lymphocytes.^{44 45} To test whether auto-Abs could be produced in TNF-Rp55^-/- mice, ie, whether lymphocyte stimulation had occurred even in the absence of cellular heart infiltration, we analyzed the titers of anti-myosin auto-Abs (Fig 2). Whereas all diseased TNF-Rp55^+/+ mice developed high titers of IgG auto-Abs, the auto-Ab titers in TNF-Rp55^+/- littermates were lower and correlated with the severity of cellular heart infiltration. Surprisingly, TNF-Rp55^-/- were capable of producing cardiac myosin–specific auto-Abs at titers similar to those in heterozygous littermates. TNF-Rp55^-/- mice injected with FCA alone did not produce significant auto-Ab titers (Fig 2). It should be noted that TNF-Rp55^-/- mice have normal basal levels of Ig subclasses.³¹ These data show that TNF-Rp55^-/- mice were protected from organ-specific autoimmunity even though autoaggressive T and B cells were activated.

View larger version (12K): [in this window] [in a new window]   Figure 2. Myosin IgG auto-Ab titers in TNF-Rp55+/+, TNF-Rp55+/-, and TNF-Rp55-/- mice. Solid circles represent individual mice with myocarditis, and open circles, mice without cellular heart infiltrates. Myosin IgG auto-Ab titers were determined as described in "Methods."

TNF-Rp55 Controls MHC Class II Expression on Heart Interstitial Cells
Autoimmune myocarditis is dependent on CD4⁺ T cells and MHC class II expression,^{36 37 38} and heart interstitial cells present cardiac myosin peptides in association with MHC class II.⁴⁶ Previously, it was shown that TNF- injections into mice can induce MHC class II expression in various organs⁴⁷ and that aberrant expression of MHC class II can promote autoimmunity.⁴⁸ Therefore, we analyzed whether the TNF-Rp55 mediates the expression of MHC class II on heart interstitial cells, ie, whether differences in class II antigen expression could be seen in hearts of TNF-Rp55^-/- and TNF-Rp55^+/+ littermate mice. As shown in Table 2, MHC class II (I-A^k) expression in the hearts of untreated TNF-Rp55^-/- or TNF-Rp55^+/+ mice was scarcely detectable by immunoperoxidase staining, whereas heart interstitial cells (CD45⁺/CD11b⁺/CD3^-) were frequently detected in similar numbers in TNF-Rp55^-/- and TNF-Rp55^+/+ mice (day 0). Eight days after the first LPS injection, induction of MHC class II expression was observed only in the hearts of TNF-Rp55^+/+ mice but not in TNF-Rp55^-/- littermates (Table 2 and Fig 3A and 3B). Injection of saline alone had no effect on class II expression. In addition, 21 days after the first immunization with cardiac myosin TNF-Rp55^+/+, mice showed a massive upregulation of MHC class II expression on heart interstitial cells, whereas heart interstitial cells from cardiac myosin–immunized TNF-Rp55^-/- littermates did not upregulate MHC class II expression (Table 2). It should be noted that in double immunoperoxidase stainings, MHC class II expression was confined to CD11b-positive heart interstitial cells (not shown). By contrast, lack of the TNF-Rp55 had no apparent effect on the expression of the adhesion receptor ICAM-1 on heart interstitial cells (Fig 3C and 3D). Although these data do not exclude an effect of the TNF-Rp55 on adhesion receptor expression in autoimmune heart disease, our results imply that the TNF-Rp55 may control target organ susceptibility via upregulation of MHC class II expression.

View this table: [in this window] [in a new window]   Table 2. Frequency of MHC Class II–Positive Cells and of Interstitial Cells in the Myocardium of TNF-Rp55+/+ and TNF-Rp55-/- Littermate Mice

View larger version (566K): [in this window] [in a new window]   Figure 3. Immunoperoxidase staining for ICAM-1 and MHC class II (I-Ak) expression on heart interstitial cells after injection of LPS into TNF-Rp55+/+ and TNF-Rp55-/- littermate mice. A, MHC class II expression in TNF-Rp55+/+ mice; B, MHC class II expression in TNF-Rp55-/- mice; C, ICAM-1 expression in TNF-Rp55+/+ mice; and D, ICAM-1 expression in TNF-Rp55-/- mice. LPS injection and immunoperoxidase staining were as described in "Methods." Magnification x250.

Autoimmune Heart Disease Cannot Be Adoptively Transferred Into TNF-Rp55^-/- Mice
To directly address the question of whether the low-molecular-weight TNF-Rp55 regulates target organ susceptibility, adoptive transfer studies were performed. Normal A/J (H-2^k/k) donors were immunized with cardiac myosin, and autoreactive T cells were harvested and then transferred into H-2^k/k congenic LPS-pretreated TNF-Rp55^+/+ or TNF-Rp55^-/- recipients.⁴¹ Ten days after the transfer, 67% of the TNF-Rp55^+/+ recipients had developed severe inflammation of the pericardium and the adjacent myocardium (perimyocarditis) (Table 3). In contrast to TNF-Rp55^+/+ littermates, TNF-Rp55^-/- recipient mice did not show any signs of inflammation after adoptive transfer of splenic T cells from the same A/J donors (Table 3). These data directly demonstrate that the TNF-Rp55 is a key regulator of target organ susceptibility in autoimmune heart disease.

View this table: [in this window] [in a new window]   Table 3. Prevalence and Severity of Adoptively Transferred Perimyocarditis in TNF-Rp55+/+ and TNF-Rp55-/- Recipients

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The data presented here show that the low-molecular-weight TNF-Rp55 is a key regulator for the induction of inflammatory infiltration into the heart and the onset of experimental autoimmune myocarditis. TNF-Rp55^-/- mice were completely protected from autoimmune myocarditis. However, activation of autoreactive B and T cells had occurred in TNF-Rp55^-/- mice, as indicated by the production of cardiac myosin–specific IgG auto-Abs. Production of auto-Abs in autoimmune myocarditis crucially depends on functional T lymphocytes and Ig class-switching.^{44 45} The finding that the lack of TNF-Rp55 expression has no apparent effect on the activation of autoreactive T and B cells in autoimmune heart disease, however, does not preclude a role for the TNF-Rp55 in normal lymphocyte function. Also, these data do not prove that the autoreactive T-cell populations were similar in TNF-Rp55^-/- and TNF-Rp55^+/+ mice.

Cardiac myosin–reactive T cells from A/J donors were capable of inducing autoimmune myocarditis in MHC congenic TNF-Rp55^+/+ but not in TNF-Rp55^-/- recipients, which indicates that the low-molecular-weight TNF-Rp55 has a crucial role in target organ susceptibility. The normal myocardium is not accessible to autoreactive T cells.⁴¹ However, upregulation of MHC class II molecules on heart interstitial cells has important functional consequences for the pathogenesis of the disease, since the induction of autoimmune myocarditis is dependent on heart interstitial cells presenting cardiac myosin peptides in association with MHC class II molecules to autoreactive T cells.^{36 37 38 46} TNF- injections can increase MHC class II expression in target organs of other experimental autoimmune disease models.^{47 48} We also recently showed that upregulation of MHC class II and ICAM-1 molecules on heart interstitial cells precedes lymphocyte infiltration into the heart and that LPS injections can mimic a state of target tissue activation that precedes inflammatory infiltration of the heart after autoantigen immunization.^{41 49} That MHC class II upregulation was seen only in animals expressing the TNF-Rp55 but not in TNF-Rp55–deficient mice suggests that the TNF-Rp55 is a key regulator in autoimmune target organ susceptibility. Since the TNF-Rp55 controls MHC class II but not ICAM-1 expression on heart interstitial cells, other members of the nerve growth factor–receptor/TNF-R superfamily and/or other cytokine receptors might also be involved in target organ susceptibility and/or selective homing of autoreactive T lymphocytes.

The possibility that TNF-Rp55^-/- mice lose susceptibility to cardiac myosin–induced myocarditis during the process of backcrossing into an A/J background is unlikely, but it cannot be excluded with complete certainty. In all experiments, only littermate mice of the H-2^k/k haplotype, all of which are susceptible to cardiac myosin–induced myocarditis,³³ were used. In addition, autoimmune myocarditis has been linked to certain MHC class II genes in mice, and the MHC class II haplotype has been determined to be the single most important genetic factor that confers disease susceptibility.³³

The facts that the TNF-Rp55 appears to control MHC class II expression and that TNF-Rp55–deficient mice were protected from autoimmune myocarditis make the low-molecular-weight TNF-Rp55 a candidate target for therapeutic intervention that allows for a rational drug design in prevention and treatment of autoimmunologically mediated chronic myocarditis and dilated cardiomyopathy. Since expression of MHC class II molecules has a pathogenic role in a variety of other autoimmune disorders, this approach might also be useful for the therapy of other autoimmune diseases such as insulin-dependent diabetes, rheumatoid arthritis, or pemphigus vulgaris.

	Selected Abbreviations and Acronyms

 

auto-Ab = autoantibody ConA = concanavalin A FCA = Freund's complete adjuvant ICAM = intercellular adhesion molecule LPS = lipopolysaccharide MAb = monoclonal antibody MHC = major histocompatibility complex TNF-R = tumor necrosis factor receptor

	Acknowledgments

 
This work was supported by a grant from the Austrian Fonds zur Forderung der Wissenschaftlichen Forschung (FWF) to Dr Bachmaier. We thank D.P. Siderovski, J.L. de La Pempa, L.-M. Boucher, C. Brunaud, T.M. Kundig, P.S. Ohashi, R. Schmits, V. Wallace, P. Waterhouse, J. Simard, and H.-W. Mittrucker for comments.

Received June 19, 1996; revision received September 11, 1996; accepted September 30, 1996.

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