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The Journal of Immunology, 1999, 163: 5265-5268.
Copyright © 1999 by The American Association of Immunologists

Autoimmune Myocarditis Does Not Require B Cells for Antigen Presentation1

Susan Malkiel, Stephen Factor and Betty Diamond2

Departments of Microbiology and Immunology, Medicine, and Pathology, Albert Einstein College of Medicine, Bronx, NY 10461


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
T cells constitute the pathogenic effector cell population in autoimmune myocarditis in BALB/c mice. Using mice rendered deficient for B cells by a targeted disruption to the IgM transmembrane domain or by treatment with anti-IgM Ab from birth, we asked whether B cells are a critical APC in the induction of autoimmune myocarditis. B cell-deficient mice immunized with cardiac myosin develop myocarditis comparable in incidence and severity to that in wild-type mice, suggesting that autoreactive T cells that cause myocarditis in BALB/c mice are activated by macrophages or dendritic cells. Since it does not appear that presentation of cryptic epitopes is critical for the breakdown of self tolerance, potentially pathogenic T cells recognizing dominant myosin epitopes must have escaped tolerization. Either anatomic sequestration of cardiac myosin peptide-MHC complexes or subthreshold presentation of cardiac myosin peptides by conventional APC can explain the survival of these autoreactive T cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Autoimmune myocarditis is an autoimmune heart disease characterized by an inflammatory infiltrate in the myocardium and adjacent myocyte necrosis (1). The disease can be induced in susceptible mouse strains by coxsackie B virus infection or by immunization with cardiac myosin (2, 3). Both models of disease are T cell-mediated in BALB/c mice (4, 5, 6). T cell-deficient mice develop little or no myocarditis (4), and T cells from mice with myocarditis are able to transfer disease to SCID recipients (6). In addition, while BALB/c mice produce anti-cardiac myosin Ab, the Ab alone cannot induce cardiac pathology in this strain (5, 6, 7).

The process leading to the activation of this self-reactive T cell response is unknown. Immunization with cardiac myosin may expose previously sequestered class II-myosin peptide complexes to nontolerized T cells. Alternatively, the amount of myosin present in immunization may bring the density of class II-myosin peptide complexes up to a critical threshold for T cell signaling. Finally, myosin immunization may lead to the production and presentation of novel myosin peptides by B cells to T cells not tolerized to those epitopes by macrophages and dendritic cells.

To test the hypothesis that anti-myosin B cells are critical APCs in autoimmune myocarditis, we have examined the induction of myocarditis in BALB/c mice rendered deficient for B cells in two ways: 1) by a targeted disruption of the IgM transmembrane domain (µMT mice) (8), and 2) by treatment with anti-IgM Ab from birth (anti-µ mice) (9). We show that B cell-deficient mice developed myocarditis comparable to wild-type mice. Ag processing and presentation by B cells do not appear necessary for the activation of autoreactive T cells in myocarditis induced by myosin immunization in BALB/c mice.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

BALB/c mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and maintained in the Albert Einstein College of Medicine barrier animal facility. µMT mice on a (C57BL/6 x 129/Sv) background were obtained from K. Rajewsky (Cologne, Germany) (8) and backcrossed to the BALB/c strain for seven to nine generations. At each generation, the heterozygous breeders were identified by Southern blot analysis of tail DNA. They were then intercrossed to generate homozygous B cell-deficient mice.

BALB/c anti-µ mice were injected i.p. with 50 µg of goat anti-mouse IgM Ab (Southern Biotechnology Associates, Birmingham, AL), administered five times a week for the first week of life and on alternate days thereafter. Following cardiac myosin immunization, the dosage was increased to 100 µg of Ab every other day. Normal goat IgG (NGIgG)3 (Cappel Research Products, Durham, NC) was used as a negative control.

Cardiac myosin

Cardiac myosin was purified from BALB/c hearts according to the method of Pollack et al. (10). The concentration was determined by spectrophotometry, using an extinction coefficient of 5.4. Purity was determined by SDS-PAGE.

Induction of myocarditis

{gamma}-Irradiated cardiac myosin (10, 30, and 100 µg) was emulsified in sterile CFA (Difco, Detroit, MI) and injected into 5- to 12-wk-old mice at four sites s.c. Mice were boosted s.c. with the same dose of cardiac myosin in CFA 1 and 3 wk after the initial immunization. They were sacrificed 1 wk after the last boost.

Histology

Mouse hearts were fixed in 10% buffered formalin and embedded in paraffin. Sections of each heart were obtained at five different levels and stained with hematoxylin and eosin. These were evaluated by a cardiac pathologist (S.F.), who was blinded to the status of each mouse. The diagnosis was according to the Dallas criteria, which established myocarditis as the presence of an inflammatory infiltrate and accompanying myocyte necrosis (1).

FACS analysis

The presence of B220-, CD4-, and CD8-positive cells in the spleen was determined by staining with anti-B220-PE (PharMingen, San Diego, CA), anti-CD4-PE (Becton Dickinson Immunocytometry Systems, San Jose, CA), and anti-CD8-FITC (PharMingen) and analysis with a FACScan.

ELISAs

Mouse serum was tested for IgM and IgG anti-cardiac myosin Abs. Falcon microtiter plates (Becton Dickinson Labware, Lincoln Park, NJ) were coated with either cardiac myosin (0.5 µg/well) or anti-IgM Ab at a 1/1000 dilution (Southern Biotechnology Associates). Anti-IgM-coated plates were blocked with 1% BSA/PBS, and cardiac myosin-coated plates were blocked with 2% BSA/PBS. Serum samples were serially diluted, and titers were detected by an alkaline phosphatase conjugated anti-mouse IgG or IgM Ab (Southern Biotechnology Associates) diluted 1/1000 and the substrate, p-nitrophenyl phosphate (Sigma, St. Louis, MO). OD was measured at 405 nm.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Induction of myocarditis in µMT mice

The µMT gene disruption that deletes the transmembrane domain of IgM was backcrossed onto the susceptible BALB/c strain for more than seven generations. The backcrossed homozygous mice had no detectable mature B cells expressing B220 in the spleen, but still possessed CD4+ and CD8+ T cells (Fig. 1Go). Additionally, they had little or no detectable IgM (<0.2 µg/ml) in their sera (Table IGo). Although homozygous mice immunized with cardiac myosin had some IgG in their sera (data not shown), they demonstrated no Ag-specific IgG response (Fig. 2Go). Eight of 10 homozygotes immunized with cardiac myosin developed myocarditis (Table IIGo). Both the incidence and the severity of myocarditis in the homozygotes were similar to those observed in the control heterozygous littermates (Table IIGo and Fig. 3Go). To determine whether B cells might be required for Ag presentation when less myosin is available, homozygous and wild-type mice were immunized with lower doses of cardiac myosin. When immunized with 30 µg of cardiac myosin, four of five homozygotes developed myocarditis (data not shown). However, immunizing with 10 µg of cardiac myosin did not induce disease in either homozygous or wild-type mice (data not shown).



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  		FIGURE 1. FACS analysis of splenocytes from cardiac myosin-immunized BALB/c µMT homozygous and heterozygous mice. Spleen cells were stained for surface expression of B220 (A and B), CD4 (C and D), and CD8 (E and F) in homozygous (left) and heterozygous (right) mice. One representative mouse of each genotype is shown.

 

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  		Table I. Serum levels of IgM in immunized B cell-deficient BALB/c mice

 


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  		FIGURE 2. Anti-cardiac myosin IgG response in myosin-immunized µMT and anti-µ BALB/c mice. The ELISA protocol is described in Materials and Methods. The µMT homozygous mice (n = 10) and the anti-µ mice (n = 5) exhibit no detectable cardiac myosin-specific IgG titers, in contrast to myosin-immunized µMT heterozygous mice (n = 10) and NGIgG-treated mice (n = 6).

 

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  		Table II. Induction of autoimmune myocarditis in B cell-deficient BALB/c mice1

 


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  		FIGURE 3. Histology of hearts from immunized µMT homozygous (A), µMT heterozygous (B), anti-µ treated (C), and NGIgG-treated (D) BALB/c mice. A, Extensive myocarditis in base of free wall of left ventricle. B, Myocarditis in right ventricular free wall with pericarditis. C, Multiple foci of myocarditis. D, Myocarditis in left ventricular base. Arrows point to necrotic myocytes and infiltrates of lymphocytes. Original magnification, x80.

 
Induction of myocarditis in anti-µ mice

Because it is possible that a lack of B cells during fetal development can alter the T cell repertoire in mice, we decided to analyze BALB/c mice that were depleted of B cells after birth. Chronic injection of animals with anti-IgM Ab from birth is a technique previously demonstrated to deplete mice of B cells. Anti-µ-treated mice had no detectable B220+ splenocytes, but still possessed CD4+ and CD8+ T cells (Fig. 4Go). As observed with the µMT homozygous mice, anti-µ mice produced little or no detectable IgM (Table IGo). Although they did produce some IgG (data not shown), they also failed to demonstrate cardiac myosin-specific IgG following immunization (Fig. 2Go). All eight anti-µ mice immunized with cardiac myosin developed myocarditis, and there was no difference in the incidence or the severity of disease compared with that in the wild-type mice that were treated with normal goat IgG (Table IIGo and Fig. 3Go).



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  		FIGURE 4. FACs analysis of splenocytes from cardiac myosin-immunized, anti-µ-treated, and NGIgG-treated BALB/c mice. Spleen cells were stained for surface expression of B220 (A and B), CD4 (C and D), and CD8 (E and F) in anti-µ-treated (left) and NGIgG-treated (right) mice. One representative mouse from each group is shown.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We found that mice genetically deficient in B cells and mice rendered B cell deficient after birth develop myocarditis following immunization with cardiac myosin. Although these B cell-deficient mice are not completely depleted of serum IgG, there are essentially no B220+ cells in the spleen as determined by FACS analysis, and the mice clearly do not make myosin-specific B cells. This suggests that myosin-specific autoreactive T cells in BALB/c mice can be activated in the absence of myosin-specific B cells, and dendritic cells or macrophages are sufficient for the priming of these autoreactive T cells. The induction of myocarditis in the µMT homozygotes immunized with a lower dose of myosin is further evidence that myosin-specific B cells are not required to break T cell tolerance to myosin in BALB/c mice. We were unable to find a dose of Ag that led to disease in B cell-competent mice and no disease in B cell-deficient mice.

The role of B cells in priming naive T cells specific for foreign Ag has been controversial, and over recent years the role of B cells in activating autoreactive T cells has proven equally complex (11, 12, 13, 14, 15, 16, 17, 18, 19, 20). In an initial study to determine whether B cells can break T cell tolerance, Mamula et al. found that adoptive transfer of B cells cross-reactive to foreign and self cytochrome c (Cyt c) into naive recipients resulted in the activation of an autoreactive T cell response (21). Parallel transfer of macrophages from mice immunized with foreign Cyt c did not break T cell tolerance (21). These results were confirmed using small ribonucleoprotein particles (snRNPs) as an Ag (22) and using genetically B cell-deficient mice (23). Presumably due to altered processing of Ag, the activated cross-reactive B cells present a novel self peptide or cryptic epitope to which T cells have not been tolerized. In other studies, nonobese diabetic (NOD) mice genetically deficient in B cells failed to develop diabetes, insulitis, or autoreactive T cells (24, 25), again demonstrating a critical role for B cells as APCs in autoimmunity. However, in a number of other models of autoimmune disease, B cells were shown to be unnecessary for the activation of autoreactive T cells. In collagen-induced arthritis and autoimmune myasthenia gravis, the T cell responses to collagen and to the acetylcholine receptor, respectively, are normal in the absence of B cells (26, 27). In experimental autoimmune encephalomyelitis, a T cell-mediated disease, mice genetically deficient in B cells developed disease in a manner comparable to that of wild-type mice (28).

The commonality of the cardiac myosin-induced model of myocarditis and the other models of autoimmune disease in which B cells are not needed to prime autoreactive T cells is that immunizing with native self Ag in adjuvant is sufficient to break T cell tolerance. In these models it can be assumed autoreactive T cells have not been tolerized by macrophages and dendritic cells and that T cells recognizing immunodominant epitopes of self Ag are still present in the T cell repertoire. This most likely reflects a lack of T cell exposure to dendritic cells and macrophages presenting self-peptides or a subthreshold density of peptide-MHC complexes presented by dendritic cells and macrophages. Immunization with self Ag in these models may either increase self-peptide presentation to the threshold required for T cell signaling and activation or expose normally anatomically sequestered MHC-self peptide complexes for the first time. Autoreactive T cell responses, such as the response to Cyt c or snRNPs, cannot be induced by immunization with native self-Ag in adjuvant. Because autoreactive T cells may have already been tolerized to immunodominant peptides presented by macrophages and dendritic cells, B cells presenting cryptic epitopes of self Ag are required for activation of an autoreactive T cell response.

Consistent with this hypothesis, Smith and Allen have shown that cardiac APCs in naive mice constitutively process and present cardiac myosin and can activate a T cell hybridoma derived from a mouse with myocarditis (29). These data demonstrate that epitopes of myosin that activate pathogenic T cells are constitutively presented in the heart. This may explain how cardiac damage in the absence of foreign Ag can give rise to autoimmune myocarditis. In the ischemic heart, the release of intracellular myosin exposes autoreactive T cells to APCs presenting myosin peptides and increases the level of that presentation.

In general, it may be that B cells are needed as APCs in diseases where the autoantigen is normally presented in a tolerogenic fashion, to expose cryptic epitopes of self Ag. For autoantigens to which T cells have not been tolerized, exposure to immunodominant peptides of self Ag by macrophages and dendritic cells may be sufficient to initiate autoreactivity and, perhaps, autoimmune disease.


   Footnotes
 
1 This study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and by Grant T32HL07675 (to S.M.). Back

2 Address correspondence and reprint requests to Dr. Betty Diamond, Department of Microbiology and Immunology, 1300 Morris Park Avenue, Room 405, Building Forchheimer, Bronx, NY 10461. E-mail address: Back

3 Abbreviations used in this paper: NGIg, normal goat IgG; GCyt c, cytochrome c; snRNPs, small ribonucleoprotein particles. Back

Received for publication June 15, 1999. Accepted for publication September 1, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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