postinfectious autoimmunity: two distinct phases of coxsackievirus b3-induced myocarditis

Postinfec t ious Autoimmunity : Two Distinct Phases of Coxsackievirus

B3-Induced Myocarditis“ NOEL R. ROSE, LUANNE J. WOLFGRAM,

AHVIE HERSKOWITZ, AND KIRK W. BEISEL Departments of Immunoiogy and Infectious Diseases

and of Medicine The Johns Hopkins Medical Institutions

Baltimore, Maryland 21 205

An encounter between an infectious agent and a host involves a complex of interactions that may or may not lead to disease. The genetic composition of both the host and the infectious agent will determine the extent of the initial infection and the severity of the resulting pathology. The immune response toward the invading pathogen is the major host mechanism affecting the severity both of the infection and of the resultant disease and in limiting subsequent infections. The immune response, however, can play a paradoxical role by leading to exacerbation of disease rather than promoting recov- ery.

A wide variety of viruses has been shown to produce myocarditis in man.’ The most common are the R N A viruses of the Picornavirus,24 Orthomyx~virus ,~ Paramyxovi- rus,6 Togavirus,’ Rhabdovirus: and Arenavirus’ families. The most common of these viruses, the Coxsackievirus B group, is associated with about half of the clinical cases of infectious myocarditis.’”” Of this group, Coxsackievirus B, (CB,) induces the highest incidence of myocardial disease.12 Usually, the association of this virus with cardiac disease is inferred from serological studies since isolation and identification of the virus itself has been difficult. The diagnosis of myocardiopathy often requires endomyocardial biopsy.13 The principal drawbacks of this diagnostic method are the focal nature of the inflammatory cellular infiltrate and the lack of universally accepted guidelines for histologic assessment. 14,’

Several pathogenetic mechanisms have been proposed to account for virus-induced myocardiopathy.’.1”18 Since CB, is a lytic virus, one plausible mechanism is direct injury to the myofibers. In addition, myocardial tissue injury can be correlated with the severity of the inflammatory lesions, suggesting that inflammation itself may be responsible for the injury. On the other hand, a protective effect has been associated with the inflammatory response.1gs20 Treatment of mice with cor t icos te r~ ids~~ and cyclophosphamideZ0 to reduce inflammation caused more severe disease. During the last decade, several lines of evidence have pointed to autoimmunity as a cause of myocarditis. Maisch and his colleagues’* have described heart-specific autoantibodies in patients with infectious myocarditis. These antibodies were found to mediate myocyte lysis by complement,21 as well as cell-mediated antibody-dependent cytotoxic- ity.22 In a murine model using BALB/c mice, Woodruff and his colleagues’*23 and

‘This work was supported by U. S. Public Health Service grant nos. HL-27932, HL-30144, and CA-34202 from the National Heart, Lung, and Blood Institute and from the National Cancer Institute.

146

ROSE et al.: POSTINFECTIOUS AUTOIMMUNITY 147

subsequently Huber et ul.24.25 demonstrated the presence in the spleens of CB,-infected animals of cytolytic T cells capable of damaging myocytes.

HISTOPATHOLOGY

We have undertaken an investigation designed to dissect the immunopathological mechanisms responsible for postinfectious myocarditis. We have concluded that Coxsackievirus-induced myocarditis is a complex polygenic disease, but with distin- guishable stages. Based on the pioneering reports of W ~ o d r u f f ' ~ and of Lerner,26 we constructed a murine model that allowed us to study the progression of disease in a variety of strains. For these studies, we infected two-week-old animals with 0.1 ml of 10' TCIDSO of CB, (Nancy) obtained from a Vero cell lysate. Tissue samples were

E R I T Y

7 14 21

DAYS AFTER INFECTION

FIGURE 1. Schema of the time course of the early virus-induced and the late immunopathic Coxsackievirus B,-induced myocarditis.

removed from infected and noninfected animals a t various times after infection. We have been able to take advantage of the large number of genetically defined mouse strains to highlight the diversity in the progression of CB3-induced myocardial disease. This approach was used to great advantage by Yoon el ~ 7 1 . ~ ~ to determine susceptibility to CB,-induced diabetes.

A time-course experiment was set up to delineate the progression of myocardial disease, as represented in FIGURE 1. This idealized concept is based mainly on a study using six different inbred strains (A.BY, A S W , A.CA, C3H.NB, BlO.PL, and BlO.S), which varied greatly in the tempo and severity of myocarditis. Histological examination of the hearts from these animals showed two distinct pattern^.'^.^^ The first histological evidence of myofibril injury was observed at the third day after infection. In general, the h is t~pa thology~~ was similar in all strains , with no gross abnormalities being observed in the hearts. Myocardial lesions were focal and were

148 ANNALS NEW YORK ACADEMY OF SCIENCES

associated with contraction band necrosis. The injured myocytes could be identified by dense eosinophilic changes, loss of myofibrillar definition, and disruption of the cell membranes. These histological changes were associated with small cellular infiltrates predominantly of polymorphonuclear leukocytes (PMN) and occasional macrophages. By day 7, the focal lesions had become less cellular and more fibrotic. Still, the lesions contained cellular infiltrates, consisting primarily of PMNs, and some mononuclear cells.

Later, the histopathological picture changed considerably. Some mouse strains (B1O.S and B1O.PL) were characterized by the absence of new focal lesions and by the replacement of the older lesions with dense linear bands of connective tissue that divided the muscle bundles. There was no evidence of active inflammation after day 9 in these strains. In general, the myocardial injury continued to resolve, as indicated by a gradual decrease in the total proportion of the myocardium affected. In contrast, a pattern of ongoing increasing inflammation was found in the A.BY, A S W , A.CA, and C3H.NB strains. At day 9, the focal lesions were heavily calcified and quite discrete. Inflammatory cells within the lesions were prominent and they were principally macrophages and lymphocytes. A diffuse interstitial infiltrate characterized this later stage of myocarditis. This interstitial infiltrate, composed of both large and small mononuclear cells, peaked 15 to 21 days after infection. Contraction band necrosis was rarely observed after day 9, except in the most severely affected cases. Some focal lesions containing PMNs reflected ongoing acute necrosis. Even 45 days after infection, evidence of continued inflammation with persistent interstitial mononuclear cellular infiltration was present, thus indicating a more chronic disease. Heart-specific autoantibodies were also present in mouse strains with the continuing disease. We therefore refer to the second phase of disease as “immunopathic.”

Several other investigator~’*’”~~ have examined the histopathology of the heart after infection with CB,. Reexamination of their data has indicated that their strains developed varying degrees of continuing myocarditis. However, they did not separate and distinguish the initial virus-induced myocardial damage and the accompanying inflammation from the ensuing immunopathic disease.

CHARACTERISTICS OF EARLY DISEASE

During the time-course study, several characteristics of the early disease were noted.” There were differences in the level and duration of viremia, in the content and persistence of virus in the heart, spleen, thymus, and pancreas, in the onset of the neutralizing antibody response, and in the severity of myocarditis. As demonstrated in FIGURE 2, the six strains could be separated into two significantly different categories. The more susceptible strains, A.BY and A S W , had virus levels in the serum greater than 104/ml two and three days after infection. In contrast, the more resistant strains, A.CA, BlOS, BlO.PL, and C3H.NB, had significantly lower CB, virus levels. Day 3 appeared to be a critical point for the appearance of neutralizing antibodies in the serum of the resistant strains since the two most susceptible strains (A.BY and A S W ) had no detectable antibodies to CB, on day 3. Yet no significant differences were observed in the final neutralizing antibody titers among the six strains. In general, the virus content of the spleen, thymus, and pancreas was greater in the susceptible strains. However, the amounts of CB, recovered from the heart did not show any statistical difference (FIGURE 3). The virus content of the heart peaked in all strains a t day 5, paralleling the time of the initial peak of myocardial injury. No infectious virus was detected in the heart after day 15. In contrast, the pancreas has been found to contain infectious CB, as long as 21 days after infection. Recently, other investigators, using

ROSE ef al.: POSTINFECTIOUS AUTOIMMUNITY 149

the technique of in situ hybridization, have been able to identify CB, RNA in the hearts of infected mice 35 days after infection (Tracy and Gauntt, personal communi- cation). Thus, these animals have a persistent viral infection.

As judged by histological appearance, the peak of myocardial injury was greatest a t 5 to 7 days after infection in all strains e ~ a m i n e d . * ~ ~ ~ ~ There were differences among the six strains in both the prevalence and severity of disease. Three categories of myocarditis were distinguished, namely, susceptible, intermediate, and resistant (TABLE 1). Some pathological changes were observed even in the most resistant strains, but disease was confined to several small focal lesions.

4

a - 3 E W a2

5 1

2 3 5

DAY FIGURE 2. Strain differences in viremia. The titer of infectious CB, was determined for each strain at day 2, 3, and 5 after infection and was expressed as the log,, mean CB3 titer/O.l ml of serum. The strains examined were A.BY (W), A S W (a), A.CA (A), B1O.S (v), B1O.PL (+), and C3H.NB (0) (from Wolfgram et aL3").

Genetic analysis suggests that susceptibility to infection by CB, is under polygenic c ~ n t r o l . ' ~ The A S W (H-2') mice were highly susceptible to the CB3 infection and the resulting myocarditis, whereas the BIO.S (H-2') animals were resistant to CB, infection and developed moderate to mild myocardial lesions (see TABLE 1). The BI0.S strain carries the H-28 haplotype derived from the A S W congenic line. From this comparison, we conclude that the non-H-2 background gene(s) determines susceptibility or resistance of mice to the CB, infection and the ensuing myocarditis. A major histocompatibility complex (MHC) influence was discerned by comparing various H-2 congenics on the A strain background (i.e., A.BY and A.SW versus A.CA). Thus, both MHC and non-MHC genes influence the degree of susceptibility to CB, infection and the resulting virus-induced myocarditis. In a subsequent study,34 we have examined a


DAY FIGURE 3. Strain differences in heart CB3 content. The content of infectious CB, in the heart from various strains was determined at days 2, 3, 5 , 7 , 9 , and 15 after infection. The titer of CB, was expressed as the log,, mean CB, titer/O.l g of heart tissue. The strains examined were A.BY (H), A.SW (O), A.CA (A), B1O.S (v), BIO.PL (+), and C3H.NB (0) (from Wolfgram et ~71. ’~ ) .

larger panel of B10 H-2 congenic strains carrying independent haplotypes for their susceptibility to myocardial injury (TABLE 2). Three different phenotypes of disease were observed: the susceptible stains were Bl0.Q (H-Zq), BlO.BR (H-Z’), and B10.D2 (H-Zd); the intermediate strains were BlO.PL (H-2”) , BIO.M (H-2‘), B1O.WB (H-2J), BlO.SM (H-2’), and B1O.S (H-2’); and the resistants were BlO (H-2b),

TABLE 1. Strain Variations in Early Myocarditis“ H-2

Strain Haplotype Phenotypeb A.BY A.SW

B1O.S B1O.PL C3H.NB

susceptible susceptible

intermediate intermediate intermediate

A.CA f resistant “Adapted from Wolfgram et a1.” ’The phenotype of myocarditis was determined by the prevalence and severity of the

myocardial lesions observed in animals at days 5 and 7 after infection.


B1O.RIII (H-2‘), and BI0.A (H-2”). These studies support the finding that the M H C influences the severity of myocarditis.

Mouse strains that carry the A background genome have been reported to carry several genetic traits that lead to increased susceptibility to various infectious diseases.35 First, a macrophage defect has been identified.36 Also, the A strains are low producers of a/@ interferon.” There may be many other heritable properties that are responsible for the general susceptibility of this strain to viral infection.38 Our current working hypothesis is that the non-MHC gene(s) determines mainly the extent of virus infectivity and the amount of virus replication in the tissue. If left unchecked by neutralizing antibody, severe disease ensues. However, if the M H C gene(s) directs a more vigorous immunological response, then moderate to little disease results.

The interrelationship between the non-H-2 and H-2 genes may be a complex

TABLE 2. Influence of the M H C on Early Myocarditis”

Strain

Bl0.Q BlO.BR B10.D2

B 1O.PL BIO.M B1O.WB BlO.SM BIO.S

B10 B1O.RIII B1O.A

-

H-2 Haplotype

9 k d

f U

j V S

b r a

Phenotype of Early Myocarditis

susceptible susceptible susceptible

intermediate intermediate intermediate intermediate intermediate

resistant resistant resistant

“Adapted from Beisel el al.34

CHARACTERISTICS OF LATER DISEASE

There are two markers of late disease: diffuse mononuclear infiltration and heart-specific a ~ t o a n t i b o d i e s . ~ ~ ~ ~ * * ~ ~ Transition from the early to late myocarditis began a t day 9, when an interstitial mononuclear cell infiltrate was first noted. In strains that did not develop late disease, no new lesions appeared and the older focal lesions were replaced by dense linear bands of fibrous scar tissue. These healing lesions contained few infiltrating cells. In strains that developed late disease, myocarditis was most severe 15 to 21 days after i n f e ~ t i o n . ~ ~ . ~ ~

Several different autoantibodies were found in the postinfection sera. These sera were tested, using indirect immunofluorescence, with normal uninfected heart, liver, pancreas, salivary gland, skeletal muscle, kidney, and stomach. Reactions were observed in a majority of postinfection sera from all six mouse strains (both with and without the later myocarditis) and they were most often directed to smooth and skeletal muscle and to nuclei. Such autoantibodies are commonly found in association with many viral infection^.^' However, only in animals with the late disease were there detectable heart-specific antibodie~.~’ Two fluorescent patterns were recognized, one characterized by localization at the sacrolemma/myolemma and the other by reaction with contractile proteins of both hkart and skeletal muscles. Because the antisera


reacted with both skeletal and heart tissues, absorption analyses were done.’g Exhaus- tive absorptions with lyophilized whole skeletal muscle homogenate~’~ removed the reactions with skeletal muscle, but left autoantibodies to the sarcolemma/subsarco- lemma and to the contractile proteins of heart (TABLE 3). These heart-specific autoantibodies were not species-specific because they reacted with rat and baboon hearts3g and have now been found to react with cardiac myosin.”

The presence of sarcolemmal/subsarcolemmal antibodies could be used as an indicator of autoimmune disease since almost all of the animals with these antibodies had the characteristic histopathology of late disease. Similar heart-specific autoantibodies have been described in patients with poststreptococcal rheumatic fever:’ Chagas’ postpericardiotomy syndrome,”*4s and postmyocardial infarction syndrome.”*45

Detailed comparisons were made between animals with and without heart autoantibodies using mouse strains that had been classified by pathological criteria as having the late disease. These findings showed that the late disease was more severe in animals with heart-specific autoantibodies. This observation was well borne out in the A.CA strain, which has a high prevalence of the late disease and a high titer of heart-specific a~toantibodies.’~ Both the characteristic mononuclear cellular infiltrate and the

TABLE 3. Absorption of Autoantibodies with Tissue Homogenates“ Reaction withb

Treatment Liver Skeletal Muscle Heart Unabsorbed 0

Absorbed with: liver 0 skeletal muscle 0 heart 0

3

3 0 0

4

4 2 0

“Adapted from Wolfgram et %sue reaction was determined by indirect immunofluorescence. The intensity of fluorescence

observed was graded on a C-4 scale.

presence of heart-specific autoantibodies support the concept that the late disease is immunopathic with an autoimmune origin. Recent studies in our laboratory suggest that the presence of IgG autoantibodies specific for cardiac myosin is a serological marker of immunopathic my~card i t i s .~~

Strain differences were noted in the prevalence and in the severity of the late disease (TABLE 4). Examination of the genetics suggested that the non-MHC gene(s) led to a predisposition to the autoimmune myocarditi~.’~ This conclusion was derived from observations that all the A strain congenics produced immunopathic disease, whereas the B10 congenics did not. No differences were seen in the severity of immunopathic disease among the three A congenic strains studied. Recent data from our laboratory have suggested that the MHC may also play some role in determining predisposition because three of eleven B10 congenic lines (B10.D2, BlO.BR, and Bl0.Q) with differing independent haplotypes developed immunopathic myocarditis.” These three B10 H-2 congenics were the ones with the most severe forms of early disease. At present, we suggest that heart-specific autoimmunity may also be produced in non-predisposed strains of mice as a result of unusually extensive myocardial injury caused by the earlier viral infection.

The MHC does play a role in regulating the heart-specific humoral resp~nse.’~ A/J

ROSE ef al.: POSTINFECTIOUS AUTOIMMUNITY 153

TABLE 4. Strain Variations in Late Myocarditis" H-2

Strain Haplotype Phenotype' A.BY A.CA A.SW C3H.NB

susceptible susceptible susceptible susceptible

B1O.S S resistant B1O.PL U resistant

"Adapted from Wolfgram et ~ 1 . ' ~ bThe phenotype of myocarditis was determined by the presence of heart-specific autoantibodies

and an interstitial mononuclear cell infiltrate at days 15 and 21 after infection.

(H-2'), A.BY (H-Zb), A.CA (H-2'), and A.SW (H-2') strains were examined for the prevalence and titer of heart-specific autoantibody (TABLE 5). W e found that the A S W and A.CA strains are high responders, the A / J animals are intermediate, and the A.BY animals are low responders. Thus, late myocarditis is an immunopathic disease under polygenic regulation. Predisposition to heart autoimmunity is determined by non-MHC gene(s), whereas the strength of the heart-specific antibody response is influenced by the MHC.

VALUE OF THE MURINE MODEL

There has been much speculation about chronic myocarditis and the development of cardiac immunity. Clinical studies have described the presence of heart-specific autoantibodies in patients with suspected viral myocarditis,'8.21 Adriamycin cardiomyopathy?' Trypanosoma cruzi myocarditi~:~.~~ postperi~ardiotomy,".~~ and postinfarction syndrome^!^.^^ The diagnosis of immunopathic myocarditis has been difficult because of the requirement for needle biopsies for their detection. The presence of heart-specific autoantibodies in serum may be a useful marker of ongoing myocardial disease.

Our model emphasizes the wide diversity of patterns of myocardial disease, depending upon the genetic predisposition of the individual to virus-induced myocardial injury and to the subsequent development of autoimmune myocarditis. With further genetic analyses, a number of genes may be identified that can determine an individual's susceptibility to heart disease and provide a means of risk assessment, as well as suggest the most appropriate treatment. Use of selected mouse strains will also provide excellent tools to explore the mechanism of autoimmune tissue damage. Mouse sera containing heart-specific autoantibodies can identify the pertinent myocardial

TABLE 5. M H C Influence on Heart-Specific Autoantibody Response ~

H-2 Percent Positive for Strain Haplotype Autoantibodies A.BY b 14

a 50 f 100

AIJ A.CA A S W S 100


autoantigen(s). I t is possible tha t t he spectrum of expressions of myocardial disease observed in our mouse strains can serve to provide insight into the question of why viral myocarditis resolves in some patients, while it progresses to chronic cardiomyopathies in others.

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DISCUSSION OF THE PAPER

P. CHRISTADOSS (University of Vermont, Burlington, V T ) : Have you tested F, mice? Is there dominant gene control of susceptibility or is there codominant control?

N. R. ROSE (Johns Hopkins Medical Institutions, Baltimore, MD): F, experiments have been carried out and the answer depends on what trait you are looking for. Are you considering, for example, early disease or late disease? Those are two different phenomena. In addition, autoantibody production is under separate genetic control. My colleague, K. W. Beisel, is studying genetic regulation of CB,-induced myocarditis.

K. W. BEISEL (Johns Hopkins Medical Institutions, Baltimore, MD): In the F, mice, resistance to both the early and late myocardial disease is under dominant genetic control. Most likely, these two disease processes are under separate regulation. Preliminary data from our laboratory suggest that the quantitative differences in heart-specific autoantibody production is under dominant control by the MHC.

S. A. HUBER (University of Vermont, Burlington, V T ) Is there any influence of the Ig-1 locus?

ROSE: We do not have any data concerning the Ig-1 as yet. That might be one of the non-H-2 traits.

H. WEINER (Harvard University, Boston, MA): In the late disease, have you been able to alter the course with immunosuppression? Have you looked for any T-cell reactivity to the myocardial antigens?

ROSE: Immunosuppression experiments trying to alter the second part of this disease have been carried out with cyclosporine. The critical event is when one gives the drug. I f one gives it a little too early, then one can make the viral disease worse; if one gives it too late, it may not have a therapeutic effect on the immunopathy. The therapeutic window may be very narrow. Thus, it is going to be extremely important to decide when the process has become primarily autoimmune rather than a virus- induced process. We have not examined cellular immunity in autoimmune myocarditis.

G. WICK (Institute of Innsbruck, Innsbruck, Austria): I want to raise a general question about molecular mimicry in the context of your work. The origins of that term had to do with the evolution of parasite-host relationships. I think it is especially interesting in relation to your model because we are dealing with an abnormal host for a particular virus. An example of the consequences of molecular mimicry is rheumatic fever, which occurs only in a few individuals after infection with Streptococci.

ROSE: I agree with what you are suggesting. It looks as if, a t least in some cases, an autoimmune response may be the price that some individuals have to pay to develop an immune response to certain infectious agents. Nevertheless, thus far, we have been unable to demonstrate any cross-reaction of the autoantibodies we have described and CB, viral proteins.

postinfectious autoimmunity: two distinct phases of coxsackievirus b3-induced myocarditis

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