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PII S1050-1738(05)00204-5
TCM
b 1-Adrenergic Receptor Function,
Autoimmunity, and Pathogenesis
of Dilated Cardiomyopathy
Roland Jahns*, Valérie Boivin, and Martin J. Lohse
Dilated cardiomyopathy (DCM) is a heart disease characterized by
progressive depression of cardiac function and left ventricular dilatation
of unknown etiology in the absence of coronary artery disease. Genetic
causes and cardiotoxic substances account for about one third of the
DCM cases, but the etiology of the remaining 60% to 70% is still unclear.
Over the past two decades, evidence has accumulated continuously
that functionally active antibodies or autoantibodies targeting cardiac h1-adrenergic receptors (anti-h1-AR antibodies) may play an
important role in the initiation and/or clinical course of DCM. Recent
experiments in rats indicate that such antibodies can actually cause
DCM. This article reviews current knowledge and recent experimental
and clinical findings focusing on the role of the h1-adrenergic receptor as
a self-antigen in the pathogenesis of DCM. (Trends Cardiovasc Med
2006;16:20–24) D 2006, Elsevier Inc.
Roland Jahns is at the Department of Internal Medicine, Medizinische Klinik und
Poliklinik I, and Institute of Pharmacology
and Toxicology,University of Würzburg,
D-97078 Würzburg, Germany. Valérie Boivin
and Martin J. Lohse are at the Institute of
Pharmacology and Toxicology, University of
Würzburg, D-97078 Würzburg, Germany.
* Address correspondence to: Roland Jahns,
MD, Medizinische Klinik und Poliklinik I, University of Würzburg, Josef-Schneider-Strasse 2,
D-97080 Würzburg, Germany. Tel.: (+49) 931201-71190; fax: (+49) 931-201-70730;
e-mail: [email protected].
D 2006, Elsevier Inc. All rights reserved.
1050-1738/05/$-see front matter
20
Progressive cardiac dilatation and pump
failure of unknown etiology and in the
absence of coronary artery disease has
been termed idiopathic dilated cardiomyopathy (DCM) (Richardson et al.
1996). Today, DCM represents one of
the main causes of severe heart failure
and disability in younger adults with an
annual incidence of up to 100 patients
and a prevalence of 300 to 400 patients
per million (American Heart Association
2005, Centers for Disease Control and
Prevention 1998). Mutations in genes
encoding myocyte structural proteins
and several cardiotoxic substances,
including alcohol and anthracyclines,
account for about one third of the cases
(Morita et al. 2005). The etiology of
the other two thirds, however, remains poorly understood. Patients with
DCM often present alterations in both
humoral and cellular immunity (Jahns et
al. 1999b, Limas 1997, Luppi et al. 1998).
Therefore, current theories on cardiac
tissue injury in DCM focus on abnormal
or misled immune responses to infections caused by cardiotropic viruses,
bacteria, or parasites (Limas 1997, Rose
2001). In the context of their humoral
immune response, a substantial number
of cardiomyopathic patients develop
cross-reacting antibodies and/or autoantibodies to various cardiac antigens,
including membrane proteins (e.g., cell
surface receptors [Jahns et al. 1999b,
Magnusson et al. 1994]), mitochondrial
proteins (e.g., adenine nucleotide translocator [Schultheiss and Bolte 1985]),
and myocyte structural proteins (e.g.,
actin, laminin, myosin, troponin [Caforio
et al. 2002, Neumann et al. 1990, Okazaki
et al. 2003]). In addition, genetic factors
may contribute to the susceptibility to
immunologic factors or to the phenotypic expression of the disease (Limas et
al. 2004). Irrespective of whether development of DCM is primarily triggered by
acute or chronic inflammatory or ischemic myocyte damage, or by abnormalities in the adaptive or innate immune
system (Eriksson et al. 2003, Luppi et al.
1998), in both cases progressive cardiac
tissue injury is thought to be mediated
mainly by cytokines and/or heart-specific autoantibodies (Caforio et al.
2002, Eriksson et al. 2003, Limas 1997).
The pathophysiologic importance of
such heart-specific antibodies is, however, far from clear. Low titers of autoantibodies to certain housekeeping
antigens are also found in healthy subjects as a part of the natural immunologic repertoire (Rose 2001). Moreover,
under physiologic conditions at least the
intracellularly localized myocyte antigens are not easily accessible for the immune system. From a pathophysiologic
point of view, it seems thus very likely
that the disease-inducing (i.e., harmful)
potential of a specific autoantibody
depends on two major factors: (a) the
accessibility and (b) the functional
importance of the respective target.
Therefore, cell surface receptors, and in
particular the contraction/relaxationregulating cardiac h1-adrenergic receptors (h1-ARs), represent ideal candidates
TCM Vol. 16, No. 1, 2006
for pathophysiologically relevant antibodies (Freedman and Lefkowitz 2004,
Limas 1997). The present article reviews
current knowledge and recent experimental and clinical data focusing on
the role of the h1-AR as an autoantigen
in the pathogenesis of DCM.
The Cardiac h 1-AR
The h1-AR belongs to the family of the G
protein-coupled receptors and constitutes about 70% to 80% of the cardiac
h-AR complement (Frielle et al. 1987).
It has ligand-binding properties that
clearly distinguish it from the other
h-ARs (Hoffmann et al. 2004). The
receptor molecule consists of seven
transmembrane (TM) a-helices with a
general structure as revealed by x-ray
crystallography of the blight-receptorQ
rhodopsin (Palczewski et al. 2000). The
a-helices form a hydrophobic pocket
that spans the membrane lipid bilayer
and serves as binding site for receptor
ligands (Bywater 2005). The seven TMhelices are linked by three extracellular
(h1-ECI-III) and three intracellular loops
(h1 -IC I-III ). With their intracellular
domains, h1-ARs couple to stimulatory
G proteins (Gs) (Figure 1).
Stimulation of h1-AR by their physiologic ligands epinephrine or norepinephrine triggers a signaling cascade
leading to sequential activation of Gs,
adenylate cyclase (which generates
cAMP), and cAMP-dependent protein
kinase (PKA). Activated PKA phosphorylates molecules involved in the regulation of sarcoplasmic Ca2+ concentration,
thereby increasing myocyte inotropy and
lusitropy (Freedman and Lefkowitz
2004, Lohse et al. 2003).
In the h2-AR subtype, amino acids in
TM-helices III, V, and VI have been
assigned an anchoring function for agonists, suggesting that the extracellular
loops do not directly participate in
ligand binding (Wieland et al. 1996).
However, the second extracellular loop
(ECII) is predicted to form a b-hairpin,
which dips down partly into the ligandbinding site and thus might in fact
influence receptor–ligand interactions
to some extent (Bywater 2005). The
conformation of this hairpin is thought
to be stabilized by cysteines situated in
ECI and ECII. In the case of h2-AR, it has
been shown that reduction or mutation
of one or several of these cysteines
results indeed in a significant reduction
TCM Vol. 16, No. 1, 2006
Figure 1. Schema depicting antibodies (Ab) targeting the second extracellular loop of the h1-AR.
Binding of the antibody induces or stabilizes an active receptor conformation and thereby
engenders an intracellular signaling cascade leading to activation and subsequent dissociation of
the heterotrimeric Gs protein in Gas and Ghg subunits. Gas activates both adenylyl cyclase (AC),
which catalyzes cAMP formation (ATP Y cAMP + Pi) and the L-type calcium channel (not
depicted); cAMP in turn activates PKA, which then phosphorylates various substrates critically
involved in the regulation of intracellular/sarcoplasmic calcium levels (not shown).
of agonist and antagonist affinities
(Dohlman et al. 1990, Noda et al. 1994).
Thus, in h-AR correct folding of one or
both extracellular loops (ECI/II) may be
essential for correct formation of the
ligand-binding pocket and might explain
why antibodies directed against these
loops can interfere with ligand binding,
modulate receptor conformation, and
thereby also modulate receptor activity
(Jahns et al. 2000).
Etiology of Autoantibodies Against
Membrane Receptors
Homologies between myocyte surface
molecules such as surface membrane
21
receptors and microbial determinants
may represent one key mechanism for
the generation of endogenous receptor
autoantibodies by antigen mimicry
(Hoebeke 1996). Chagas’ heart disease,
a slowly evolving inflammatory cardiomyopathy, is probably one of the best
examples to illustrate this mechanism
(Elies et al. 1996). The disease results
from an infection with the protozoon
Trypanosoma cruzi; molecular mimicry
between the ribosomal PO protein of
T. cruzi and a polyanionic stretch within
the N-terminal half of h1-ECII results in
cross-reacting antibodies in about 30%
of the Chagas’ patients (Ferrari et al.
1995). In contrast, receptor antibodies
associated with DCM have been found to
recognize mainly epitopes encompassing
the cysteine residues situated in the
C-terminal half of h1-ECII (Wallukat et
al. 1995). It has been speculated that
recognition of this epitope might also
originate from molecular mimicry
between h1-ECII and a hitherto unidentified viral pathogen (Magnusson et al.
1996).
Another hypothesis for the etiology of
endogenous receptor autoantibodies is
that antigenic determinants from the
surface or cytosols of the myocytes
themselves, which are protected against
the immune system under physiologic
conditions, may become accessible
after myocyte injury. Such injury most
likely occurs during ischemic (acute
myocardial infarction) or infectious
heart disease (acute myocarditis) leading to myocyte apoptosis and/or necrosis
(Caforio et al. 2002, Rose 2001). Subsequent liberation and presentation of
myocardial self-antigens to the immune system may then induce an autoimmune response. In the worst case, this
response might result in perpetuation of
immune-mediated myocyte damage
involving either cellular (i.e., T cell) or
humoral (i.e., B cell) immune responses
or coactivation of both the innate and
the adaptive immune system (Eriksson
et al. 2003, Rose 2001).
The h 1-AR as an Antigen
To serve as an antigen, myocyte membrane receptors must be degraded to
small oligopeptides, and one or more of
the degradation products must be able to
form a complex with one of the major
histocompatibility complexes or HLA
22
class II molecules of the host. More than
a decade ago, the human h1-AR has been
analyzed for potential immunogenic
amino acid stretches accomplishing the
requirements for a peptide to be complexed and presented to a T-cell receptor (Guillet et al. 1991). The analysis
confirmed previous experimental data
inferring that the only stretch of the
h1-receptor molecule containing B- and
T-cell epitopes and being accessible to
antibodies is in fact the predicted h1-ECII
loop (Hoebeke 1996). This might explain
the successful use of h1-ECII peptides for
the generation of anti-h1 -EC II antibodies in various animal models with
or without the use of carrier proteins
and suggests the presence of a T-cell
epitope in the ECII loop (Jahns et al.
1996, 2000, Matsui et al. 1997). Subsequently, several groups have independently demonstrated that almost all
anti-h1-ECII antibodies preferentially
recognize a native h1-AR conformation
in a variety of immunologic assays
(whole cell ELISA, immunoprecipitation, immunofluorescence), indicating
that most anti-h1-ECII antibodies are
bconformationalQ antibodies (Hoebeke
1996, Jahns et al. 2000). Moreover, functional tests revealed that the same antibodies were able to affect receptor
function, such as intracellular cAMP
production and/or cAMP-dependent PKA
activity, suggesting that anti-h1-EC II
antibodies may also act as allosteric
regulators of receptor activity (Figure 1).
A striking feature of such allosterically
modulating anti-h1-AR antibodies is that
they may promote, reduce, and/or stabilize conformational changes of the
receptor similar to those induced by
agonist or partial agonist ligands (Jahns
et al. 2000, Vilardaga et al. 2005).
Because these anti-h1-AR antibodies recognize a native receptor conformation, it
seems conceivable that they may recognize different conformational states
within the targeted receptor domain
(i.e., some antibodies recognize and
stabilize the active and others the inactive form).
Pathogenetic Impact of Stimulating
Anti-h
h1-AR (Auto)antibodies
Following Witebsky’s postulates
(Witebsky et al. 1957), indirect evidence
for an autoimmune etiology of a disease
requires identification of the corre-
sponding self-antigen and induction of
an analogous immune response in an
experimental animal, which finally must
also develop a similar disease. Direct
evidence, however, requires reproduction of the disease by transfer of homologous pathogenic antibodies or
pathogenic autoreactive T-cells from
one to another animal of the same
species (Rose and Bona 1993). For more
than a decade, it has been accepted
that h1-ECII represents a self-antigen
(Magnusson et al. 1989). In 1997, Matsui
et al. were able to show that rabbits
immunized against h1-ECII develop a
cardiomyopathic phenotype. Three years
later, Omerovic et al. (2000) reported
that intraperitoneal injection of blood
lymphocytes from anti-h1-AR antibodypositive DCM patients into immunodeficient mice may lead to an early stage of
cardiac dilatation. Nonetheless, direct
evidence for a cause-and-effect relation
between anti-h1-EC II antibodies and
DCM still remained to be obtained.
To analyze the pathogenetic potential
of anti-h1-AR antibodies, we chose an
experimental in vivo approach that met
the Witebsky criteria for direct evidence
of autoimmune diseases. We induced
DCM by immunizing inbred rats against
h1 -EC II (100% sequence homology
between human and rat [indirect evidence]) and then reproduced the disease
in healthy isogenic rats by transferring
the bautoantibodiesQ (direct evidence)
(Jahns et al. 2004). The cardiomyopathic
phenotype in these rats was characterized by progressive left ventricular dilatation and dysfunction, a relative
decrease in left ventricular wall thickness, and selective downregulation of
h1-AR, a feature that is also seen in
human DCM (Lohse et al. 2003). These
results, in conjunction with the demonstrated agonist-like short-term effects of
the antibodies in vivo (Jahns et al. 2004),
suggest that both the induced and the
transferred cardiomyopathic phenotypes have to be attributed mainly to
the mild but sustained receptor activation achieved by stimulatory anti-h1-ECII
antibodies. This hypothesis is supported by the large body of data
available on the cardiotoxic effects of
excessive and/or long-term h1-AR activation seen after genetic or pharmacologic
manipulation (Engelhardt et al. 1999,
Woodiwiss et al. 2001). Therefore, antih1-AR-induced dilated immune cardioTCM Vol. 16, No. 1, 2006
myopathy should now be regarded as a
pathogenetic disease entity of its own,
together with other established receptordirected autoimmune diseases such as
myasthenia gravis or Graves disease
(Freedman and Lefkowitz 2004, Hershko
and Naparstek 2005).
Clinical Impact of Stimulating
Anti-h
h1-AR Antibodies and Future
Perspectives
The actual clinical importance of autoantibodies directed against cardiac antigens is difficult to assess because low
titers of such antibodies can also be
detected in the healthy population as a
part of the natural immunologic repertoire (Rose 2001). However, regarding
functionally active anti-h1-AR antibodies, we have previously shown that their
prevalence was very low in healthy
individuals (b1%), when a screening
procedure based on cell systems presenting the respective target (e.g., the
human h1-AR) in its natural conformation is used (Jahns et al. 1999b). By
using the same screening modality, we
could also exclude significant amounts
of circulating anti-h1-AR antibodies in
patients with heart failure due to
chronic valvular or hypertensive heart
disease (Jahns et al. 1999a). In contrast,
the prevalence of stimulating anti-h1-AR
antibodies was ~10% in ischemic and
~30% in dilated cardiomyopathy (Jahns
et al. 1999b), which was significantly
higher than in healthy collectives, but in
the lower range of the values obtained
for DCM patients in previous studies,
reporting antibody prevalences from
33% up to 95% (Limas et al. 1992,
Magnusson et al. 1994, Wallukat et al.
1995). It seems conceivable that differences in screening modalities aiming to
detect functionally active anti-h1-AR
antibodies, which may comprise autoantibodies directed against h1-ECII, h1ECI, or against both epitopes, account
for the wide range of anti-h1-AR antibody prevalences reported in the past.
In this regard, it has been shown that of
ELISA-defined human autoantibodies
against h-AR, only a minor fraction
seems to be able to bind to cell surface
located native h1- or h2-AR. Only this
fraction recognized (as determined by
immunofluorescence) and activated (as
determined by increases in cellular
cAMP and/or PKA activity) human h1TCM Vol. 16, No. 1, 2006
AR expressed in the membrane of intact
cells (Jahns et al. 1999b, 2000). We
therefore advocate cell systems presenting the target in its natural conformation as an important tool in the
screening for functionally relevant antih-AR autoantibodies.
Clinically, the presence of anti-h1-AR
autoantibodies in DCM has been shown
to be associated with a more depressed
cardiac function (Jahns et al. 1999b), the
occurrence of more severe ventricular
arrhythmia (Chiale et al. 2001), and a
higher incidence of sudden cardiac death
(Iwata et al. 2001). Concordantly, in our
DCM patients judged to be positive for
anti-h1 -EC II antibodies, we found a
higher prevalence of ventricular arrhythmia (Lown class III-IV) compared with
antibody-negative DCM patients during
a follow-up period of more than 10 years
(Störk et al. 2004). Moreover, multivariate analysis of the follow-up data
revealed that, in DCM patients, the
presence of activating anti-h1-ECII antibodies was independently associated
with an almost three-fold increase in
cardiovascular mortality risk (Störk et
al. 2004). Taken together, the preliminary clinical data underscore the pathophysiologic relevance of functionally
active anti-h1-AR antibodies in DCM
and encourage further research in the
evolving field of antibody-directed strategies as a therapeutic principle (Freedman and Lefkowitz 2004, Hershko and
Naparstek 2005). In this regard,
one aspect of the beneficial effects of
h1-receptor blockade in DCM might be
the pharmacologic neutralization of
autoantibody-mediated stimulatory effects (Freedman and Lefkowitz 2004,
Jahns et al. 2000), at least if h-blockers
can indeed completely or largely prevent the antibody-induced activation
of the receptors. Alternative therapeutic
options would include elimination of
activating anti-h1 -AR antibodies by
nonselective or selective immunoadsorption (Hershko and Naparstek 2005,
Wallukat et al. 2002) or direct targeting
of the anti-h1-ECII-producing B-cells
themselves (Anderton 2001). Although a
recent smaller pilot study in DCM
patients did not show a correlation
between hemodynamic benefit of immunoadsorption and anti-h1-AR antibody
positivity (Mobini et al. 2003), the results might be difficult to interpret
because native human h-ARs were not
used to define anti-h1-AR antibody status. One prerequisite for an unequivocal
interpretation of future clinical trials
would be a standardized screening procedure for functionally active human
anti-h1-AR antibodies using cell systems
presenting the target receptor in its
natural conformation.
In conclusion, although stimulating
anti-h1-AR antibodies can clearly be
pathogenic, the pathophysiologic
sequence of events leading to their generation, their relative contribution to the
pathogenesis of human DCM, and their
relevance for prognosis and therapy still
remain to be determined.
Acknowledgments
Our work was supported by the Deutsche Forschungsgemeinschaft (grants Ja
706/2-3 and Ja 706/2-4).
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