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Complement activation in muscle fiber necrosis Demonstration of the membrane attack complex of complement in necrotic fibers.

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Complement Activation in Muscle Fiber
Necrosis: Demonstration of the Membrane
Attack Complex of Complement
in Necrotic Fibers
Andrew G. Engel, MD," and Gregory Biesecker, P h D t
The membranolytic C5b-9 complement membrane attack complex (MAC) is assembled after activation of either
the classic or the alternative complement pathway. The quaternary configuration of the MAC macromolecule
presents neoantigenic determinants not present on precursor molecules. Consequently, antibodies specific for these
neoantigen(s) do not detect nonspecifically bound native complement precursors of MAC. By means of antibodies
rendered specific for MAC neoantigen(s), MAC was localized by the immunoperoxidase reaction in cryostat sections
of human muscle. In 66 biopsy specimens containing necrotic muscle fibers (Duchenne dystrophy, 13; other dystrophies, 15; inflammatory myopathies, 31; miscellaneous myopathies, 7) all of the necrotic fibers reacted for MAC
neoantigen(s). C3 and C9 were also consistently localized in necrotic fibers, but localization of Clq, C4, and IgG was
variable and often did not exceed background staining. None of the nonnecrotic fibers reacted for immunoglobulin
or complement. Detection of MAC neoantigenb) in necrotic fibers in a wide variety of muscle diseases unambiguously shows that ( 1 ) the lytic complement pathway is consistently activated and participates in muscle fiber necrosis
in vivo, and (2) complement reaction products are generated that can stimulate cellular infiltration and
phagocytosis of the necrotic fiber. The findings also suggest that cell necrosis in general may involve participation
of complement.
Engel AG, Biesecker G: Complement activation in muscle fiber necrosis: demonstration of the membrane
attack complex of complement in necrotic fibers. Ann Neurol 12:289-296, 1982
Although muscle fiber necrosis occurs commonly in
many neuromuscular diseases, its mechanisms are
poorly understood. In o n e disorder, Duchenne dystrophy, defects of the surface membrane have been
demonstrated in nonnecrotic fibers by ultrastructural
studies [12, 25, 391. Such defects allow ingress of
calcium-rich extracellular fluid [8, 251, which may
initiate fiber necrosis, but it has not been established
that similar small defects of the surface membrane
precede fiber necrosis in all myopathies. Focal calcium increases have also been observed in circumscribed regions of nonnecrotic fibers in
Duchenne dystrophy and less frequently in other
muscle diseases [6].Further, abnormal deposition of
calcium occurs in all necrotic fibers [6, 311. Intracellular calcium excess may promote muscle fiber
necrosis by impairing the respiratory activities of
mitochondria [43, 441, by activation of a calciumdependent neutral protease [ 1, 101, by depolymerization of microtubules [ 381, and by overloading
the calcium uptake capability of the sarcoplasmic
reticulum [ l l , 131.
In this paper we present evidence for an additional
mechanism of muscle fiber destruction. We demonstrate that complement activation leading to the formation of the mcmbranolytic C5b-O membrane attack complex (MAC) consistently occurs in the
course of muscle fiber necrosis in vivo. In most cases,
immunoglobulin cannot be detected in the necrotic
fibers. T h e MAC can directly damage muscle fibers,
and the chemotactic fragment C5a produced concomitant with MAC formation can recruit macrophages and neutrophils to the damaged fibers.
From the *Department of Neurology and the Neuromuscular Research Laboratory, Mayo Clinic and Mayo Foundation, Rochester,
M N 55905, and the tDepartment of Pathology, h h n e m a n n
Medical College, Philadelphia, PA 19102.
Received Dec 1,198 1, and in revised form Jan 14,1982. Accepted
for publication Jan 23, 1982.
Materials and Methods
C h ical Material
Limb muscles of patients suffering from neuromuscular
diseases were biopsied for diagnosis. The muscle specimens, mounted on a chuck, were flash-frozen at - 150°C in
isopentane chilled by liquid nitrogen and subsequently
Address reprint
D~ ~
0364-5 134/82/0')O289-O8$01.25@ 1981 by the American Neurological Association
were stored under liquid nitrogen. Sixty-six specimens that
contained necrotic fibers were studied. T h e following cases
were represented: Duchenne dystrophy, 13; other dystrophies, 15; inflammatory myopathies, 3 1; idiopathic
myoglobinuria, 4 ; myophosphorylase deficiency, 1; and
other myopathies, 2. Serial 10 p m sections were cut from
each specimen in a cryostat and processed without fixation.
One or more sections in each series were stained
trichromatically I151 and the remainder were used for immunocytochemical studies.
bit antihuman C 3 and C l q immunoglobulins (Bio-Rad
Laboratories); goat antiserum to rabbit IgG (Miles
Laboratories Ltd); and staphylococcal protein A (Pharmacia
Fine Chemicals). Immunoglobulins were prepared from
antisera by amnioniun~sulfate fractionation 1421. Rabbit
antihuman C3 and antihuman C9 immunoglobulins, goat
antirabbit IgG immunoglobulin, and protein A were
labeled with peroxidase by the method of Nakane and
Kawaoi [28l, as previously described [14, 371.
I mmu nocytochemical Procedures
Preparation o f Antibodies Directed Against C5b-9
Neoantigen (s)
Human MAC was extracted from complement-lysed rabbit
erythrocyte membranes and purified by the method of
Biesecker et a1 [ S ] . Antibodies to MAC were raised in rabbits by injection of 200 pg of antigen emulsified with complete Freund’s adjuvant followed by bimonthly injections
of 100 p g of antigen in incomplete Freund’s adjuvant.
Animals were bled five days after each injection. T h e antisera were analyzed by Ouchterlony double immunodiffusion with purified MAC and whole human sera in
agarose using a 0.03 M Tris-glycine buffer also containing
1 9 ) Triton X-100 and 10 mM EDTA. Antisera reacting
against MAC neoantigens, as evidenced by spurring of the
precipitin line with MAC over the precipitin lines with
whole serum [23 1, were pooled. The pooled sera were rendered specific for neoantigenic determinants of MAC by
adsorption with whole human plasma coupled t o Sepharose
Proof of Specificity of the Adsorbed Antiserum for
Neoantigenic Determinutits of MAC
Specificity was established in four ways. (1) In Ouchterlony
analysis, the adsorbed rabbit antisera produced a precipitin
line with MAC but not with fresh whole serum containing
native complement components. (2) The agglutination by
antineoantigen(s) of glutaraldehyde-fixed sheep erythrocytes coated with MAC [23] was not inhibited by the addition of whole human serum, but was abolished by prior
adsorption of the antineoantigeds) with purified MAC. (3)
A radioimrnunoassay was also devised to test the specificity
of the antineoantigen(s) (Biesecker G , Curd JG, and MullerEberhard HJ: unpublished Jata). Briefly, purified . M A C
labeled with
by the lactoperoxidase method (Enzymobeads, Bio-Rad Laboratories), was incubated with antineoantigen(s) for 8 hours. Goat antirabbit immunoglobulin was then added and the incubation continued for 16
hours. The immune precipitate was pelleted and the
radioactivity in the pellet and supernatant quantitated [ 2 11.
The labeled MAC was precipitated by antineoantigen(s),
but not by normal rabbit serum. Addition of fresh whole
human serum had n o effect, but excess unlabeled MAC
completely inhibited the precipitation. ( 4 ) Finally, the
binding of antineoantigen(s) to target sites (described in
Results) was not inhibited by the addition of fresh whole
human serum to the incubation system.
Other Imniunoreugents
The following reagents were obtained commercially: rabbit
antisera to human C 9 and C4 (Behring Diagnostics); rib-
290 Annals of Neurology Vol 12 No 3 September 1982
The direct or indirect immunoperoxiciase method was used
to demonstrate antigens in cryostat sections of unfixed
muscle [ 14, 371. MAC neoantigen(s1 were demonstrated by
the indirect method. Rabbit immunoglobulin specific for
MAC neoantigen(s) (25 to 50 pg/ml) was used as the first
reagent; peroxidase-labeled goat antirabbit IgG ( 10 pgjml:~
was employed as the second reagent. The immunoreagents were in phosphate-buffered saline, p H 7.2, which
also contained 1P (v/v) nonimmune, heat-inactivated goat
serum and 2‘2 ( w h ) bovine serum albumin. Specificity
controls consisted of adsorption of the first reagent with
MAC coupled to Sepharose 4B-CL; substitution of preimmune rabbit immunoglobulin for the first reagent; application of the first reagent in the presence of fresh whole
human serum; omission of either the first or second reagent; and omission of H20, from the diaminobenzidine
C l q and C4 were localized by the indirect method with
rabbit antisera at 1 :800 dilution as first reagents and with
peroxidase-labeled goat antirabbit IgG (10 pg/ml) as the
second reagent. Controls consisted of substitution of
preimmune rabbit serum for the first reagent; omission of
either first or second reagent; and omission of H,O, for the
diaminobenzidine medium. C3, C9, and IgG were localized
by the direct method with peroxidase-labeled rabbit antibodies to C3 and C9 and protein A, respectively, as described before 14, 371.
Loculization of M A C Neountigen(J)
Necrotic fibers were readily identified in trichromatically stained fresh-frozen sections by their pale
green to green-blue color (normal color, deep blue).
Such fibers have absent, attenuated, or clumped
intermyofibrillar membranous networks and may
o r may not be invaded by macrophages (Fig l A ,
C, E, G; Fig 2A; Fig 3A). Remnants of necrotic
fibers can persist immediately adjacent to regenerating fiber elements within confines of areas previously
occupied by nonnecrotic fibers (Fig 1G).
T h e presence of MAC neoantigen (or antigens)
was demonstrated in all necrotic fibers in each of
the biopsy specimens. Those portions of necrotic
fibers not replaced by macrophages reacted vividly
(Fig lB, D, F, H: Fig 2B; Fig 3B). Muscle fiber regions showing signs of regeneration (prominent nuclei
and pink-blue cytoplasm in trichromatically stained
sections) did not react for MAC neoantigen(s) even
F i g 1 . Adjacent sectiom in Ducbenpie dystrophy (A. B ) , limb
girdle dystrophy ( C , 0).polyniyositis ( E , F ) , and idiopathic
niyoglobinuria (G, Hi. either stained trichronzatically ( A . C.
E , G ) or reacted for M A C neoantigen(s) aiid then lightly
counterstained with hetnatoxylin ( B , D , F , H i . In trichromatically stained sections the necrotic fibers are reudily
identifed by their pale cytoplasm. Macrophages (arrows) in-
zlade uerroticfibet-sin A and E , and zti A one Jiber has been
nearly completely remoiled by the macrophages (asterisk). I n G .
contours of severalfibers contain necrotic material and regeneratiiig elements (arrowheads). All necrotic fibers react
strongly for M A C neoantigen(s1. The background staining i s
negligible. ( A . B. ~ 4 0 0C-F,
~ 2 5 0G
: ,H , ~800.1
Engel and Becker: Complement Participates in Muscle Fiber Necrosis
when immediately adjacent to necrotic fiber remnants (Fig lG, H). Background staining of interstitial
elements was absent except for strong reaction associated with eosinophils. These cells were readily
distinguished from necrotic fibers (Fig 2B). Replacement of the first reagent with preimmune rabbit
IgG gave no or minimal nonspecific staining of necrotic fibers. Adsorption of the first reagent with
MAC (Fig 2C), omission of either the first or second
reagent, or omission of H,O, from the diaminobenzidine medium abolished the reaction in the
necrotic fibers. Application of the first reagent in
the presence of fresh whole human serum did not
inhibit the reaction for MAC neoantigen(s) in the
necrotic fibers. The reaction in eosinophils was eliminated only by omission of H,O, from the diaminobenzidine medium, indicating that it was due to
the peroxidatic activity of eosinophilic granules,
F i g 2. Adjacent sections in Duchenne dystrophy stained trireacted f o r M A C neoantigenls) ( B ) , reacted
chromatically (A).
for. M A C neoantigen(J) after adsorption of the primary immunoreagent with MAC ( C ) ,and reacted for C9 (Di. Sections
B. C , und D are also lightly counterstained with hematoxyiin.
The iiecroticjibers are iiwaded und partly replaced by itiacrophages (arrows). Necrotic elenients n o t replaced by tnacrophages react s i d h for M A C neoaiitigeri(s)and C9. Adsorption of anti-MAC neoantigetiis) with M A C aboLishes the
cytochemiral reaction in the necrnticfibers ( C ) .Small, intensely
reacting triangular spots between muscle fibers in B represent
peroxida tic act iz'ity as tociated with eosinophils (asterisks).
( x250.j
Localization of Other Coniplemerzt Proteim
The presence of MAC neoantigen(s) in necrotic
fibers was evidence that the lytic phase of the complement reaction sequence had gone to completion.
Therefore, it was of interest to search for other complement proteins in the necrotic fibers. Because native complement proteins are also present in the interstitial fluid, which can permeate the necrotic
fibers, localization was considered significant only
Annals of Neurology Vol 12 N o 3
September 1982
when it was clearly more intense than the background staining.
C 9 was localized in all necrotic fibers in all specimens, with negligible background staining (Fig 2D).
The intensity of the reaction was comparable to that
for MAC neoantigen(s) (Fig 2B).
C 3 was localized in all necrotic fibers in all specimens, with slight background staining (Fig 3C). In 57
specimens the intensity of the reaction in necrotic
fibers was stronger than the background staining, but
in 9 specimens (Duchenne dystrophy, 1; limb girdle
dystrophy, 4 ; inflammatory myopathy, 3; myophosphorylase deficiency, 1) the reaction in the necrotic
F i g 3. Nonconsecutizle serial sec-tiotis i n limb girdle dystrophy
stained trichromatically (A)and reacted for M A C ( B ) , C3
(Ci. C4 (Di, C l y ( E i , and IgG ( F ) . Sections B , C,D , E, and
F are also lightly counterstained with hematoxylin. Two necroticfibers invaded by macrophages are uisualized i n all sections. The reactiotisfor C9 and C3 are more intense than the
background stain. The rea~-tionsfor Clq,C4, and IgG do n o t
exceed the background stain except for a small zone i n one fiber
(arrow) tohere the reaction for C l q exceeds the background
stain. Empty spares in fibers in D and I’ represent preparatory
artifact. ( X240.)
fibers was only slightly more intense than the background staining.
C l q and C4 participate in the assembly phase of
the classic complement pathway [26]. However, C l q
binding is reversible and C4 is subject to proteolytic
degradation. Therefore, lack of localization of these
complement components does not preclude involvement of the classic pathway in fiber necrosis. In
most necrotic fibers the reaction for C l q or C4 did
not exceed background staining. However, in each
disease group a few necrotic fibers were found in
which the intensity of the reaction for either C l q or
C4 was greater than the background staining (Fig 3D,
Localization of IgG
Substantive localization of IgG in necrotic fibers
would be consistent with activation of the classic
pathway since IgG molecules attached to antigenic
sites may fix C l q [26].However, since abundant IgG
is present in interstitial fluid, the reaction in the necrotic fibers must distinctly exceed background staining to have any significance. In 56 specimens no
significant IgG deposits occurred in necrotic fibers
(Fig 3F), but in 10 specimens (Duchenne dystrophy,
1; limb girdle dystrophy, 1; idiopathic myoglobinuria, 3 ; inflammatory myopathy, 5 ) the reaction for
IgG in some necrotic fibers was more intense than
the background staining.
Engel and Becker: Complement Participates in Muscle Fiber Necrosis
Pdthways of Complement Actiwation
Complement activation can occur through either the
classic pathway (via C l q , C l s , C l r , C4, C2, and C3)
or the alternative pathway (interaction of c3 with
properdin [PI and factors B and D) [26, 271. Either
pathway leads to the formation of a C5 convertase:
C4b2a3b for the classic pathway and C3bBbC3bP for
the alternative pathway(C4b, C2a, C3b, and Bb representing cleavage products of C4, C2, C3, and factor
B, respectively). Both C5 convertases generate C5a
and C5b, and C5b initiates self-assembly of MAC.
MAC is a highly stable, cylindrical macromolecule
that avidly binds to membrane phospholipids and
thus induces focal and irreversible membrane lesions
[3, 5, 361. Complement activation products have additional effects. The product C5a is chemotactic for
macrophages and neutrophils [ 17, 361, enhancing
their migration to sites where C5 is split; Bb immobilizes and spreads macrophages that reach the
target surface [4,40]; and targetbound C3b enhances
phagocytosis by interacting with specific macrophage
receptors (opsonization) [ 191.
Specificity and Significance of MAC Localization i n
Necrotic Fibers
Previous immunofluorescent studies showed no consistent or specific association between necrosis of
skeletal muscle fibers and deposition of complement.
C3 was observed in degenerating [20, 411 as well as
in normal fibers [20, 321, and the reaction was often
accompanied by staining for IgG or IgM [32, 411. In
one study [41], deposits of IgG, IgM, or C 3 were
observed in abnormal fibers in 22 of 39 cases of
idiopathic inflammatory myopathy but were also
found in similarly abnormal muscle fibers in many
other conditions. From this it was concluded that
muscle fiber deposition of immunoglobulin and C3
appeared to carry little importance other than that
such deposits may be found in structurally altered
fibers. More recently, C 3 was localized in ischemic
baboon myocardium, implicating the complement
system in myocardial injury following coronary occlusion [35].
This study shows that the presence of MAC in necrotic muscle fibers cannot be due to nonspecific adsorption of native complement precursors, because
the antibody used to localize MAC recognized only
the neoantigenic determinants of the C5b-9 macromolecule. Further, the cytochemical localization of
MAC could not have been due to nonspecific binding
of rabbit antibodies to necrotic material, for sections
incubated with preimmune rabbit immunoglobulin
or with immunoglobulin from immune serum that
had been adsorbed with MAC gave negative results.
Therefore, the localization of MAC neoantigen(s) in
all necrotic fibers indicates the following: (1) there is
294 Annals of Neurology Vol 12 No 3 September 1982
ingress of complement components into the fiber; (2)
the lytic pathway becomes activated; (3) MAC is assembled; (4) MAC binds to target surfaces within the
fiber; and (5) the cleavage of C5, required for MAC
assembly, releases the chemotactic C5a molecule,
which can recruit neutrophils and macrophages to the
necrotic fiber, where other complement reaction
products (C3b and Bb) can stimulate phagocytosis of
the necrotic fiber.
Why and Hozv Is Complement Activated during
Muscle Fiber Necrosis?
The localization of C3 in necrotic fibers implicates
either the classic or the alternative pathway, whereas
the variable localization of C l q and C4 neither
proves nor disproves involvement of the classic pathway. T h e classic pathway might be activated by C l q
binding to immune complexes. For example, circulating autoantibodies (antistriational [34], antirnyoglobin [29], antinuclear [30]), known to exist in certain disorders, could recognize specific antigens in
damaged fibers and thus trigger the classic pathway.
This could have occurred in only a small proportion
of our cases in which there was strong IgG localization in necrotic fibers: in 3 of 4 cases of idiopathic
myoglobinuria and 5 of 3 1 cases of inflammatory
myopathy, but in only 2 of 58 other specimens examined. The high incidence of IgG localization in
necrotic fibers in idiopathic myoglobinuria may be
pathologically significant. However, a number of
antibody-independent mechanisms of complement
activation could operate in all cases.
C l q , which initiates the classic pathway, binds to
intermediate (10 nm) cytoskeletal filaments in cultured human fibroblasts rendered permeable to
serum by detergents [24]. C l q also binds to Creactive protein attached to choline phosphatides
[22]. Human heart mitochondria incubated with
human serum activate both complement pathways
[18]. Cultured human kidney cells injured by heat
(56°C for 1 hour) activate the alternative pathway [2].
Proteolytic degradation of C3 may initiate the classic
or alternative pathway, and proteolytic cleavage of
C5 may lead to the assembly of MAC directly [7, 91.
Finally, stripping of sialic acid residues from sheep
erythrocytes activates the alternative pathway [ 16,
331. The last finding is particularly intriguing, as it
suggests that altered biological membranes may
“self-destruct” by triggering the alternative pathway.
Although further studies will be required to define
the manner in which complement is activated in the
course of muscle fiber necrosis, exposure of complement proteins to intracellular organelles (mitochondria, intermediate filaments), altered biological membranes, o r proteolysis could be inferred
to cause activation. Whatever the triggering mechanism, complement activation products are formed
that directly damage membranous organelles (MAC)
and promote the efficient removal of critically injured fibers by macrophages. Finally, cell necrosis in
general may involve the participation of complement.
Supported in part by Grant N S 6277 from the National Institutes
of Health and a Research Center Grant from the Muscular Dystrophy Association.
We thank Miss LouAnn Gross for expert technical assistance and
Mrs Linda McConahey for preparation of this manuscript.
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