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Common variable immunodeficiency and inclusion body myositis A distinct myopathy mediated by natural killer cells.

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Common Variable
Immunodeficiency and
Inclusion Body Myositis:
A Distinct Myopathy
Mediated by Natural
Kdler Cells
Marinos C. Dalakas, MD, and Isabel Illa, M D
Inclusion body myositis developed in two men, 36 and
48 years old with long-standing common variable immunodeficiency. Immunophenotypic analysis of the endomysial cells showed an increased number of natural
killer ( N K ) cells (defined as CD57+, CD56+, CD3-,
CD8-, CD68-) accounting for 8.5 to 9.5% of the total
cells, compared with a mean of 1% in sporadic inclusion
body myositis. The remaining cells were CD8+, macrophages, and CD4+ T cells. NK cells were positive for
intercellular cell adhesion molecule-I and invaded muscle fibers negative for major histocompatibility complex
(MHC) class I. In contrast to ubiquitous endomysial expression of MHC class I antigen in sporadic inclusion
body myositis, the MHC class I in common variable immunodeficiency and inclusion body myositis was absent
or weakly expressed in only some of the muscle fibers
surrounded by CD8+ cells. Enteroviral or retroviral
R N A sequences were not amplified. Treatment with intravenous immunoglobulin improved strength in 1 patient whose repeated muscle biopsy specimen showed
normal N K cells. We conclude that inclusion body myositis can develop in patients with common variable immunodeficiency. Common variable immunodeficiency
with inclusion body myositis is an immune myopathy
mediated by N K cells in a non-MHC class I-restricted
cytotoxicity, and by CD8' cells in an MHC class Irestricted process. This is the first description of an inflammatory myopathy in which N K cells participate in
the myocytotoxic process.
Dalakas MC, Illa I. Common variable
immunodeficiency and inclusion body myositis:
a distinct myopathy mediated by natural killer cells.
Ann Neurol 1995;37:806-8 10
The cause of inclusion body myositis (IBM) is unknown [l-31. A T cell-mediated cytotoxic process has
From the Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health,
Berhesda, MD.
Received Nov 1, 1994, and in revised form Jan 23, 1995. Accepted
for publication Feb 16, 1995.
Address correspondence to D r Dalakas, Medical Neurology Branch,
N I H , Building 10, Room 4N-248, 10 Center Drive, MSC 1382,
Bethesda, M D 20892-1 382.
806 Annals of Neurology
Vol 37
No 6 June 1995
been implicated because CD8+ T cells along with macrophages invade nonnecrotic and major histocompatibility complex (MHC) class I antigen-expressing muscle fibers C3, 41. A degenerative process also has been
proposed on the basis of amyloid deposits, absence of
inflammation in some muscle biopsy specimens, and
lack of satisfactory response to imrnunotherapies. We
report 2 patients with common variable irnrnunodeficiency (CVI), a disorder marked by agammaglobulinernia and immunological abnormalities, in whom IBM
developed, and provide evidence that natural killer
(NK) cells participate in the muscle fiber injury.
Case Histories and Methods
Case Histories
Patierzt 1 , a 36-year-old man, presented with a 5-year history
of frequent falls and difficulty climbing stairs, lifting, or manipulating fine objects. At the age of 13, he was diagnosed
with CVI 151 following recurrent infections. Serum IgG and
IgA levels were 0 mgidl and the IgM level was 17 mgidl
(normal, 56-352 mgidl). H e had a normal antibody response
to mitogens. The cerebrospinal fluid (CSF) and computed
tomography (CT) scan of the brain showed normal findings.
A trial with prednisone did not improve his strength. O n
admission, he had atrophy and severe weakness (2-415 MRC
scale) in the musclegroups selectively affected in IBM 11-31,
He had bilateral footdrop, absent tendon reflexes, and normal sensation. Blood chemistry results and serum muscle
enzyme levels were normal. Serum IgG level (while patient
was on a maintenance monthly dose of 100 ml of intravenous
immune globulin [IVIg]) was 1,000 mgidl (normal, 6281600 mgidl), IgA level was less than 25 mgidl (normal, 93333 mgidl), and IgM level was 33 mgidl. Lymphocyte subsets
including NK cells were normal.
Patient 2. a 48-year-old man, presented with a 4-year history of frequent falls, buckling at the knees, and difficulty
manipulating fine objects. H e was wearing braces and walked
with crutches. Serum creatine kinase (CK) concentration was
elevated twofold on one occasion. At the age of 13, he was
diagnosed with CVI [ 5 } following recurrent infections. Serum IgG level was 3 1 mgidl; IgA, 5 mgidl; and IgM, 24 mgi
dl. H e developed a gluten-sensitive enteropathy that responded to diet, and an ulcerative jejunoileitis that responded to prednisone. O n admission, he had atrophy and
marked weakness (2-415 MRC scale) in the muscle groups
selectively affected in IBM [l-31. Tendon reflexes were
trace or absent, and sensation was normal. Serum CK level
was normal and aldolase level was 14 unitsiliter (normal, 1-7
unitsiliter). Serum IgG level (while patient was on maintenance monthly dose of 60 gm of IVIg) was normal, IgA was
less than 25 mgidl, and IgM was 32 mgidl. The N K cells in
the circulation were increased (30%; normal, 8-18"/.
Neither patient demonstrated antibodies against Jo-1,
RNP, SM, SSA, SSB, antinuclear antibody, cytomegalovirus,
Epstein-Barr virus, coxsackievirus, echovirus, poliovirus, human immunodeficiency virus, or human T-cell lymphotropic
virus type I. Electromyography showed active myopathic
units. Nerve conduction was normal. Muscle biopsy specimens, two from each patient, showed typical features of IBM
characterized by primary endomysial inflammation, numerous red-rimmed vacuoles, amyloid deposits, atrophic fibers,
and the typical 15- to 18-nm filaments as seen by electron
microscopy. Search by polymerase chain reaction for enteroviruses and retroviruses in the RNA extracted from the muscle biopsy specimens and their cultured myotubes was negative.
lmmunocytochemisty and N K Cell Determination
Serial 4-pm fresh-frozen sections of the muscle biopsy specimens were processed for immunocytochemistry using one of
the following monoclonal antibodies and biotinylated horse
antimouse IgG in an avidin-biotin peroxidase complex, as
described [6, 71: anti-CD8, CD4, CD2, CD3, macrophage
[Ber-Mac] (CD68), B cells (CD22), MHC class I and 11, N K
cells (CD56 and CD57) [8), and $6 T cells. The percentage
of each cell subset was calculated as described [6-81.
Single and double immunostaining, in pairs, was performed on serial sections searching for N K cells (defined as
CD56+, CD57+, CD3-, CD8-, CD4-, CD68-) and for
expression of MHC class I and intercellular cell adhesion
molecule-1 (ICAM-1) on the muscle fibers invaded by N K
cells, as follows: (a) CD3/CD56, (b) CD8/CD56, (c) CD68/
CD56, (d) CD41CD56, (e) CD571CD56, (f) MHC class I/
CD56, and (g) ICAM-UCD56. For all experiments we followed previously described methods [6-8); for (e) the IgM
anti-CD57 antibody was demonstrated with pchain-specific
fluorescein-conjugated goat antimouse IgM, while for the
IgG anti-CD56 antibody a biotinylated secondary anti-IgG
antibody followed by avidin-rhodamine was used. The slides
were photographed with fluorescein filters, rhodamine filters,
and double exposure.
Disease Control Specimens
Muscle biopsy specimens from 4 patients with sporadic IBM
and 3 with polymyositis were processed simultaneously.
The predominant endomysial cells were macrophages
(43.5% for Patient 1 and 55.5% for Patient 2), followed by CD8' cells (29.5% and 19.5%) and CD4+
T cells (20% and 18%). N o y/6 T cells were found.
B cells accounted for less than 1%. A surprisingly high
number of N K cells was noted, accounting for 9.5%
(Patient 1) and 8.5% (Patient 2) of all the cells
counted. The cells were identified as NK because they
were CD56+, CD57+, CD3-, C D K , CD4-, CD68-,
as confirmed with dual immunostaining (Figs 1, 3). N K
cells were the only cells invading muscle fibers in the
absence of MHC class 1 but in connection with
ICAM-1 (Fig 2A-F). MHC class I was expressed in
only a few scattered fibers (Fig 2G), especially those
invaded by CD8' cells (not shown). In contrast, in
sporadic IBM all the muscle fibers expressed MHC
class I (not shown), while N K cells accounted for less
than 1% of the total cells.
Treatment and Repeat Biopsy
Patient 1 received IVIg, as described {9, 101, but had
no objective improvement. Patient 2 reported no tripping or falls 3 weeks after the first infusion of IVIg.
By the second infusion, he stopped using crutches. His
deltoid, biceps, and foot extensors improved by one
MRC grade. A muscle specimen obtained at repeat
biopsy showed unchanged vacuolated fibers but normalization of N K cells from 8.5 to 1%, with a concomitant increase of CD8+ cells from 19.55 to 37% and
reduction of macrophages from 55.5 to 4796. The pattern of MHC class I expression did not change. A
reduction of circulating N K cells from 30 to 12% was
In the muscles of patients with inflammatory myopathies, the N K cells are rare, not exceeding more than
1% of the total cells [3, 4, 6-81. The abundance of
N K cells in the muscles of our patients who had the
combination of two rare diseases, CVI and IBM, was
unexpected but important because of their capacity to
mediate muscle fiber injury. Although the antibodies
to CD56 and CD57 could also recognize epitopes on
some other T cells 1111, the cells that we called N K
cells were CD56+ and CD57+, but CD3-, C D V ,
CD4-, and CD68-.
In polymyositis and sporadic IBM, autoaggressive
CD8+ cells exert cytotoxicity in the context of MHC
class I expression which is present on all the muscle
fibers {3,4, 12). In CVIABM the MHC class I expression was absent or weakly present in only a few of the
fibers surrounded by CD8+ cells. Because N K cellmediated cytotoxicity is antigen independent and not
linked to MHC class I { l l , 131, our findings suggest
that in CVI/IBM there is a dual mechanism of cytotoxicity, one non-MHC-restricted mediated by N K cells,
and the other MHC class I-restricted mediated by
CD8' cells. As the N K cell-injured muscle fibers begin to express MHC class I, a CD8+ T cell-mediated
autoimmune process follows. Because toxicity by N K
cells is inversely proportional to the level of MHC class
I expression, the N K cell-mediated myocytotoxicity
may become restrained as the MHC class I expression
is upregulated. Inflammatory myopathies, therefore,
can be mediated by all three types of cytotoxic cells:
CD8+ {4],$6 [14], and N K cells. Our observations
support in vitro studies showing a susceptibility of human myotubes to destruction by allospecific NK cells
The mechanism by which N K cells adhere to the
muscle fibers is unclear. A homotypic interaction between the CD56 (N-CAM) molecule expressed by
both N K cells and regenerating muscle fibers [8] is
unlikely because N K cells were also found within
CD56- fibers (see Fig 3). Further, the majority of the
Brief Communication: Dalakas and Illa: Common Variable Immunodeficiency and IBM
Annals of Neurology Vol 37
No 6 June 1995
Fig 1 . A muscle fiber dually immunostainedfor NK cells with
antibodies against CD57 (A)and CD56 (B) shows that the
same cells are stained with both CD57 and CD56. (C) Double
exposure shows that both of these antibodies recognize the same
NK cells. (B) Some ofthe small muscle fibers are CD56+ because this antibody recognizes muscle neural-cell adhesion molecule {8}. Serial sections of the same muscle Jiber ( 0 - F ) dually
stained with CD56 (0)and CD8 (E)show that the two cells
within the muscle fiber are CD56+ but CD8-, as confirmed
with the double exposure (F). ( x 475 before 25% reduction.)
Pig 2. Serial sections of a muscle fiber stained Jor NK (CD56)
cells (A), CD8 cells (Bj, macrophages (Cj, CD4 cells (D), intercellular adhesion molecule-1 (ICAM-I) (E), and MHC class I
(F). The three cells that have invaded the muscle fiber are NK
cells (A).There are rare CD8+ cells (B) and macrophages (C)
that do not appear to invade the muscle fiber. Further, the muscle fiber is negative for MHC class I (F). Within and around
the muscle fiber invaded by the NK cells there are areas positive
for ICAM-1 (E). ( X 575 before 26% reduction.) (G) A larger
area of the muscle stainedfor MHC class I shows that the majority of the infiltrates and endothelial cells are positive for
MHC clau 1; only a few muscle fibers in certain regions express
MHC class I . ( X 375 before 50% reduction.)
F i g 3. Serial section of a muscle fiber stained for NK (CD56)
cells (A),CD8 cells (B), CD4 cells (C), and macrophages
The muscle fiber is invaded exclusively by NK
(CD68) (0).
cells; the fiber is CD56-. ( X 750 before 24% reduction.)
CD56+ regenerating fibers were not invaded by N K
cells, allowing the muscle fibers to regenerate, as proposed {ls]. N K cells may attach to CD56- targets
via leukocyte function-associated antigen (LFA)-l/
ICAM-1 interaction. Our finding of ICAM-1 expression on the regions of the muscle fibers invaded by
N K cells and the observation that circulating T cells in
some CVI patients express increased phenotypic markers for CD56 and ICAM-1 1161 suggest that N K cells
may use ICAM-1 as their ligand to invade the muscle.
CVI is a disease of abnormal immunoregulation in
which up to 205% of the patients develop one or more
autoimmune diseases 151. Because at least 15% of
IBM patients may have autoimmune phenomena
[l-31, the present findings support an association bew e e n IBM and autoimmunity. In one of our patients
IVIg improved the strength and normalized the endomysial N K cells. This supports the observation that
N K cells can exert a myocytotoxic effect and is consistent with the known effect of IVIg to suppress N K
cell function. Interestingly, some CVI patients with autoimmune hemolytic anemia have also responded to
IVIg 151.
Dr Ilia was supported by a grant (SAF9210228) from the Comisi6n
Interministerial de Ciencia y Technologia, Spain.
Brief Communication: Dalakas and Illa: Common Variable Immunodeficiency and IBM 805)
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Encephalopathy with
Parkinsonian Features in
Children Following Bone
Marrow Transplantations
and High-Dose
Amphotericin B
Stephen H. Mott, MD,"? Roger J. Packer, MD,V
L. Gilbert Vezina, MD,"$ Sudesh Kapur, MD,"Q
Patricia A. Dinndorf, MD,"Il Joan A. Conry, MD,V
Michael R. Pranzatelli, MD,"?
and Ralph R. Quinones, MD"11
Encephalopathy, leukoencephalopathy, and secondary
parkinsonism occurred in 3 children with refractory leukemia undergoing allogenic bone marrow transplantation (BMT) who were treated with high-dose amphotericin B for pulmonary aspergillosis or sinus aspergillosis
that did not involve the nervous system. Treatment included high-dose cytosine arabinoside, cyclophosphamide, and total body irradiation prior to the BMT. The
children developed a progressively worsening encephalopathy and parkinsonian features, characterized by resting tremor, cogwheel rigidity, and masklike facies. Neuroimaging studies showed cerebellar, cerebral, and basal
ganglia atrophy, as well as frontal and temporal lobe
white matter involvement. Two of the 3 patients recovered, although 1 has residual intellectual impairment.
The third succumbed to non-central nervous system Epstein-Barr virus-lymphoproliferative disease and had
autopsy-confirmed leukoenephalopathy .
Mott SH, Packer RJ, Vezina LG, Kapur S,
Dinndorf PA, Conry JA, Pranzatelli MR,
Quinones RR. Encephalopathy with parkinsonian
features in children following bone marrow
transplantations and high-dose amphotericine B.
Ann Neurol 1995;37%10-8 14
Leukemic patients undergoing bone marrow transplantation (BMT) are often exposed to potentially
neurotoxic agents, including high-dose chemotherapy,
focal cranial and total body radiation therapy, and intensive antibiotic therapy 11]. Neurologic complications of therapy are often difficult to separate from the
effects of systemic illness or the cancer itself. In one
From the Departments of "Pediatrics, $Neurology, $Radiology, $Pathology, and llHematology/Oncology, Children's National Medical
Center and The George Washington University, Washington, DC.
Received Aug 17, 1994, and in revised form Dec 27. Accepted for
publication Feb 23, 1995.
Address correspondence to Dr Mott, Department of Neurology,
Children's National Medical Center, 111 Michigan Avenue, NW,
Washington, DC 20010.
Copyright 0 1995 by the American Neurological Association
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myopathy, immunodeficiency, distinct, variables, natural, common, inclusion, killer, myositis, body, cells, mediated
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