Brain, Vol. 123, No. 10, 2030-2039,
October 2000
© 2000 Oxford University Press
Clonal restriction of T-cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time
Studies in repeated muscle biopsies
Neuromuscular Disease Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
Correspondence to:
Marinos C. Dalakas, MD, Neuromuscular Diseases Section, NINDS, National Institutes of Health, Building 10, Room 4N248, 10 Center Drive MSC 1382, Bethesda MD 20892-1382, USA E-mail: dalakas{at}helix.nih.gov
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Abstract |
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Inclusion body myositis (IBM) is an inflammatory myopathy characterized immunohistologically by prominent invasion of the non-necrotic, MHC-I class antigen-expressing muscle fibres by CD8+ cytotoxic T cells. If the autoinvasive CD8+ T cells are recruited specifically to the muscle and play a primary pathogenetic role in the disease, a clonal restriction persisting over time should be anticipated. In this study, we analysed the T-cell receptor (TCR) gene usage by endomysial T lymphocytes in three sequential muscle biopsies from three different IBM patients over a 19–22 month period using immunohistochemistry, reverse transcription–polymerase chain reaction (RT-PCR) and sequence analysis of the complementarity determining region (CDR3) of the amplified TCRs. We found that CD8+ T lymphocytes persist in the endomysial infiltrates in all biopsies during a 19–22 month period. The most frequently detected TCRs were the Vß3, Vß5.1, Vß6.7 and Vß13 gene families, and several of the autoinvasive CD8+ T cells expressed the TCRs Vß6.7 and Vß5.1. A restricted usage of the examined Vß6 gene family was found to persist in the complementarity CDR3 determining region of the autoinvasive T cells over the 22 month period. Identical Vß6 CDR3 gene arrangements were also found in the multiple muscle biopsies from two of the three IBM patients. The results indicate that in IBM there is a restricted expression of the TCR gene families among the autoinvasive T lymphocytes with homologies in the CDR3 region that persist over the course of the disease. A continuous, antigen-driven T-cell response is prominent in the muscle of patients with IBM.
T-cell receptor; inclusion body myositis; autoimmunity
CDR = complementarity determining region; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; s-IBM = sporadic inclusion body myositis; RT-PCR = reverse transcription–polymerase chain reaction; TCR = T-cell receptor
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
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Sporadic inclusion body myositis (s-IBM) is the most common inflammatory myopathy in patients over the age of 50 years (Dalakas, 1991
; Engel et al., 1994). Although its cause is unknown, an autoimmune pathogenesis is supported by (i) the presence of CD8+ cytotoxic T cells that surround and invade non-necrotic muscle fibres expressing MHC-I class antigen (Arahata and Engel, 1984; Engel and Arahata, 1984; Dalakas, 1995); (ii) a strong immunogenetic association with alleles in HLA-DR and DQ haplotypes (Koffman et al., 1998a); (iii) the frequent association with other autoimmune diseases (Koffman et al., 1998b); and (iv) signs of a limited expression of T-cell receptor (TCR) genes of the Vß families by the endomysial T cells, in some but not all studies, suggesting a limited number of antigens presented to the invading cytotoxic T cells (Lindberg et al., 1994; O'Hanlon et al., 1994; Fyhr et al., 1996, 1997; Bender et al., 1998). Since s-IBM is a chronic progressive disease, the clonal restriction of the TCR gene expression should be limited and persist over the course of the disease if the same antigen drives the immune response. This is fundamental in view of the conflicting results of the TCR gene rearrangement in s-IBM (Lindberg et al., 1994; O'Hanlon et al., 1994; Fyhr et al., 1996, 1997; Bender et al., 1998) and the suggestion that the T-cell response may be secondary and increase non-specifically over time while the disease remains resistant to immunotherapies (Barohn et al., 1995). To determine if clonal restriction of TCR expression does occur in the endomysial T cells during the course of the disease, we examined the TCR expression in multiple muscle biopsies from three IBM patients over a 19–22 month period. |
Material and methods |
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Patients
The muscle biopsy specimens from three patients with s-IBM were studied. Three normal (non-inflammatory) control muscle specimens were examined concurrently. The diagnosis of IBM was determined by clinical, laboratory and muscle histological findings as described at presentation (Dalakas, 1991
, 1995; Engel et al., 1994). The IBM patients, two men and one woman, had disease duration ranging from 4 to 10 years when they were first examined. As shown in Table 1, all three patients had repeated open muscle biopsies. The second biopsy was carried out after 11.4–18.6 (mean 15.4) months and then the third biopsy 3.7–7.7 (mean 5.1) months later. The second biopsy was taken from the same muscle of the other extremity. The third biopsy was taken from the same site as the second. The biopsies were performed during an experimental randomized trial using IVIg and prednisone under a clinical protocol approved by the NINDS Institutional Review Board for which the patients gave an informed consent and were admitted to the Clinical Center of the NIH. The biopsy specimens were selected from the patients randomized to placebo.
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Immunohistochemistry
Frozen muscle biopsy sections (5 µm) were prepared as previously described (Leon-Monzon et al., 1994
). Serial sections were incubated with commercially available mouse monoclonal antibodies against CD8 (Immunotech, Westbrook, Me., USA) and various TCR families including: Vß1, Vß2, Vß3, Vß5.1, Vß5.2, Vß5.3, Vß6.7, Vß8a, Vß13, Vß16, Vß18 and Vß20 (T Cell Diagnostics, Inc., Woburn, Mass., USA). Specific reactivity was determined by a secondary goat anti-mouse IgG antibody conjugated to peroxidase and visualized by a DAB (diaminobenzidine)-peroxidase reaction (Vector Laboratories, Calif., USA). Double immunofluorescent labelling was performed with a secondary antibody labelled with rhodamine or FITC (fluorescein isothiocyanate), as described (Leon-Monzon et al., 1994), to determine if the Vß-expressing cells were CD8+ autoinvasive T cells. This was fundamental because the selection of the Vß families for cloning and sequencing, as mentioned below, was based on the most frequently expressed families judged by inspection among the autoinvasive CD8+ T cells noticed in low magnification fields.
Preparations of RNA
Frozen muscle biopsy sections (10–15 sections, 20 µm thickness) were homogenized in a total volume of 0.2 ml of TRIZOL (Life Technologies, Gaithersburg, Md., USA) and RNA extracted and precipitated as per manufacturers instructions. RNA was suspended in 12–15 µl of RNase-free water and heated for 10 min at 56°C and stored at –80°C.
Reverse transcription (RT)-polymerase chain reaction (PCR)
cDNA was prepared using a GeneAmp RNA PCR kit (Perkin-Elmer, Roche Molecular Systems, Inc., Branchburg, NJ, USA) with 1.0 µg of total RNA in a final volume of 20 µl as per manufacturer's instructions. For amplification of the cDNA, 4 µl of the RT reaction mixture was used for each PCR reaction (50 µl), as per manufacturer's instructions, with 1 µM Vß family-specific or glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-specific primers. The most frequent Vß families represented among the CD8+ autoinvasive T cells determined immunocytochemically, were those that we further examined with PCR. Primer sequences for Vß3, Vß5.1, Vß6.7 and Vß13 were previously reported (Panzara et al., 1992). The sequences of the RNA control GAPDH primers, which resulted in a PCR product of 398 base pairs, were the following: sense, 5'-TGAAGGTCGGAGTCAACGGATTTGG-3'; antisense, 5'-GTTCACACCCATGACGAACATGG-3'. All primers were obtained from Genosys Biotechnologies, Inc. (The Woodlands, Tex., USA). After an initial 3 min period at 95°C, the PCR reaction mixtures were incubated for 45 cycles at the following temperatures: 95°C, 1 min; 55°C, 1min; 72°C, 1 min; with a final extension of 72°C for 7 min. The amplified products (10 µl) were analysed by electrophoresis using a 3% Nusieve (3 : 1) agarose gel (FMC, Rockland, Me., USA) with 0.5 µg/ml of ethidium bromide.
Cloning and sequencing
In order to determine and analyse the sequence of the Vß TCRs, the RT-PCR products were cloned using the T/A Cloning kit (Invitrogen, San Diego, Calif., USA), plasmid DNA purified (QUIAGEN, Valencia, Calif., USA) and inserts verified by EcoRI digestion. The Vß TCR sequences were determined commercially (Bioserve Biotechnologies, Columbia, Md., USA).
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Results |
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Persistence of inflammation in multiple biopsies
The IBM patients studied (Table 1
) had a progressive decline in muscle strength and function over a 4–10 year period (mean duration of symptoms, 6 years). Histochemical analysis of the multiple biopsies revealed the persistence of many infiltrating endomysial lymphocytes and autoinvasive T cells in all three sequential biopsies in each patient. Many of the persisting endomysial lymphocytes in the sequential biopsies were CD8+, as demonstrated by immunohistochemical staining (Fig. 1). No lymphocytic infiltrates were seen in any of the control muscle biopsies (data not shown).
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Immunohistochemical analysis of Vß TCR expression on the autoinvasive CD8+ T cells in multiple muscle biopsies
A limited number of Vß TCR gene families were persistently expressed in all three muscle biopsies in each of the IBM patients over the 19–22 month period. The most frequently immunostained TCR among the endomysial lymphocytes that persisted in the three biopsies belonged to the Vß6.7 gene family (Fig. 2
), followed by those belonging to Vß5.1, Vß3 and Vß13
families (not shown).
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Examples of autoinvasive cells expressing the TCR Vß6.7 are shown in Fig. 3
from patient 1 (biopsy III, panel A) and from patient 3 (biopsy III, panel B). Autoinvasive cells expressing the TCR Vß5.1 are shown in Fig. 3 from patient 2 (biopsy I, panel C) and patient 3 (biopsy III, panel D). Many of the families studied belonged to the autoinvasive CD8+, as demonstrated with dual immunostaining for both Vß6.7 and CD8 markers in a representative sample (Fig. 4).
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RT-PCR analysis of multiple muscle biopsies confirms the limited expression of TCR families by cytotoxic T cells
The limited number of TCR families present on the cytotoxic T cells in the muscle biopsies of the IBM patients was further confirmed by examining the expression of the TCRs by RT-PCR analysis. The mRNAs of the same TCR families (Vß3, Vß5.1, Vß6, Vß13) were present in the muscle biopsies of all the three IBM patients confirming the immunocytochemical findings (Fig. 5
). A similar analysis with the RNA from the non-inflammatory muscle control patients resulted in no detection of these same TCR families (data not shown).
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Sequence analysis of TCR clones confirms the limited expression of Vß6 TCR gene family in muscle biopsies of IBM patients
The RT-PCR products of the amplified TCR families were cloned and the complementary determining region (CDR) 3 was sequenced. We specifically examined the Vß6 TCR family in patient 1 (Table 2
) and patient 3 (Table 3) because of its predominant expression among the T cells.
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In the first biopsy of patient 1, we examined 15 clones that had 12 different sequences (Table 2
). Two sets of two clones had identical CDR3 sequences. The 10 remaining clones belonged to only four Jß subfamilies of the ß6 TCR gene family. In the second biopsy of this patient, we obtained 16 clones with six different sequences that belonged to only three different Jß subfamilies of the Vß6 TCR gene family (2.1, 2.3 and 2.7). These were also present in the first biopsy. Identical CDR3 regions were seen in two, four and seven sets of the Vß6 TCRs. In the third biopsy of patient 1 we examined 12 clones which had eight different sequences. Six of the clones had two different CDR3 regions. Only six different Jß subfamilies of the Vß6 TCR gene family were found in the 12 clones. Two sets of clones from biopsies II and III had identical sequences in the CDR3 region. The average length of the CDR3 region from patient 1 was 10.4, 10.1 and 9.4 amino acids in the clones from biopsies I, II and III, respectively. One Vß6 TCR CDR3 sequence (LRGRGAYEQY) which was present in the second and third biopsy of patient 1 was also found in the third biopsy of patient 3, as discussed below and summarized in Table 5.
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In the first biopsy of patient 3 (Table 3
) we examined the sequence of 15 clones and found six Jß subfamilies of the Vß6 TCR present. Only two of the clones had identical amino acids present in the TCR CDR3 region. In the second biopsy of patient 3 we examined the sequence of 16 clones and found only five subfamilies of the Vß6 TCR present. Among them, there were three pairs of clones with identical sequences and one set with three clones containing the same sequence in the CDR3 region. We examined the sequence of 19 clones from the third biopsy of patient 3 and found five subfamilies of the Vß6 TCR present. Two sets of clones had identical sequences in the CDR3 region: one set with two identical sequences and the other set with three identical sequences. The average number of amino acids in the CDR3 region in biopsy I was 9.1, in biopsy II 9.3 and in biopsy III 9.2 (Table 3). One Vß6 TCR CDR3 sequence which was present in biopsy I, and three Vß6 TCR CDR3 sequences present in biopsy II were also found in biopsy III (Table 3).
Sequence analysis shows that expression of the TCR Vß5.1 is more limited in patient 3 than in patient 1
We examined 16 clones from the first muscle biopsy of patient 1 and found that they belonged to eight subfamilies of the Vß5.1 TCR gene family (data not shown). There were 13 different CDR3 sequence rearrangements among the 16 clones examined with three pairs each having identical CDR3 sequences. From the second biopsy, 10 clones were examined, which were found to belong to five different subfamilies. Three clones out of the 10 had identical CDR3 sequences. Eleven clones were examined from the third biopsy and we found six subfamilies of the Vß5.1 TCR gene family present. All eleven clones had different CDR3 sequences. The average length of the CDR3 region was 9.1, 9.4 and 9.2 amino acids in the clones from the muscle biopsies I, II and III, respectively, from patient 1. No common sequence rearrangement in the TCR CDR3 region was found in the three muscle biopsies from patient 1.
In the first biopsy of patient 3, we found seven different subfamilies among the 16 clones examined (Table 4). There were nine different CDR3 sequences present with five clones having different CDR3 sequences, two sets having identical CDR3 sequences, one set having three identical sequences and another set having four identical sequences. In the second biopsy, we examined 21 clones and found only four different subfamilies (1.1, 2.1, 2.3 and 2.7) present. Sixteen of the clones belonged to one subfamily (2.7) with four clones having one CDR3 sequence and 12 clones having another CDR3 sequence. In the third biopsy of patient 3, 15 clones were examined and they belonged to only three subfamilies (2.1, 2.5 and 2.7). Eight clones belonged to the subfamily 2.1, one clone belonged to the subfamily 2.5 and six clones belonged to the subfamily 2.7. One identical TCR CDR3 sequence arrangement was found present in all three biopsies and another TCR sequence was found present in biopsies I and III. The average length of the CDR3 region from patient 3 was 10.1, 12.9 and 10.0 amino acids in the clones examined from biopsies I, II and III, respectively.
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A summary of the CDR3 sequences of the TCRs present in more than one muscle biopsy in patients 1 and 3 is shown in Table 5
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Discussion |
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If the T-cell inflammatory response in IBM patients is caused by a continuous presentation of putative host antigen(s), we would expect to see the presence of similar TCR Vß gene usage and similar CDR3 gene sequence rearrangements or Jß gene usage that persists over time among the autoinvasive CD8+ endomysial T cells. We present evidence from multiple muscle biopsies of three IBM patients over a period of 19–22 months, that the endomysial CD8+ cytotoxic T lymphocytes not only persist over time, but also demonstrate a limited clonal expression of their TCRs. Furthermore, sequence analysis of the CDR3 region of the Vß6-expressing endomysial T cells showed a number of identical sequence rearrangements in two or three of the muscle biopsies from the same patients. The results suggest that in IBM there is a limited number of polypeptides presented by the MHC class I-expressing muscle fibres to the autoinvasive CD8+ cells during the course of the disease, implying a persistent antigenic stimulation to the same antigens. The small number of amino acids found in the CDR3 region is also consistent with the MHC-I TCR interaction, which is in contrast to MHC-II TCR interaction where a larger number of amino acids is seen in the CDR3 region.
One or more of the same (Vß3, Vß5.1, Vß6 or Vß13) TCR gene families amplified in the present study have also been found expressed by the endomysial T lymphocytes in single muscle biopsies of IBM patients from three different countries (Lindberg et al., 1994; O'Hanlon et al., 1994; Fyhr et al., 1996, 1997; Bender et al., 1998) indicating that, in spite of their heterogeneity, certain T cells may be responding to common antigens. The predominant usage of specific Jß genes (2.1, 2.5 and 2.7) by the T cells expressing the Vß6 gene family in the repeated biopsies provides additional support that the clonal restriction among the endomysial T cells persists over time. Restricted usage of TCR V genes has been found in other chronic autoimmune diseases such as multiple sclerosis (Oksenberg et al., 1993; Hafler et al., 1996), rheumatoid arthritis (Howell et al., 1991; Sottini et al., 1991; Struyk et al., 1993; Hingorani et al., 1996) and Sjögren's syndrome (Yonaha et al., 1992). In contrast to those diseases, however, in IBM the endomysial inflammation persists even in the late stages of the disease when there is significant loss of muscle fibres. Persistence of T cells specific for an immunodominant myelin basic protein peptide over an extended period has also been shown in the repeated analysis of a patient with multiple sclerosis (Wucherpfennig et al., 1994).
When we examined the CDR3 sequences of the clones present in more than one biopsy, we noted variability in the TCRß and Jß gene sequences not only in biopsies of the same patient but also between patients. Such variability has also been observed in patients with multiple sclerosis and animals with experimental autoimmune encephalomyelitis where the immunodominant epitope is known (Heber-Katz and Acha-Orbea, 1989; Vandevyver et al., 1995). In spite of the variability, however, several observations confer a degree of specificity as summarized in Table 5. First, the 5'-end of the CDR3 sequence began with either leucine (L) or serine (S), regardless of the Vß or Jß gene usage. Secondly, the ß gene segments associated with these repeated CDR3 sequences were very restricted (2.1, 2.5 or 2.7), as also noted by others (O'Hanlon et al., 1994; Fyhr et al., 1997; Bender et al., 1998). In the biopsies from the first patient with Vß6 gene usage, two types of TCR clones appear to be present: those with Jß gene segment 2.1 and those with 2.7. The CDR3 sequence with the 2.7ß gene segment (LRGRGA . . . YEQY) has also been found in the muscle biopsy (III) of patient 3. Interestingly, the 5'-sequence of this CDR3 region (LRG) has been reported in other studies of IBM patients (O'Hanlon et al., 1994; Fyhr et al., 1997; Bender et al., 1998), although not necessarily with the same Jß gene segment. The recurrent CDR3 sequences found in the third patient with the Vß6 gene usage could be placed into two groups based on the amino acid at the 5'-end: those that began with leucine (L) and the others that began with serine (S). In the first group, the CDR3 sequences also contained glutamine (Q) or glutamine (Q)-alanine (A) within one to two amino acids from the 5'-leucine (L). In the second group, there were two CDR3 sequences which began with serine serine (S)-proline (P). Finally, the two CDR3 sequences of the TCRs from patient 3 with the ß5 gene usage began with leucine (L) and aspartic acid (D). Collectively, the homology at the 5'-end of the CDR3 sequences and the restricted Jß gene segment usage suggest that in IBM the 5'-end of the CDR3 regions may be implicated in the recognition or the interaction with a specific epitope on an antigen presented by the antigen presenting cell.
Recent data indicate that in IBM the autoinvasive T cells express the counter-receptor CD28 and CTLA4 and make cell-to-cell contact with the muscle fibres that express the BB1 marker (Behrens et al., 1998; Murata and Dalakas, 1999). This observation strengthens the information presented here that the muscle fibre can behave as an antigen presenting cell and the autoinvasive T cells have the specific rearrangement in the TCR gene for recognition of such, heretofore unknown, antigens. The reported upregulation of cytokines in the muscle microenvironment and the adhesion molecules ICAM-1 (intracellular cell adhesion molecule) and VCAM (vascular cell adhesion molecule) (De Bleecker and Engel, 1994; Lundberg et al., 1995; Tews and Goebel, 1995, 1996; Dalakas 1998) are critical elements participating in the antigen recognition and sensitization of the autoinvasive T cells.
Although our observations are based on a limited number of samples, the association of common features in the repeated CDR3 sequences (with certain Vß and Jß gene usage) suggests response to a persistent antigenic stimulation, the nature of which still remains elusive. IBM remains a mystery disease because in spite of the autoimmune features, the patients do not respond to immunotherapies. Whether the recent finding that B crystalline, which represents a stressor effect to the muscle fibre, may also serve as one of the putative autoantigens, as suggested (Banwell and Engel, 2000), remains unclear. It is likely that other factors, such as ß-amyloid, mitochondrial abnormalities and abnormal nuclei (Engel et al., 1994; Dalakas 1995), whether primary or secondary due to various immune factors, may also participate in the disease process.
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Received February 21, 2000. Revised May 21, 2000. Accepted June 26, 2000.
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M. C. Dalakas Inflammatory, immune, and viral aspects of inclusion-body myositis Neurology, January 24, 2006; 66(1_suppl_1): S33 - S38. [Abstract] [Full Text] [PDF]
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Y. Yakushiji, J. Satoh, M. Yukitake, K. Yamaguchi, I. Nakamura, I. Nishino, and Y. Kuroda Interferon {beta}-responsive inclusion body myositis in a hepatitis C virus carrier Neurology, August 10, 2004; 63(3): 587 - 588. [Full Text] [PDF]
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J. Schmidt, G. Rakocevic, R. Raju, and M. C. Dalakas Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle: significance for CD8+ T cell cytotoxicity Brain, May 1, 2004; 127(5): 1182 - 1190. [Abstract] [Full Text] [PDF]
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C. L. O'Keefe, M. Plasilova, M. Wlodarski, A. M. Risitano, A. R. Rodriguez, E. Howe, N. S. Young, E. Hsi, and J. P. Maciejewski Molecular Analysis of TCR Clonotypes in LGL: A Clonal Model for Polyclonal Responses J. Immunol., February 1, 2004; 172(3): 1960 - 1969. [Abstract] [Full Text] [PDF]
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 M. Hofbauer, S. Wiesener, H. Babbe, A. Roers, H. Wekerle, K. Dornmair, R. Hohlfeld, and N. Goebels Clonal tracking of autoaggressive T cells in polymyositis by combining laser microdissection, single-cell PCR, and CDR3-spectratype analysis PNAS, April 1, 2003; 100(7): 4090 - 4095. [Abstract] [Full Text] [PDF]
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Randomized pilot trial of {beta}INF1a (Avonex) in patients with inclusion body myositis Neurology, November 13, 2001; 57(9): 1566 - 1570. [Abstract] [Full Text] [PDF]
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