To investigate the nature of the inflammatory response in facioscapulohumeral muscular dystrophy (FSHD), we analyzed mononuclear cells in muscle sections obtained from 18 FSHD patients and 8 controls. Monoclonal antibodies reactive for T cells, T cell subsets, B cells, and NK cells were used for cell typing. Macrophages were identified by acid phosphatase reaction. The localization of perforin, granzyme A, MHC-I and -II, dystrophin, and alpha-actinin antigens was also examined. We found that all FSHD patients, both familiar and sporadic cases, had greater amounts of mononuclear cellular infiltrates in muscle than controls, in whose specimens only few extra vascular mononuclear cells were counted. Seventy-two percent (13 of 18) of the patients had more than 50 inflammatory mononuclear cells per 1000 muscle fibers, and 33% (6 of 18) patients had numerous inflammatory cells exceeding 600 per 1000 muscle fibers (1835 +/- 482 SE). Nonnecrotic fibers invaded by mononuclear cells with either T8+, perforin+, or granzyme A+ were not observed in FSHD, while a few degenerating fibers were superficially invaded by T cells and macrophages. Occasional T cells were observed moving through the blood vessel wall. The increased number of necrotic fibers was paralleled by an increased number of inflammatory cells (r = 0.783, P = 0.0001). Genetic analysis, using the probes p13E-11, pFR-1, D4S139, and D4S163, was done in 6 patients (3 familiar, 3 sporadic) who had numerous inflammatory infiltrates. These 6 patients had small (< 28 kb) EcoRI fragments associated with the disease, and the disease was linked to 4q35. These results suggest that, in chromosome 4-linked FSHD: (1) inflammatory changes in muscle are a common histological feature; (2) mononuclear cellular infiltrates may enhance muscle fiber damage; but (3) T-cell-mediated cytotoxicity directed against muscle fibers is unlikely. We speculate that the immune effector mechanism in FSHD is different from that in previously reported inflammatory myopathies and Duchenne muscular dystrophy.
Abstract:We have immunocytochemically shown a significant reduction in the amount of laminin M (or merosin; a tissue-restricted basal lamina protein expressed in striated muscle, Schwann cells, and placental trophoblast) in the skeletal muscle of Fukuyama type congenital muscular dystrophy (FCMD).1) To inquire into the role of laminin M in the process of muscular dystrophies, we examined laminin M in several animal models that cause muscular dystrophy. Immunofluorescent, immunoblotting, and electron microscopic analyses have revealed that laminin M is missing from skeletal and cardiac muscles and peripheral nerve in the affected homozygous C57BL/6J-dy/dy mice, but not in the non-affected heterozygous Dy/dy and the other dystrophic animal models including mdx mice, BIO 14.6 hamsters, and line 413 chickens. In the dy/dy mice, laminin M mRNA is not detected by Northern blotting, but becomes detectable by RT-PCR amplification. Other components of the basal lamina such as laminin B, beta-integrin, type IV collagen, and fibronectin are normally expressed in all animals examined, including the dy/dy mice. These observations strongly suggest that laminin M defect is primarily responsible for the pathogenesis of muscle fiber damage and dysmyelination of the dystrophic dy/dy mice.
Background: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by the weakness of facial, shoulder-girdle and upper arm muscles. Most patients with FSHD have fewer numbers of tandem repeated 3.3-kb KpnI units on chromosome 4q35. Chromosome 10q26 contains highly homologous KpnI repeats, and inter-chromosomal translocation has been reported.
A 3.3-kb KpnI repeat unit within the tandem repeat locus (D4Z4) and its upstream 2.5-kb HincII/KpnI fragment of the facioscapulohumeral muscular dystrophy (FSHD) gene region at 4q35-qter were sequenced and characterized. The 3.3-kb KpnI unit was 3303 bp in length and contained two homeodomain sequences, one LSau-like sequence, and several microsatellites. The GC content in the 3.3-kb unit was very high (73%), while it was only 35% in the nonrepeated region of the 2.5-kb fragment. We identified 99% homologous sequences (918 bp) in the 3' end of the 3.3- and 2.5-kb fragments. These findings suggested that the repeated sequences at the D4Z4 start from 918 bp upstream to the first KpnI site.
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