Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): Immunocytochemical and genetic analyses

Abstract

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.

Increased Susceptibility to Complement Attack due to Down-Regulation of Decay-Accelerating Factor/CD55 in Dysferlin-Deficient Muscular Dystrophy

“…Interestingly, DAF/CD55 also suppresses T cell immunity, either locally or systemically (32). It is well known that some muscular dystrophies, such as dysferlin-deficient muscular dystrophy, studied in this report, or facioscapulohumeral muscular dystrophy, might exhibit inflammatory changes in muscle that may cause histological confusion with primary inflammatory muscle diseases such as polymyositis (33)(34)(35)(36). A local lack of DAF/CD55 may contribute to these changes.…”

DUX4 , a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1

“…Our finding of aberrant regulation of the PITX1 gene provides a potential molecular basis for the enigmatic presentation and progression of FSHD. Recent studies reporting that Pitx1 regulates expression of the IFN␣ gene in inflammatory cells and is a suppressor of RAS and tumorigenicity suggest the gene could be contributing to other clinical aspects of FSHD (34)(35)(36), including the involvement of atypical inflammatory responses and defects in myoblasts reported previously (37)(38)(39).…”

Dominant spinal muscular atrophy with lower extremity predominance

“…This inflammation is of uncertain significance. Perivascular mononuclear cell inflammation is a frequent finding in some hereditary neuromuscular disorders, including fascioscapulohumeral dystrophy 32 and the dysferlinopathies, 33 but to our knowledge, has not been reported for any SMA. Additional pathologic studies are needed to clarify whether inflammation is a consistent finding in SMA-LED.…”