Skeletal muscle includes satellite cells, which reside beneath the muscle fiber basal lamina and mainly represent committed myogenic precursor cells, and multipotent stem cells of unknown origin that ...are present in muscle connective tissue, express the stem cell markers Sca-1 and CD34, and can differentiate into different cell types. We tracked bone marrow (BM)-derived stem cells in both muscle connective tissue and satellite cell niches of irradiated mice transplanted with green fluorescent protein (GFP)-expressing BM cells. An increasing number of GFP
+ mononucleated cells, located both inside and outside of the muscle fiber basal lamina, were observed 1, 3, and 6 months after transplantation. Sublaminal cells expressed unambiguous satellite cell markers (M-cadherin, Pax7, NCAM) and fused into scattered GFP
+ muscle fibers. In muscle connective tissue there were GFP
+ cells located close to blood vessels that expressed the
ScaI or CD34 stem-cell antigens. The rate of settlement of extra- and intralaminal compartments by BM-derived cells was compatible with the view that extralaminal cells constitute a reservoir of satellite cells. We conclude that both muscle satellite cells and stem cell marker-expressing cells located in muscle connective tissue can derive from BM in adulthood.
T-cell clones of unknown significance (TCUS), assessed by monoclonal or oligoclonal T-cell patterns in PCR–DGGE, were detected in blood of 7/9 patients with anti-Hu syndrome. Clonal patterns were ...also detected in 2/2 neoplastic lymph nodes, and in 2/2 inflamed dorsal root ganglia from three patients. Only some T-cell clones found in target tissues were also detected in blood or non-target tissues, and likely corresponded to TCUS. In one patient, an identical T-cell clone was found in both neoplastic lymph node tissue and dorsal root ganglia, but not in blood. Dorsal root-infiltrating lymphocytes were cytotoxic CD8
+ TIA-1
+ T-cells. They were often found in close contact to sensory neurons, most of which expressed MHC-1. Taken together, these data support a direct effector role of cytotoxic CD8
+ T-cells, the same clones being likely operative in sensory neuron damage and immune-mediated tumor growth control.
We describe the unreported pattern of inflammatory myopathy with abundant macrophages (IMAM) as a main differential diagnosis of postimmunization aluminum hydroxide-induced macrophagic myofasciitis ...(MMF). IMAM was mainly detected among patients with a dermatomyositis (DM)-like disease. Among 113 muscle biopsies from DM patients collected from 1974 to 2000, intensity of macrophage infiltration was highly variable41.5% (−/+); 34.5% (+); 17% (++); and 7% (+++). The 27 patients from groups (++) and (+++) had a similar pattern of macrophagic infiltration and were considered to have IMAM. They were compared to 40 MMF patients. In IMAM, macrophage infiltrates were diffuse and correlated positively with both T cell infiltrates and acute muscle fiber damage, and showed pictures of hemophagocytosis (21/27). Connective tissue structures were infiltrated by noncohesive, ribbon-forming collections of large basophilic macrophages containing no crystalline inclusions. In MMF, macrophage infiltrates were focal and formed compact well-delineated aggregates of granular PAS+ cells, loaded with crystalline aluminum hydroxide particles, in the absence of either hemophagocytosis or conspicuous muscle damage. Review of the literature indicates similarities between IMAM and “cytophagic histiocytic panniculitis” (CHP), a condition characterized by T cell-triggered macrophage hyperactivation. Both IMAM and CHP, but not MMF, may be associated with a life-threatening hemophagocytic syndrome.
A subset of human immunodeficiency virus (HIV)‐infected patients develop persistent CD8 hyperlymphocytosis and a Sjögren's syndrome‐like syndrome associated with multivisceral CD8 T‐cell ...infiltration, known as the diffuse infiltrative lymphocytosis syndrome (DILS). Patients with DILS tend to have higher CD4 cell counts, fewer opportunistic infections, and longer survival times than other HIV‐infected patients. Peripheral nerve involvement in DILS has been poorly documented. We studied 12 HIV‐infected patients with CD8 hyperlymphocytosis, DILS, and clinical signs of peripheral neuropathy. Two of 4 patients who were HLA typed were HLA‐DR5 and 1 was HLA‐DR6. All patients had the sicca syndrome and multivisceral involvement. The neuropathy was acute or subacute, always painful, and symmetrical in 8 cases. Electrophysiology was consistent with axonal neuropathy in 10 of 12 patients. Nerve biopsy showed marked angiocentric CD8 infiltrates without mural necrosis (12 of 12), and abundant expression of HIV p24 protein in macrophages (12 of 12). The HIV genome was detected by polymerase chain reaction in nerve homogenates. Zidovudine therapy was associated with improvement in 6 of 6 patients and steroid therapy was beneficial in 4 of 5 patients. No T‐cell lymphoma was observed during follow‐up, but 2 patients developed a primary B‐cell lymphoma. We conclude that DILS neuropathy represents HIV‐associated neuropathy, characterized by marked CD8 infiltration and abundant HIV in nerve, that improves with zidovudine or steroid therapy, and probably reflects a systemic host‐determined and antigendriven response to HIV.
OBJECTIVE To delineate the possible implication of the immunosuppressive cytokine transforming growth factor beta 1 (TGF-β1) in the pathogenesis of Guillain-Barré syndrome. Guillain-Barré syndrome is ...a disorder that may implicate cytokines in its pathogenesis. TGF-β1 is a potent anti-inflammatory cytokine occasionally shown to be regulated in the course of demyelinating disorders. METHODS The study measured circulating proinflammatory and anti-inflammatory cytokines from the progressing phase to early recovery in patients with Guillain-Barré syndrome. Plasma concentrations of TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-10, and TGF-β1 were prospectively evaluated in 15 patients with Guillain-Barré syndrome every three days for the first 15 days after admission to hospital, and in 15 controls with non-inflammatory neurological diseases. RESULTS Concentrations of TGF-β1 in plasma were decreased in 13/15 patients (87 %) at day 1, remained low during progression and the plateau of paralysis (days 1–10), and then progressively increased up to control concentrations during early recovery (days 12–15). Concentrations of plasma TGF-β1 correlated positively with motor function, the lowest values being found in the most disabled patients. Concentrations of plasma TGF-β1 were decreased before any treatment, and during treatment by either plasma exchange or intravenous immunoglobulins, plasma exchange being associated with a more pronounced decrease in TGF-β1 at day 7. Circulating TNF-α concentrations were raised, as previously reported, when other cytokines were either randomly increased (IL-2, IL-6), or undetectable (IL-1, IL-4, IL-7, IL-10). CONCLUSIONS Down regulation of TGF-β1 in the early course of Guillain-Barré syndrome could participate in neural inflammation.
The urokinase-type plasminogen activator (uPA) system is a dynamic complex in which the membrane receptor uPAR binds uPA that binds the plasminogen activator inhibitor (PAI)-1 localized in the ...extracellular matrix, resulting in endocytosis of the whole complex by the low-density lipoprotein receptor-related protein (LRP). High expression of PAI-1 is paradoxically associated with marked tumor spreading and poor prognosis. We previously reported a nonproteolytic role of the uPAR:uPA:PAI-1:LRP complex operative in cell migration. Here we explored whether matrix PAI-1 could be used as a migration support by human breast cancer cells. We showed that the uPA system and LRP are localized at filopodia of invasive cells, and that formation/internalization of the uPAR:uPA:PAI-1:LRP complex is required for attachment and migration of cancer cells on plastic and on a PAI-1 coat. PAI-1 increased both filopodia formation and migration of cancer cells suggesting a chemokine-like activity. Migration velocity, expression of the uPA system, use of the uPAR:uPA:PAI-1:LRP complex to migrate, and promigratory effects of PAI-1 paralleled cancer cell invasiveness. Phenotyping and functional analysis of invasive cancer cell subclones indicated that different cell subpopulations may use different strategies to migrate depending on both the environment and their expression of the uPA system, some of them taking advantage of abundant available PAI-1.
Anti-Hu syndrome is a paraneoplastic neurologic disease seemingly associated with an efficient antitumoral immune response against HuD protein expressed by both small cell lung cancer (SCLC) and ...neurons. Since anti-Hu antibodies are not pathogenic, and oligoclonal CD8
+ T cells infiltrate neoplastic and nervous tissues, we examined MHC class I-restricted immunogenicity of human HuD. Among 14 HuD-derived peptides potentially immunogenic in HLA-A*0201 restriction, 10 had actual in vitro binding capacity to the HLA molecule, 8 elicited specific cytotoxic T lymphocyts (CTLs) in a humanized murine model after peptidic vaccination, 2 also elicited specific CTLs in healthy humans, and 1 was naturally processed and presented to the immune system.
The diagnosis of Type 2 myotonic dystrophy (DM2/proximal myotonic myopathy) is often overlooked because of a nonspecific clinical presentation and muscle biopsy findings of a "denervation-like" ...pattern of unknown specificity that combines increased fiber size variation, central nucleation, small angulated fibers, Type 2 fiber atrophy, and nuclear clumps. We determined the presence of these features in 104 patients designated as having an unidentified myopathy from a series of 2,100 muscle biopsies. Because CCUG expansions form pathogenic ribonuclear accumulations that can be detected by in situ hybridization, we validated and then used automated (CCUG)8 in situ hybridization as a reference standard to evaluate the value of each histologic feature for DM2 detection, identifying 8 DM2-positive and 96 DM2-negative cases. Multivariate analyses identified the combination of Type 2 fiber atrophy and central nucleation as the most predictive of DM2 (sensitivity, 1.0; specificity, 0.92). These features were mutually exclusive in non-DM2 patients (p < 0.0001). The relevance of this combination of features was confirmed in an additional independent series (15 DM2-positive vs 17 DM2-negative). Further investigation revealed that central nucleation selectively affects Type 2 fibers in DM2 and, conversely, that it affects Type 1 fibers in DM1 (p < 0.0001). These results will facilitate the routine detection of DM2 and further support the concept that DM2 has a distinct pathophysiology involving type 2 myofibers.
To evaluate a possible implication of cytokines in the pathogenesis of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome, we studied five consecutive patients ...with this condition, of which four had sclerotic bone lesions and four had multicentric Castleman’s disease, lnterleukin-1β (IL-1β) and IL-6 serum levels were determined in these patients (13 serum samples) and in patients with multiple myeloma (5) and Waldenström’s macroglobulinemia (5). In situ hybridization of the revelant mRNAs was performed on lymph node specimens of two patients with POEMS syndrome who had Castleman’s disease. Elevated serum levels of IL-1β (13/13 samples), and IL-6 (7/13 samples) were found in patients with POEMS syndrome. In the other patients, serum IL-1β was undetectable or slightly increased and IL-6 was elevated in a single patient with Waldenström’s macroglobulinemia. Abundant IL-1β mRNA-producing cells were present in interfollicular spaces in the two tested patients, while IL-6 mRNA-producing cells were rare. We conclude that IL-1β and IL-6 serum levels may be chronically elevated in patients with POEMS syndrome, and that lymph node may be one site of IL-1β overproduction. These results are in keeping with the hypothesis that cytokines mediate systemic manifestations of POEMS syndrome.
To investigate the role of MMP-9 in Guillain-Barré syndrome, the authors correlated electrophysiologic abnormalities and MMP-9 plasma levels in a series of 21 patients. MMP-9 plasma levels were ...higher in the demyelinating group than in the nondemyelinating group, and in patients with high CSF protein level. Increase of MMP-9 circulating levels correlated with the increase of F waves latencies, reduction of CMAP amplitude, and decrease of nerve conduction velocities. Circulating MMP-9 may contribute to the peripheral nerve dysfunction of demyelinating Guillain-Barré syndrome.
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