Showing papers by "Geraldine S. Pinkus published in 2005"

Interferon‐α/β–mediated innate immune mechanisms in dermatomyositis

Abstract: Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, antibody and complement-mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon-alpha/beta were highly overexpressed, and immunohistochemistry for the interferon-alpha/beta inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon-alpha, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon-alpha/beta inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus.

A mouse model of juvenile hemochromatosis

Abstract: Hereditary hemochromatosis is an iron-overload disorder resulting from mutations in proteins presumed to be involved in the maintenance of iron homeostasis. Mutations in hemojuvelin (HJV) cause severe, early-onset juvenile hemochromatosis. The normal function of HJV is unknown. Juvenile hemochromatosis patients have decreased urinary levels of hepcidin, a peptide hormone that binds to the cellular iron exporter ferroportin, causing its internalization and degradation. We have disrupted the murine Hjv gene and shown that Hjv–/– mice have markedly increased iron deposition in liver, pancreas, and heart but decreased iron levels in tissue macrophages. Hepcidin mRNA expression was decreased in Hjv–/– mice. Accordingly, ferroportin expression detected by immunohistochemistry was markedly increased in both intestinal epithelial cells and macrophages. We propose that excess, unregulated ferroportin activity in these cell types leads to the increased intestinal iron absorption and plasma iron levels characteristic of the juvenile hemochromatosis phenotype.

Plasma cells in muscle in inclusion body myositis and polymyositis.

Abstract: Background: Previous immunohistochemical studies of muscle from patients with inclusion body myositis and polymyositis found many more T cells than B cells, suggesting a role for intramuscular cell-mediated immune mechanisms rather than humoral mechanisms. Methods: Microarray studies were performed on muscle biopsy specimens from 40 patients with inclusion body myositis (IBM; n = 23), polymyositis (PM; n = 6), and without neuromuscular disease (n = 11). Reverse transcription PCR of selected immunoglobulin gene transcripts was performed on two patient samples. Qualitative immunohistochemical studies for B-cell lineage cell surface markers were performed on 28 muscle specimens and quantitative studies performed on a subset of 19 untreated patients with IBM or PM. CD138+ cells were isolated from muscle using laser capture microdissection, and immunoglobulin transcripts were PCR amplified to determine the presence or absence of immunoglobulin gene rearrangements unique to the B-cell lineage. Results: Immunoglobulin gene transcripts accounted for 59% in IBM and 33% in PM of the most stringently defined highest differentially expressed muscle transcripts compared with normal. Plasma cells, terminally differentiated B cells expressing CD138 but not CD19 or CD20, are present in IBM and PM muscle in numbers several times higher than B cells. Conclusions: There are differentiated B cells in the form of CD138+ plasma cells within the muscle of patients with inclusion body myositis and polymyositis. The principle of linked recognition of B-cell activation predicts several strategies for autoantigen discovery that could not otherwise be pursued through the study of the infiltrating T-cell population alone.

First reported cases of intravascular large cell lymphoma of the NK cell type: clinical, histologic, immunophenotypic, and molecular features.

Abstract: Most cases of intravascular large cell lymphoma are of B-cell phenotype, with a few cases of T-cell lineage and rare cases with histiocytic features described. A definitive natural killer (NK) cell variant has not been recognized. This report is the first to describe the clinical, histologic, immunophenotypic, and molecular features of 2 cases of intravascular lymphoma with an NK cell phenotype (CD3e+, CD2+, CD7+, CD56+, T-cell intracytoplasmic antigen-1+ (TIA-1), perforin+, granzyme B+, CD20-, CD4-, CD5-, CD8-, T-cell receptor [TCR] βF1-). Molecular studies for TCR gene rearrangements revealed a germline configuration. A 41-year-old man had erythematous plaque-like subcutaneous lesions of the lower extremities in which biopsy revealed Epstein-Barr virus-positive intravascular lymphoma. Following chemotherapy and stem cell transplantation, he was alive with no evidence of disease at 1 year. A 47-year-old woman had myalgias, arthralgias, weakness, fever, altered mental status, and pancytopenia. Bone marrow biopsy demonstrated intravascular lymphoma. Therapy was initiated; however, her condition deteriorated rapidly, and she died. Autopsy revealed involvement of multiple organs, including brain, kidneys, ovaries, and bone marrow. These cases represent the first documented examples of an NK cell variant of intravascular lymphoma.

First Reported Cases of Intravascular Large Cell Lymphoma of the NK Cell Type

Abstract: Most cases of intravascular large cell lymphoma are of B-cell phenotype, with a few cases of T-cell lineage and rare cases with histiocytic features described. A definitive natural killer (NK) cell variant has not been recognized. This report is the first to describe the clinical, histologic, immunophenotypic, and molecular features of 2 cases of intravascular lymphoma with an NK cell phenotype (CD3ɛ+, CD2+, CD7+, CD56+, T-cell intracytoplasmic antigen-1+ (TIA-1), perforin+, granzyme B+, CD20–, CD4–, CD5–, CD8–, T-cell receptor [TCR] βF1–). Molecular studies for TCR gene rearrangements revealed a germline configuration. A 41-year-old man had erythematous plaque-like subcutaneous lesions of the lower extremities in which biopsy revealed Epstein-Barr virus–positive intravascular lymphoma. Following chemotherapy and stem cell transplantation, he was alive with no evidence of disease at 1 year. A 47-year-old woman had myalgias, arthralgias, weakness, fever, altered mental status, and pancytopenia. Bone marrow biopsy demonstrated intravascular lymphoma. Therapy was initiated; however, her condition deteriorated rapidly, and she died. Autopsy revealed involvement of multiple organs, including brain, kidneys, ovaries, and bone marrow. These cases represent the first documented examples of an NK cell variant of intravascular lymphoma.

TRAF1 expression and c-Rel activation are useful adjuncts in distinguishing classical Hodgkin lymphoma from a subset of morphologically or immunophenotypically similar lymphomas.

Abstract: We demonstrate that the expression of TRAF1 and activated c-Rel, two proteins that function in signaling events downstream of activated CD30 in Reed-Sternberg cells, reliably distinguish classical Hodgkin lymphoma from anaplastic large cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and nonmediastinal diffuse large B-cell lymphoma. By immunohistochemistry, we found strong TRAF1 staining in 21 of 25 cases of classical Hodgkin lymphoma. In contrast, strong TRAF1 staining was present in only 1 of 17 cases of anaplastic large cell lymphoma, 0 of 15 cases of lymphocyte predominant Hodgkin lymphoma, and 2 of 36 cases of nonmediastinal diffuse large B-cell lymphoma. Nuclear staining for c-Rel, a pattern consistent with NFκB activation, was observed in the Reed-Sternberg cells in 23 of 25 cases of classical Hodgkin lymphoma but only in 1 of 15 cases of anaplastic large cell lymphoma and 3 of 15 cases of nodular lymphocyte predominant Hodgkin lymphoma. A heterogeneous pattern of subcellular c-Rel localization was found in nonmediastinal diffuse large B-cell lymphoma. Taken together, the combination of strong cytoplasmic TRAF1 expression and nuclear c-Rel was present in 80% of cases of classical Hodgkin lymphoma (n = 25) but in only 3% of cases of the other malignant lymphomas tested (n = 62). Thus, the differential expression patterns of downstream components in the CD30 signaling pathway may prove a useful adjunct in distinguishing cases of classical Hodgkin lymphoma from other malignant lymphomas in routine clinical practice.