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Biomedical subjects

R G Phelps

Publications and source records attributed to R G Phelps.

At least 37 records · Page 2Linked to original sources
PubMed1998

Effect of targeted mutation in collagen V alpha 2 gene on development of cutaneous hyperplasia in tight skin mice.

Collagen V plays a major regulatory role in the formation of heterotypic fibers of the dermis and cartilaginous tissues as well as in the assembly of extracellular matrix. The pN/pN mouse, which is defective in collagen V alpha 2 gene, exhibits skeletal abnormalities, skin fragility, and alterations in the collagen fiber organization, whereas the TSK/+ mouse, which is defective in fibrillin-1, the major component of microfibrils present in the extracellular matrix, develops cutaneous hyperplasia and autoimmunity. We have studied the role of collagen V in the formation of heterotypic collagen fibers in F1 mice, which are obtained by breeding pN/pN with TSK/+ mice. Our results show that F1 progeny neither develop cutaneous hyperplasia nor produce anti-topoisomerase I autoantibodies, unlike TSK/+ mice. The diameter of the collagen fibrils in the skin is also comparable to that found in control mice. Thus, the phenotypic changes observed in the TSK mouse could be reversed by genetic complementation with a collagen V-defective mouse.

Alleles↗
PubMed1997

B-cell deficiency does not abrogate development of cutaneous hyperplasia in mice inheriting the defective fibrillin-1 gene.

Tight-skin (TSK) mouse, the experimental model for scleroderma, develops cutaneous hyperplasia, cardiac hypertrophy, pulmonary emphysema and autoimmunity against scleroderma target autoantigens. The cutaneous hyperplasia is associated with the accumulation of microfibrils and elastic fibers in the middle and deep dermis. Fibrillin-1 (Fbn-1) is a major component of the 10-12 nm microfibrils found in the extracellular matrix. In this study we report the identification of a genetic marker in the Fbn-1 gene that can distinguish the mutant phenotype. TSK mice exhibit an unique polymorphism in the Fbn-1 gene. RNA analysis, PCR analysis and sequence determination of the mutant gene showed that the Fbn-1 gene polymorphism is due to intragenic duplication of a segment of the gene coding for 3.0 Kb of mRNA sequence (10 Kb of the genome). Histological analysis of skin samples from F1 progeny obtained by crossing TSK mice with JH-/-, RAG2-/- or vit/vit showed a significant correlation between the inheritance of the defective Fbn-1 gene and the development of cutaneous hyperplasia. Further, our results also show that in mice deficient in mature B cells inheriting the defective Fbn-1 gene, development of cutaneous hyperplasia is not abrogated. Thus, production of autoantibodies or the presence of mature B lymphocytes do not play an integral role in the pathogenesis of cutaneous hyperplasia.

Amino Acid Sequence↗
PubMed1996

Direct identification of naturally processed autoantigen-derived peptides bound to HLA-DR15.

Biochemical analysis of HLA class II-associated peptides from antigen-pulsed cells is a potentially useful approach to the analysis of antigen processing and presentation because it examines directly which antigen-derived peptides are presented. This is especially advantageous in the analysis of self-antigen presentation where conventional approaches utilizing antigen-specific T cells may be biased by the presence of self-tolerance. However, successful biochemical analysis has been reported for only one exogenous antigen and no autoantigens. We have used a novel analytical approach coupling biochemical data with the reported properties of class II-associated peptides to characterize the peptides derived from a clinically relevant autoantigen presented on the disease-associated class II type. Incubating the target of autoimmune attack in patients with Goodpasture's disease, the 230-amino acid NC1 domain of the alpha3 chain of type IV collagen (Goodpasture antigen, alpha3(IV)NC1), with human B cells homozygous for HLA-DR15, the allele carried by 80% of patients, we find that alpha3(IV)NC1 is presented as at least two sets of three to five peptides centered on common core sequences (nested sets). Synthetic peptides containing these core sequences bind to HLA-DR15 with intermediate affinity (IC50, 1.1-6 microM).

Amino Acid Sequence↗
PubMed1996

Correlation between the concentration of serum anti-topoisomerase I autoantibodies and histological and biochemical alterations in the skin of tight skin mice.

Cutaneous hyperplasia observed in tight skin mice is due to a mutation located on chromosome 2. While homozygous mice die in utero, the heterozygotes survive. TSK syndrome is associated with the presence of autoantibodies specific for scleroderma target autoantigens. The presence of autoantibodies specific for topoisomerase I is characteristic of both human and murine disease. We have generated two distinct genotypes of mice, TSK/+ and +/+ with respect to the TSK trait by breeding TSK mice with immunodeficient mouse strains. Since the mutated gene of TSK syndrome has not yet been cloned, only histological and biochemical criteria were used for defining TSK genotype. In the F1 mice derived by mating TSK/+ mice with RAG2-/-, JH-/-, or C57BLvit/vit mice, we have found a good correlation between the amount of serum anti-topoisomerase I autoantibodies present and the histopathological and biochemical alterations that are characteristic of TSK scleroderma-like syndrome.

Animals↗
PubMed1995

Type II collagen in mixed tumors of the skin. An immunohistochemical study and new speculations concerning histogenesis.

We studied 11 cases of mixed tumor of the skin with a polyclonal antibody against human type II collagen. Two of the cases were of the eccrine type, six were apocine, and three were malignant. In all of the benign cases of mixed tumor and in some of the malignant type, "chondroid" and mucinous portions stained. The clearly epithelial portions of the tumor stained as well, and staining was most intense in the eccrine types and least intense in the malignant types. The positive staining in mixed tumors may help elucidate the histogenesis of these unusual tumors as well as help differentiate among the various subtypes.

Adenoma, Pleomorphic↗
PubMed1995

Panniculitis of pancreatic disease masquerading as systemic lupus erythematosus panniculitis.

We describe a patient with systemic lupus erythematosus (SLE) who presented with severe refractory pannicular lesions diffusely involving the buttocks and lower extremities. Due to the severity of these lesions, a biopsy was performed, which implicated panniculitis associated with pancreatic disease, rather than lupus panniculitis. Serum amylase was normal, but the serum lipase was markedly elevated. An abdominal computerized tomographic scan demonstrated a pancreatic mass, which upon laparotomy was found to be an acinar cell carcinoma. After resection of the mass, her symptoms improved, where they had not responded to prior immunosuppressive therapy. She has subsequently remained well without recurrence of the disease. This case illustrates that an uncharacteristic presentation of panniculitis in a patient with lupus does not necessarily imply lupus panniculitis, and a biopsy is imperative to distinguish other sometimes life threatening etiologies.

Carcinoma, Acinar Cell↗
PubMed1993

Induction of skin fibrosis and autoantibodies by infusion of immunocompetent cells from tight skin mice into C57BL/6 Pa/Pa mice.

Tight skin (TSK/+) mice develop a cutaneous hyperplasia associated with the occurrence of autoantibodies characteristic for scleroderma. In order to study the role of autoimmunity in the production of skin fibrosis, we conducted adoptive transfer experiments in which bone marrow cells of TSK/pa mice were infused into pa/pa mice littermates. (C57BL/6 pa/pa mice are used to produce heterozygous TSK/pa mice). Our results showed that after a prodromal period of several months, the transfer of bone marrow cells led to skin fibrosis, the presence of autoantibodies, and increased transcription of (alpha 1) collagen I and TGF beta genes. Infusion of enriched B or T cells alone did not cause skin fibrosis but of B cells alone increased autoantibody production. By contrast, transfer of T and B lymphocytes led to earlier mild fibrosis, cellular infiltration and autoantibody production as well as increased transcription of the (alpha 1) collagen gene. Our results strongly demonstrate, for the first time, that immunocompetent cells can play a role in the activation of collagen synthesis leading to skin fibrosis.

Animals↗
PubMed1993

Multiple hamartoma syndrome with osteosarcoma.

Multiple hamartoma syndrome, also known as Cowden's disease, is a rare genodermatosis with characteristic mucocutaneous lesions associated with multiple internal abnormalities. We describe a patient having classic dermatologic manifestations of Cowden's disease and multiple neoplasia including follicular adenocarcinoma of the thyroid gland with lung metastasis, intraductal breast carcinoma within a fibroadenoma, and an osteosarcoma. To our knowledge, this is the first reported case of an osteosarcoma in Cowden's disease.

Adult↗
PubMed1992

Pathologic manifestations of the eosinophilia myalgia syndrome: analysis of 11 cases.

We describe the histopathologic changes of skin, muscle, vessels, and fascia in 11 patients with eosinophilia myalgia syndrome, a newly described entity that has been linked to the ingestion of L-tryptophan. This syndrome is defined clinically by severe incapacitating myalgias and a peripheral eosinophilia. Arthralgias, edema of the extremities, morbilliform rashes, skin induration, weakness, fatigue, and respiratory weakness may be present as well. The earliest apparent histologic changes were observed at the septa between subcutaneous fat lobules and in the deep dermis or fascia. The septa and fascia were infiltrated with a sparse mixture of lymphocytes and histiocytes. In the deep fascia, in addition to inflammatory cells, there were distinctive, reactive mesenchymal cells that showed features of both histiocytes and fibrocytes. Minimal tissue eosinophilia was seen despite the extent of blood eosinophilia. Dermal thickening and homogenization of collagen bundles occurred with replacement of fat and adnexa (changes indistinguishable from scleroderma or morphea). Vessel walls in the dermis and fascia showed thickening and endothelial swelling, but no overt vasculitis was noted. Skeletal muscle biopsies showed a perimysial, epimysial, and/or fascial inflammatory infiltrate of lymphocytes and distinctive reactive mesenchymal cells with some eosinophils. Minimal myofiber atrophy, regeneration, or necrosis was seen despite the clinical history of severe myalgias in almost all patients. This syndrome should help gain insight into the mechanisms of fibrosis in environmental-induced, scleroderma-like syndromes and in idiopathic, scleroderma-like disorders as well.

Adult↗
PubMed1992

Histiocytic cytophagic panniculitis: molecular evidence for a clonal T-cell disorder.

Histiocytic cytophagic panniculitis is a systemic disease of unknown etiopathogenesis that invariably involves the subcutaneous fat and is histologically characterized by phagocytosis of blood elements by histiocytes that appear to be benign. Immunophenotypic and genotypic studies of biopsy specimens of the lesions of a 58-year-old woman showed that the lymphocytic infiltrates accompanying the histiocytes in the subcutis were composed of clonal T-cells with rearrangement of the surface receptor gene. Our findings suggest that the primary abnormality in histiocytic cytophagic panniculitis may be a clonal T-cell proliferation.

Biopsy↗