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Biomedical subjects

Carol M Artlett

Publications and source records attributed to Carol M Artlett.

At least 19 recordsLinked to original sources
PubMed2006

A cohort study of cancer incidence in systemic sclerosis.

OBJECTIVE: To describe the incidence of cancer in a large cohort of patients with systemic sclerosis (SSc) and compare it to the Surveillance Epidemiology and End Results (SEER) cancer registries. METHODS: Cancer risk in a large cohort of patients with SSc followed at our institution was assessed. A total of 769 patients with SSc who were followed between 1987 and 2002 were screened for the development of cancer. Standardized incidence ratios (SIR) for malignancies identified after diagnosis of SSc were calculated using the SEER cancer registries and stratified by sex. RESULTS: Ninety malignancies were diagnosed in 769 patients followed at our institution between 1987 and 2002. Sixty-two malignancies were diagnosed after diagnosis of SSc in a total of 3,775 patient years of followup. Twenty-eight malignancies were diagnosed prior to diagnosis of SSc. The SIR for all cancers diagnosed after diagnosis of SSc was 1.55 (1.16-1.93). The SIR for esophageal cancer was 15.9 (4.2-27.6) while that of oropharyngeal cancer was 9.63 (2.97-16.29). CONCLUSION: We identified an overall increase in the incidence of cancer in a cohort of patients with SSc compared to the general population, with statistically significant differences in the incidence of esophageal and oropharyngeal cancers.

Cohort Studies↗
PubMed2006

Morbidity and mortality of patients diagnosed with systemic sclerosis after the age of 75: a nested case-control study.

This study aims to characterize the clinical features of a cohort of patients diagnosed with systemic sclerosis (SSc) after the age of 75 and compare them to a group diagnosed at a younger age. We record the review of 769 patients diagnosed with SSc over the past 16 years. Utilizing a nested case-control model, we compare demographics, disease severity, morbidity, and mortality data of all patients diagnosed after the age of 75 to sex- and disease-type-matched, randomly selected group of patients diagnosed with SSc before the age of 60. Twelve patients were diagnosed with SSc after the age of 75, seven with the diffuse, and five with the limited form. It took longer to diagnose SSc in the older patients, and comparison of disease severity revealed a worse pulmonary picture and a more frequent development of malignancy in the older patients as compared with the younger ones. During a mean follow-up of 36.2 months, our cohort of patients did not have worsening in their disease severity, though 6 months after the last follow-up, six patients died. We conclude that a diagnosis of SSc at an older age appears to be a poor prognostic indicator related to both disease severity and comorbidities. A higher clinical suspicion will lead to an earlier diagnosis and a potential decrease in morbidity and mortality.

Aged↗
PubMed2006

Expression of allograft inflammatory factor 1 in tissues from patients with systemic sclerosis and in vitro differential expression of its isoforms in response to transforming growth factor beta.

OBJECTIVE: Allograft inflammatory factor 1 (AIF-1), a protein initially identified in chronically rejected rat cardiac allografts, is involved in the immune response and proliferative vasculopathy that occurs during allograft rejection. Three well-characterized isoforms of AIF-1 result from alternative messenger RNA (mRNA) splicing. We previously identified a strong association of systemic sclerosis (SSc) with a polymorphism in AIF-1 isoform 2. The purpose of this study was to investigate AIF-1 expression in affected tissues from patients with SSc and to examine the regulation of its isoforms by transforming growth factor beta (TGFbeta). METHODS: AIF-1 in the skin and lung tissues of patients with SSc was analyzed by immunochemistry. AIF-1 isoform expression in response to TGFbeta and interferon-gamma stimulation was examined by quantitative polymerase chain reaction (PCR). RESULTS: AIF-1 protein was present in affected vessels of the lung and skin lesions of patients with SSc. Quantitative PCR showed an average of 14-fold higher mRNA levels in affected SSc skin than in normal skin. Double-label immunofluorescence staining demonstrated that T cells, macrophages, and endothelial cells in affected tissues expressed AIF-1. Stimulation of peripheral blood mononuclear cells with TGFbeta caused a specific and significant increase in the expression of AIF-1 isoform 2 transcripts (P < 0.005), which was due to stabilization of AIF-1 isoform 2 mRNA. CONCLUSION: These data suggest that AIF-1 plays an important role in the pathogenesis of SSc owing to its increased expression in affected tissues and to the specific stimulation of AIF-1 isoform 2 by TGFbeta.

Calcium-Binding Proteins↗
PubMed2006

T cells and B cells in the pathogenesis of systemic sclerosis: recent insights and therapeutic opportunities.

Among the earliest pathologic events in systemic sclerosis (SSc) is the infiltration of mononuclear cells into the skin lesion. This inflammatory cell infiltration precedes the development of fibrosis, suggesting an integral role for the presence of these cells in the fibrotic events observed in the lesion. However, immunosuppressive therapies that are effective in other autoimmune disease have not been successful in the treatment of SSc, making the clinical management of this disease very difficult. The aim of this paper is to review the latest findings regarding the activation and the functional polarization of T cells and their role in the pathogenesis of SSc. Furthermore, the potential role of B cells, a hitherto scantily investigated inflammatory cell in SSc, is discussed. Understanding the interplay between T and B cells, and the processes that promote the fibrotic cytokine pattern seen in these patients is of utmost importance for the development of effective therapies to treat the clinical complications.

B-Lymphocytes↗
PubMed2006

Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature.

OBJECTIVES: To review the clinical and laboratory features of 12 cases of nephrogenic fibrosing dermopathy (NFD) studied at our institution and of 70 previously described cases in the literature. METHODS: Clinical evaluation and laboratory studies of 12 patients with NFD associated with chronic hemodialysis or peritoneal dialysis for end-stage renal disease and a review of 23 previous publications describing 70 patients with this disease. RESULTS: Eleven patients undergoing chronic hemodialysis and 1 patient undergoing chronic peritoneal dialysis for end-stage renal failure developed a severe and progressive cutaneous fibrotic process with woody induration of legs, thighs, hands, and forearms, and severe loss of motion and flexion contractures in multiple joints. Several patients displayed systemic involvement including fibrosis of muscles, myocardium, and lungs and marked elevations of the erythrocyte sedimentation rate and/or C-reactive protein. Three patients died within 2 years of symptom onset. A review of previously published reports of this disorder confirmed the presence of systemic involvement and a poor prognosis with a high mortality rate. CONCLUSIONS: NFD is a severe and usually progressive systemic fibrotic disease affecting the dermis, subcutaneous fascia, and striated muscles. It also appears that the disease can cause fibrosis of lungs, myocardium, and other organs.

Adult↗
PubMed2006

The role of allograft inflammatory factor 1 in systemic sclerosis.

PURPOSE OF REVIEW: The aim of this article is to review studies which support the hypothesis that allograft inflammatory factor-1, a protein initially identified in chronically rejected cardiac allografts, may be involved in the pathogenesis of the progressive fibroproliferative vasculopathy which is a hallmark of systemic sclerosis. RECENT FINDINGS: Recent findings demonstrated elevated allograft inflammatory factor-1 expression both in systemic sclerosis affected tissues and peripheral blood mononuclear cells. A detailed immunohistopathologic study examined the tissue and cellular localization of the protein in affected systemic sclerosis tissues and demonstrated its expression in the endothelium of dermal and pulmonary vessels, in the pulmonary parenchyma, and in relevant inflammatory cells including T cells and macrophages. Furthermore, functional studies showed specific allograft inflammatory factor-1 isoform expression stimulation by transforming growth factor-beta. SUMMARY: This review summarizes recent findings suggesting that allograft inflammatory factor-1 may play an important role in systemic sclerosis vasculopathy and provides supporting evidence to consider the molecule as a novel therapeutic target.

Biomarkers↗
PubMed2005

Demonstration of autoimmunity in the tight skin-2 mouse: a model for scleroderma.

The tight skin-2 (Tsk2/+) mouse has been proposed as an animal model of systemic sclerosis (SSc) because this animal exhibits increased collagen synthesis and accumulation in the dermis. The Tsk2/+ mouse also has been reported to have a mononuclear cell infiltrate in the dermis; however, to date no evidence of autoimmunity has been described in this animal model. We report here that Tsk2/+ mice harbor numerous autoantibodies in their plasma including some, which are similar to those, present in SSc patients. Immunofluorescence with HEp-2 cells revealed the presence of anti-nuclear Abs (ANAs) in the plasma of 92% of the Tsk2/+ mice. In contrast, <5% of cage-mated CAST/ei mice had a positive ANA and none of the C3H/HeJ age-matched controls were positive. Homogenous, speckled, rim, nucleolar, centromere as well as combinations of these patterns were observed. The proportion of Tsk2/+ animals with a positive ANA increased slightly with age. ELISAs showed that 93% of the Tsk2/+ animals were positive for anti-Scl70, 82% for anti-centromere, 5% for anti-RNP/Sm, and none were positive for anti-RNA-polymerase II Abs. Indirect immunofluorescence with Crithidia luciliae and ELISA for anti-dsDNA Abs showed that 76% of Tsk2/+ mice were positive for this autoantibody. The high frequency of anti-Scl70 and anti-centromere autoantibodies indicates that Tsk2/+ mice display some humoral immune alterations which are similar to those found in patients with SSc. However, the Tsk2/+ mice also develop autoantibodies to dsDNA and a majority of the mice develop multiple autoantibody specificities (anti-Scl70, anti-CENP-B, and anti-dsDNA) indicating that the mouse may be a useful model to study autoimmunity in a wider spectrum of connective tissue diseases.

Age Factors↗
PubMed2005

Immunology of systemic sclerosis.

Systemic sclerosis (scleroderma; SSc) is an autoimmune disorder of unknown etiology characterized by severe and progressive cutaneous and visceral fibrosis, pronounced alterations in the microvasculature, and numerous cellular and humoral immunological abnormalities. Clinically, systemic sclerosis is very heterogeneous, ranging from mild limited forms of skin sclerosis (LcSSc) with minimal internal organ involvement to severe skin to multiple internal organ fibrosis and extensive skin fibrosis (DcSSc). Mortality and morbidity in systemic sclerosis is very high and are directly related to the extent of the fibrotic and microvascular alterations. The interactions between blood vessels, fibroblast activity, and immunological processes play an important role in the pathogenesis of SSc.

Antibody Formation↗
PubMed2005

Pathophysiology of fetal microchimeric cells.

Microchimerism has been defined by the presence of a low number of circulating cells transferred from one individual to another. The transfer of microchimeric cells naturally takes place during pregnancy and occurs bi-directionally between the mother and fetus. Further, microchimerism can also be a result of blood transfusions and organ transplants. Microchimeric cells have been implicated in health and disease. Fetal microchimerism has been correlated with the hyporesponsiveness of the maternal immune system towards a fetal allograft and with the longevity of organ transplants. However, microchimeric cells have been implicated in the pathogenesis of autoimmune diseases including systemic sclerosis. In contrast, microchimeric cells were found to contribute to tissue repair. Much controversy exists around the role of microchimeric cells in the pathogenesis of certain diseases, and these cells in tissues may be a consequence rather than the cause of disease.

Animals↗
PubMed2005

Microchimerism and systemic sclerosis.

PURPOSE OF REVIEW: Although 6 years have elapsed since the initial report describing the presence of microchimeric cells in affected tissues from patients with systemic sclerosis, a mechanism by which these cells might contribute to the pathogenesis of the disease is still unknown. This article reviews the published literature related to the possible role of microchimeric cells in the pathogenesis of systemic sclerosis. RECENT FINDINGS: Numerous studies have reported the identification or quantification of microchimeric cells in the peripheral blood or tissues from systemic sclerosis patients; however, only one study to date has investigated their function. Recent investigations have demonstrated microchimeric cells in the clinically uninvolved tissues from patients with systemic sclerosis, suggesting that these cells are present in early disease. However, after the identification of microchimeric cells in blood and tissues of patients with systemic sclerosis, these cells have been found in organs affected by nonautoimmune conditions. These cells are also commonly detected in the peripheral blood of healthy people. SUMMARY: These observations have raised questions about whether microchimeric cells are responsible for the pathologic events in systemic sclerosis or are merely remnants of a pregnancy remote in time, and it has been suggested that they might also have beneficial effects for the host.

Adult↗
PubMed2005

Chronic graft-versus-host-disease-like dermopathy in a child with CD4+ cell microchimerism.

We report the case of an 11-year-old boy suffering from a severe progressive chronic skin disease with clinical features of progressive systemic scleroderma, systemic lupus erythematosus and dermatomyositis. Skin biopsies revealed fibrosis and lichenoid changes and muscle biopsy a myositis. Immunohistology of the skin showed a lichen-ruber-like pattern. Despite repeated extensive investigations, no autoantibodies were detectable. Some of these findings looked like those described in juvenile dermatomyositis. Finally, it could be demonstrated that the boy showed microchimerism with approximately 1% maternal CD4+ lymphocytes in his peripheral blood leukocytes. Furthermore maternal cells could be demonstrated in inflamed muscle tissue. So a graft-versus-host-disease-like pathomechanism appears to be likely. Several systemic therapies have been used with limited success to improve the condition including corticosteroids, azathioprine, cyclosporine A and mycophenolate mofetil. A distinct improvement of erythemas and sclerosis could be achieved by means of low-dose UVA1 phototherapy which was applied with escalating single doses of 3-12 J/cm2 for 35 consecutive days.

CD4-Positive T-Lymphocytes↗
PubMed2004

Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta1 expression in affected skin.

OBJECTIVE: Nephrogenic fibrosing dermopathy (NFD) is a newly recognized cutaneous fibrotic disorder occurring in individuals with end-stage renal disease (ESRD). The aim of the present study was to describe the clinical and histopathologic features of 9 new cases and to characterize the inflammatory cells and expression of transforming growth factor beta1 (TGFbeta1) in affected skin. METHODS: Clinical and laboratory assessments, including serology and pulmonary function studies, were performed in 9 patients undergoing long-term dialysis (8 hemodialysis; 1 peritoneal dialysis) for ESRD of diverse etiologies. Skin, fascia, striated muscles, lungs, and heart were examined by histopathology. Inflammatory cells were characterized by immunophenotyping using specific monoclonal antibodies. TGFbeta1 expression was determined by in situ hybridization. RESULTS: All patients displayed cutaneous features resembling both systemic sclerosis and diffuse fasciitis, with severe loss of motion and flexion contractures in multiple joints. Six patients displayed woody induration of the muscles of the legs, thighs, and forearms. Five of the 6 patients with lung involvement had a reduced diffusion capacity for carbon monoxide on pulmonary function testing. Marked elevations of the erythrocyte sedimentation rate and/or C-reactive protein level were found in 6 patients. Antinuclear antibodies were present at low titers in 4 patients. Histopathologic studies indicated that in addition to the dermis, the fibrotic process affected the subcutaneous tissue, fascia, striated muscles, lungs, and myocardium. Large numbers of CD68+/factor XIIIa+ dendritic cells and increased expression of TGFbeta1 were found in affected skin and muscle. CONCLUSION: Our findings indicate that the fibrotic process of NFD affects not only the dermis, but also the subcutaneous tissues, fascia, and other organs, including striated muscles, heart, and lungs. We therefore believe this is a systemic fibrosing process, and we suggest that dialysis-associated systemic fibrosis would be a better term for the condition.

Adult↗
PubMed2003

HLA-DQA1 is not an apparent risk factor for microchimerism in patients with various autoimmune diseases and in healthy individuals.

OBJECTIVE: Microchimeric cells have been identified in lesions and peripheral blood of patients with systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM), and HLA-DQA1*0501 is a risk factor for these diseases in some populations. Furthermore, DQA1*0501 has been associated with T lymphocyte microchimerism in SSc. To better define the strength of this association, we assessed the relationship among DQA1 alleles and microchimerism. METHODS: DNA from whole peripheral blood or magnetically sorted T cells was tested for microchimeric cells by polymerase chain reaction of the Y chromosome or of HLA-Cw in 87 SSc patients, 28 juvenile IIM patients, and 88 healthy controls. Thirty-seven mother-son pairs were also analyzed for microchimerism and DQA1*0501. RESULTS: We were unable to demonstrate that DQA1*0501 is associated with microchimerism in T lymphocytes or in whole peripheral blood DNA in patients with SSc or juvenile IIM or in healthy individuals. In the 37 mother-son pairs, we were unable to demonstrate an association of DQA1*0501 with microchimerism in peripheral blood DNA or T lymphocytes, and compatibility between the donor's and recipient's HLA alleles did not influence microchimerism in the recipient. CONCLUSION: These data suggest that HLA-DQA1 alleles do not appear to play a role in the persistence of microchimerism in the peripheral blood or T lymphocytes of patients with selected autoimmune diseases or in healthy individuals.

Adolescent↗
PubMed2003

Microchimerism and scleroderma: an update.

Microchimerism has been defined by the presence of a low number of circulating cells transferred from one individual to another. This transfer takes place naturally during pregnancy, between mother and fetus, or between fetuses in multigestational pregnancies. Furthermore, the establishment of microchimerism can also occur during blood transfusion, as well as during bone marrow and solid-organ transplants. Recently, microchimeric cells have been implicated in the pathogenesis of autoimmune diseases, particularly systemic sclerosis. Studies have demonstrated an increased presence of microchimeric cells in peripheral blood and tissues from patients with systemic sclerosis, and, more recently, microchimeric cells were demonstrated to be specifically activated and capable of recognizing patient human leukocyte antigens.

Chimera↗
PubMed2002

Oligoclonal T cell expansion in the skin of patients with systemic sclerosis.

Fibrosis, microvascular fibroproliferative alterations, and autoantibody production are the main features of systemic sclerosis (SSc), and all of them can be explained by cytokine production by activated T cells. However, little is known about the role of T cells in the pathogenesis of SSc, and there is no information on the Ag(s) that elicits such activation. To determine whether T cells infiltrating the skin biopsies of patients with SSc are oligoclonal, beta-chain TCR transcripts from T cells infiltrating the skin of five patients with SSc of recent onset were amplified by either Vbeta-specific PCR or nonpalindromic adaptor PCR. The resulting PCR products were subsequently cloned and sequenced. High proportions of identical beta-chain TCR transcripts ranging from 43 to 90% of those sequenced were found in five patients, strongly suggesting the presence of oligoclonal T cells in these infiltrates. A dominant T cell clone was found to be clonally expanded in skin biopsies obtained from a single patient with SSc at three different times (0, 8, and 13 mo earlier) and from three different skin regions. beta-chain TCR transcripts from PBMC from normal donors (methodological control) were unique when compared with each other, typical for polyclonal populations of T cells. The finding of oligoclonal T cells infiltrating the skin of patients with SSc suggests that these T cells have undergone proliferation in situ in the skin and clonal expansion in response to as yet unidentified Ag(s). These results suggest that T cells are involved in the pathogenesis of the disease.

Adult↗
PubMed2002

Increased microchimeric CD4+ T lymphocytes in peripheral blood from women with systemic sclerosis.

Recent studies have demonstrated the presence of microchimeric cells in peripheral blood and skin lesions from patients with systemic sclerosis (SSc). In a previous study we found that some peripheral blood CD3+ cells from female patients with SSc contained male DNA. Here, peripheral blood samples from 47 patients with SSc (30 with diffuse cutaneous SSc and 17 with limited cutaneous SSc) and 22 healthy controls were sorted for CD4+ and CD8+ T cells. Both positively and negatively selected populations were analyzed for male DNA by quantitative PCR. Analysis of Y chromosome sequences in the sorted cells demonstrated the presence of microchimerism in 82.9% of SSc patients compared to 63.6% of controls. The numbers of CD4+ and CD8+ T cells were found to be significantly higher in the SSc patients than in controls. Furthermore, patients with dcSSc were observed to have significantly more CD4+ microchimeric T cells than the controls. In the CD8+ T-cell population, there was a trend toward more microchimeric cells in the patients but this did not reach significance. These results support the hypothesis that microchimeric CD4+ T cells may be involved in the pathogenesis of SSc.

CD4-Positive T-Lymphocytes↗