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Biomedical subjects

K E Sullivan

Publications and source records attributed to K E Sullivan.

At least 19 recordsLinked to original sources
PubMed2003

Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a polygenic disorder of dysregulated inflammation. Numerous specific candidate genes have been identified and most relate to the handling of immune complexes or antigen presentation. This is consistent with the classic finding of immune complex deposition in affected end organs. We wished to examine combinatorial effects of polymorphic variants of genes involved in immune complex clearance in susceptibility to lupus. METHODS: This study examined the occurrence of polymorphisms in genes which encode proteins known to be involved in immune complex handling and clearance. Each polymorphic variant of a complement protein (C2, mannose binding protein and C4), complement receptor (CR1) or Fc receptor (FcgammaRIIA and FcgammaRIIIA) gene is known to affect function adversely. One hundred and sixty SLE patients and 212 control subjects were genotyped using polymerase chain reaction methods. RESULTS: We found an increasing association of SLE with increasing numbers of gene defects. Combinations of severe defects in FcgammaRIIA and FcgammaRIIIA were particularly deleterious for both African American and Caucasian patients, even though only one defective variant was individually statistically significantly associated with SLE. CONCLUSIONS: The results of the study suggest that genes may interact in ways that either synergize or modify the effect of a single genetic effect and imply that association studies must be interpreted within the genetic background of the populations.

Antigen-Antibody Complex↗
PubMed2002

An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus.

Osteopontin (SPP1) is a soluble ligand with pleomorphic immunologic activities including activation of macrophage chemotaxis, promotion of Th1 responses, and activation of B1 B cells. It has been implicated in the development of murine lupus and is overexpressed in humans with systemic lupus erythematosus (SLE). We examined a polymorphism of osteopontin for an association with lupus in humans in an effort to determine whether there is any evidence that a genetic predisposition to altered osteopontin expression might explain the overexpression seen in human SLE patients. A silent polymorphism (707C>T, rs1126616) of osteopontin was significantly associated with SLE. Additional associations with renal disease and opportunisitic infections were suggested. This is the first phenotypic association with a polymorphic variant of osteopontin.

Chi-Square Distribution↗
PubMed2001

Decreased natural killer (NK) cell function in chronic NK cell lymphocytosis associated with decreased surface expression of CD11b.

Chronic natural killer cell lymphocytosis (CNKL) is characterized by greatly increased numbers of natural killer (NK) cells and patients with this disease may survive for long periods. This is in contrast to patients with leukemic proliferations of NK cells who can have a rapidly progressive clinical course. We identified a pediatric patient who was largely healthy who had CNKL and we sought to determine if the expanded CD16(+)CD3(-) population in this patient functions differently than classical NK cells. Cytotoxic activity against NK cell-sensitive K562 target cells was present, but lower than that in control donors when calculated as lytic units per CD16(+)CD3(-) cell. This cytolytic activity was inducible in patient samples by IL-2/IL-12 stimulation proportionately to that induced in samples from control donors. Intracellular perforin was also present and induced in patient CD16(+)CD3(-) cells similarly to controls. Other presumed NK cell activities, such as IL-2/IL-12 induced IFN-gamma expression and initiation of apoptosis evidenced by annexin V binding after CD16 crosslinking were present in patient samples. Patient CD16(+)CD3(-) cells, however, differed from classical NK cells, as the majority did not express CD56, CD57, CD8, or CD11b. Most convincingly, there was a 5 log decrease in CD11b expression in patient CD16(+)CD3(-) cells compared to control as determined by mean channel fluorescence. These observed differences may explain the relatively benign phenotype of this disorder.

Apoptosis↗
PubMed2001

Cytokine and chemokine dysregulation in hyper-IgE syndrome.

Hyper-IgE syndrome is characterized by severe recurrent staphylococcal infections, eczema, bone abnormalities, and markedly elevated levels of immunoglobulin E (IgE). The genetic basis is not known and the central immunologic defect is largely undefined. Reduced neutrophil chemotaxis is often described, and variable T cell defects have been demonstrated in some patients. It has been hypothesized that hyper-IgE is associated with a Th1/Th2 imbalance. We wished to characterize cytokine and chemokine imbalances that might reflect the underlying disease process or reflect ongoing pathologic processes. Nine patients with hyper-IgE syndrome and six controls were studied. Radioimmunoassays, flow cytometry, and gene array analyses were performed to characterize cytokine and chemokine production. Hyper-IgE patients express more IL-12, while ENA-78, MCP-3, and eotaxin are markedly underexpressed. Underexpression of a set of chemokines could explain a number of features of hyper-IgE syndrome and may offer a new paradigm for the understanding of this disorder.

Adolescent↗
PubMed2001

DiGeorge syndrome/chromosome 22q11.2 deletion syndrome.

DiGeorge syndrome is characterized by conotruncal cardiac defects, hypocalcemia, and a hypoplastic thymus. Many, but not all, patients have a heterozygous deletion of chromosome 22q11.2. In its most severe form, it represents a devastating syndrome with high mortality. Patients with severe immunodeficiency are candidates for a thymic transplant or a fully matched bone marrow transplant. Fortunately, the majority of patients with either DiGeorge syndrome or chromosome 22q11.2 deletion syndrome have a mild to moderate immunodeficiency. These patients may develop recurrent infections or autoimmune disease.

Chromosome Deletion↗
PubMed2001

Interferon-gamma polymorphisms in systemic lupus erythematosus.

Interferon-gamma is a cytokine which is believed to play a role in both the susceptibility and pathogenesis of lupus. To determine whether genetic variants might influence the development of this polygenic autoimmune disease, we analyzed the gene frequency of eight different alleles in controls and patients with SLE. Ninety-nine controls and 136 patients with systemic lupus erythematosus were genotyped for a CA repeat in the first intron of the interferon-gamma gene. There were no statistically significant differences in the allele frequencies between patients and controls suggesting that these polymorphic variants do not influence susceptibility. We then examined whether any of these alleles were associated with specific clinical manifestations. Allele 1 was associated with gastrointestinal lupus while allele 6 was associated with more severe lupus. Allele 2 appeared to be protective for arthritis. This suggests that genetic variation in interferon-gamma expression might influence the disease course.

Alleles↗
PubMed2001

Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).

OBJECTIVES: To characterize immunologic function and clinical characteristics in patients with chromosome 22q11.2 deletion syndrome and determine whether there was significant change over time. METHODS: This study characterized the laboratory and clinical features of the immunodeficiency in a cohort of 195 patients with chromosome 22q11.2 deletion syndrome and used cross-sectional and analysis of variance to compare the findings in different age groups with control patients. Changes over time were also characterized by a model effect method in a subset of patients who were studied serially. RESULTS: Diminished T cell counts in the peripheral blood are common in patients with chromosome 22q11.2 deletion syndrome. The pattern of changes seen with aging in normal control patients was also seen in patients with chromosome 22q11.2 deletion syndrome, although the decline in T cells was blunted. Autoimmune disease was seen in most age groups, although the types of disorders varied according to age. Infections were also common in older patients, though they were seldom life threatening. CONCLUSIONS: Slow declines in T cell populations are seen in chromosome 22q11.2 deletion syndrome. Clinical manifestations of immunodeficiency, such as recurrent infection and autoimmune disease, were common in this population but had little relationship to specific immunologic laboratory features.

Antibody Formation↗
PubMed2001

Gamma interferon and lipopolysaccharide interact at the level of transcription to induce tumor necrosis factor alpha expression.

Lipopolysaccharide (LPS) is a very potent inducer of tumor necrosis factor alpha (TNF-alpha) expression from monocytes and macrophages. Another inflammatory cytokine, gamma interferon (IFN-gamma), can potentiate the effects of LPS, but the mechanism is not thoroughly understood. Previous reports emphasized the ability of IFN-gamma to upregulate CD14 expression (the receptor for LPS), and nearly all studies have utilized sequential stimulation with IFN-gamma followed by LPS to exploit this phenomenon. This study demonstrates that IFN-gamma can upregulate the effect of LPS at the level of transcription. Human monoblastic Mono-Mac-6 cells produced up to threefold-greater levels of TNF-alpha when simultaneously stimulated with LPS and IFN-gamma compared to treatment with LPS alone. RNase protection studies showed a similar increase in RNA beginning as early as within 30 min. The synthesis of TNF-alpha mRNA in IFN-gamma- and LPS-treated Mono-Mac-6 cells was also temporally prolonged even though the message turnover rate was identical to that seen in LPS stimulated cells. The modulatory effect of IFN-gamma may be mediated by Jak2.

Cells, Cultured↗
PubMed2000

Rapid method for determining the rate of DNA synthesis and cellular proliferation.

A new method has been developed for determination of DNA synthesis during cell proliferation. The method is based on the metabolism of [U-(13)C(6)]glucose to deoxyribose (DR) and then incorporation of [U-(13)C(5)]DR into newly synthesized DNA. Extracted cellular DNA is subjected to HCl hydrolysis (2 h at 100 degrees C), which converts DR into levulinic acid. The (13)C enrichment in DR is determined in the trimethylsilyl derivative of levulinate using gas chromatography-mass spectrometry. The method is rapid and sensitive. It can precisely determine (13)C enrichment below 1 at.% excess in as little as 4 ng DNA. We have used this method to determine the rate of cell proliferation in vitro and the level of DR in a given amount of DNA. The current approach has significant advantages over previously described methods and overcomes several difficulties related to the determination of DNA synthesis both in vivo and in vitro.

Biological Assay↗
PubMed2000

3' polymorphisms of ETS1 are associated with different clinical phenotypes in SLE.

A microsatellite repeat polymorphism was identified in the 3' flanking region of the human ETS1 gene. Sequencing revealed two CA repeat segments in close proximity. Seven different alleles comprising various combinations of CA repeat units were identified in a healthy control population. Because ETS1 plays a role in lymphocyte development and function, apoptosis, and inflammation, we examined whether any of these polymorphisms were associated with a systemic inflammatory condition, systemic lupus erythematosus (SLE). Inheritance of this disease is polygenic and a recent genome-wide screen for SLE susceptibility loci revealed linkage with chromosome 11q14-23, the region in which the ETS1 gene lies. This region has also been identified as a general autoimmune susceptibility region. None of the seven distinct ETS1 alleles appeared statistically more frequently in SLE patients than controls, however, two alleles were associated with particular clinical manifestations. Allele 1 is associated with discoid lesions and allele 7 is associated with vasculitis. While this polymorphism does not directly affect the coding region of ETS1, it may be a marker for overexpression of a particular isoform or inheritance of another polymorphism which does affect function. These data suggest that ETS1 may be involved in the phenotypic expression of systemic lupus erythematosus.

Alleles↗
PubMed2000

Genetics of systemic lupus erythematosus. Clinical implications.

Rheumatic diseases have long been recognized as having complex inheritance patterns. It has recently been estimated that over 100 genes may be implicated in the SLE disease process. Identification of these genes has led to a greater understanding of the etiopathogenesis of SLE and is beginning to lead to new types of interventions directed at correcting aberrant biological processes.

Animals↗
PubMed2000

A TNFR2 3' flanking region polymorphism in systemic lupus erythematosus.

The role of pro-inflammatory cytokines in systemic lupus erythematosus (SLE) remains somewhat controversial. Several studies have shown increased production of TNF alpha and IL-6 in patients with SLE. Increased production of IL-6, TNF alpha, and IL-1 soluble receptors have also been reported. This finding is provocative because the soluble receptors have the capacity to act as antagonists. Several other inflammatory disorders are also associated with increased production of soluble TNF alpha receptors suggesting that this may be a general compensatory mechanism designed to down-regulate inflammation. The recent identification of an SLE disease susceptibility locus near the TNFR2 locus (TNFR p75) suggested the hypothesis that genetically driven differences in soluble TNFR2 production could play a role in the genetic susceptibility to SLE. We therefore characterized the frequency of a genetic polymorphism in the 3' untranslated region of the TNFR2 gene in Caucasoid SLE patients and geographically matched controls. No difference in the gene frequency of the two base-pair polymorphism in SLE patients compared to controls was found, nor was there any association with any particular clinical phenotype.

3' Untranslated Regions↗
PubMed2000

Measurement of cytokine secretion, intracellular protein expression, and mRNA in resting and stimulated peripheral blood mononuclear cells.

Quantitation of cytokine production is a valuable adjunct to standard immunologic assays in defining several pathologic processes. Nevertheless, there is little agreement about which tissues should be assayed, which type of assay should be performed, and which stimulation protocol should be used. As these types of assays enter the clinical arena, there is need for standardization. There is also a need to maximize the amount of information which may be derived from a single sample. We compared secreted interleukin 4 (IL-4), IL-2, IL-6, tumor necrosis factor alpha (TNF-alpha), and gamma interferon proteins as measured by enzyme-linked immunosorbent assay with intracellular cytokine production (IL-2 and gamma interferon) as detected by flow cytometry and quantitative competitive PCR for IL-2, IL-4, TNF-alpha, and gamma interferon mRNA and cDNA. Results from unstimulated cells and cells stimulated with phorbol myristate acetate, phytohemagglutinin, and phorbol myristate acetate plus phytohemagglutin were compared. All three methodologies detected significant stimulation of cytokine production. The combination of phytohemagglutinin and phorbol myristate acetate was overall the most-potent stimulus.

Adult↗
PubMed2000

The role of bone marrow transplantation in pediatric rheumatic diseases.

Recent advances in bone marrow transplantation have led to improvement in its safety and it is now being used for rheumatologic disorders resistant to standard medical management. I describe some of the theories underlying its use and review the current data supporting its use.

Arthritis, Juvenile↗
PubMed1999

Loss of endothelial surface expression of E-selectin in a patient with recurrent infections.

Neutrophil accumulation at sites of inflammation is mediated by specific groups of cell adhesion molecules including the beta2 (CD18) integrins on leukocytes and the selectins (P- and E-selectin on the endothelium and L-selectin on the leukocyte). This is supported by studies of patients with leukocyte adhesion deficiency syndromes whose leukocytes are genetically deficient in the expression of beta2 integrins or selectin carbohydrate ligands (eg, sialyl-Lewis(x)). However, inherited deficiency or dysfunction of endothelial cell adhesion molecules involved in leukocyte recruitment has not been previously described. In this report we describe a child with recurrent infections and clinical evidence of impaired pus formation reminiscent of a leukocyte adhesion deficiency syndrome, but whose neutrophils were functionally normal and expressed normal levels of CD18, L-selectin, and sialyl-Lewis(x). In contrast, immunohistochemical staining of inflamed tissue from the patient showed the absence of E-selectin from the endothelium, although E-selectin mRNA was present. However, E-selectin protein was expressed as significantly elevated levels of circulating soluble E-selectin were detected, the molecular size of which was consistent with a proteolytically cleaved form of E-selectin. Gene sequencing failed to show evidence of a secreted mutant variant. These data represent, to our knowledge, the first description of a potentially inherited dysfunction of an endothelial cell adhesion molecule involved in leukocyte recruitment and provide additional human evidence of the importance of endothelial selectins in the inflammatory response.

Bacterial Infections↗
PubMed1999

Recent advances in our understanding of Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome initially was described in 1937 and then again in 1954 as an X-linked disorder associated with thrombocytopenia, eczema, and recurrent infections. It remained mysterious how different cell lineages could be affected in this syndrome and, more importantly, how the phenotypic features could be so protean. We now know that the features associated with Wiskott-Aldrich syndrome include dysfunction of nearly all effector arms of the immune system, as well as thrombocytopenia with platelet dysfunction. As a consequence of these abnormalities, children and adults with this syndrome have recurrent bleeding, recurrent and significant infections with common and opportunistic organisms, autoimmune disease, and lymphoreticular malignancies. In 1994, the gene that is defective in Wiskott-Aldrich syndrome was identified and found to be a gene with limited homology to any known gene families. In the past 4 years, much has been learned about the role of this protein in cellular function and T-cell responses specifically. This article reviews some recent clinical findings relevant to Wiskott-Aldrich syndrome, the proposed cellular role of this molecule, its biochemical interactions, and genotype-phenotype considerations.

Clinical Trials as Topic↗
PubMed1999

Longitudinal analysis of lymphocyte function and numbers in the first year of life in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).

Chromosome 22q11.2 deletion syndrome is a common syndrome typically consisting of variable cardiac defects, hypoparathyroidism, developmental delay, and immunodeficiency. The hemizygous deletion has variable effects on the immune system even within the same kindred, and the extent of the immunodeficiency is difficult to predict. Some patients have shown improvement over time; however, this is the first prospective longitudinal study of the dynamic nature of the immunodeficiency. Nineteen patients were studied prospectively between 1994 and 1997. The results of the newborn immunologic studies in the chromosome 22q11.2 deletion group were significantly different from those of a group of newborns with cardiac disease due to other causes. Peripheral blood T-cell numbers were decreased in the chromosome 22q11.2 deletion group, although T-cell function was largely preserved. The group as a whole demonstrated few changes in the first year of life, but a subset of patients with markedly diminished T-cell numbers did demonstrate improvement. Therefore, improvement in peripheral blood T-cell counts is variable in chromosome 22q11.2 deletion syndrome. The patients with the lowest T-cell counts improved the most in the first year of life.

Cell Lineage↗