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K E Sullivan

Publications and source records attributed to K E Sullivan.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1999

Frequency of the Fc gamma RIIIA-158F allele in African American patients with systemic lupus erythematosus.

OBJECTIVE: Defects in genes involved in immune complex clearance constitute one of the most common gene defects identified in patients with systemic lupus erythematosus (SLE). Defects in early complement components, complement receptors, and Fc receptors have all been implicated in the susceptibility to SLE. Recently, the role of functionally relevant Fc receptor polymorphisms in the etiology of SLE has been investigated. Specifically, a polymorphism of FC gamma RIII, termed Fc gamma RIIIA-158F, has been found to be associated with SLE in 2 largely Caucasian populations and appeared to constitute a risk factor for nephritis. We investigated the association of the Fc gamma RIIIA-158F and Fc gamma RIIIA-131R polymorphisms with SLE in an African American study population. METHODS: Nested polymerase chain reaction (PCR) and allele-specific PCR was used to genotype patients with SLE and controls. RESULTS: There was no difference in Fc gamma RIIIA-158F or Fc gamma RIIA-131R gene frequencies in the SLE populations compared to controls. There was no significant association between Fc gamma RIIIA-158F or Fc gamma RIIA-131R and any specific clinical or laboratory variable. CONCLUSION: In our African American study population, there did not appear to be any association of Fc gamma RIIA-158F or Fc gamma RIIA-131R with SLE.

Alleles↗
PubMed1999

C4A deficiency due to a 2 bp insertion is increased in patients with systemic lupus erythematosus.

OBJECTIVE: The association of C4A deficiency with systemic lupus erythematosus (SLE) is well documented. In Caucasian populations, the most common cause of C4A deficiency is a large gene deletion in linkage disequilibrium with a conserved MHC haplotype. Because of this linkage disequilibrium, it has been difficult to determine which of the genes constitutes the disease susceptibility allele. Evidence from non-caucasoid populations has supported a role for C4A deficiency in SLE. We investigated whether a specific genetic cause of C4A deficiency, not associated with A1, B8, DR3, is found with increased frequency in SLE compared to controls. METHODS: Polymerase chain reaction was used to identify carriers of a 2 base pair (bp) insertion in exon 29. In total, 188 patients with SLE from the Johns Hopkins lupus cohort and 222 controls were genotyped. RESULTS: The 2 bp insertion was found more frequently in patients with SLE compared to controls and was more common in Caucasian than in African American SLE patients. There were no clinical differences between patients that carried the mutation and those that did not. CONCLUSION: The association of this C4A null allele with SLE supports a role for C4A deficiency independent of other MHC associations in the etiopathogenesis of SLE.

Black People↗
PubMed1998

The Fc gammaRIIIA-158F allele is a risk factor for systemic lupus erythematosus.

OBJECTIVE: To study whether the Fc gammaRIIIA-158V/F polymorphism, which affects IgG binding affinity, is a risk factor for systemic lupus erythematosus (SLE). METHODS: We genotyped a group of 70 Caucasian SLE patients for all known Fc gammaR polymorphisms. Of this group, 45 patients (64%) had nephritis. In 35 patients, this diagnosis was confirmed by renal biopsy. RESULTS: In the total group of 70 SLE patients, the frequency of the Fc gammaRIIIA-158F allele was 0.74, versus 0.57 in healthy controls (P = 0.003). The genotype distribution of the Fc gammaRIIIA-158V/F polymorphism was also significantly different from that of the control population (P = 0.004). The distribution of the other Fc gammaR polymorphisms--Fc gammaRIIA-131R/H, Fc gammaRIIIB-NA(1,2), and Fc gammaRIIIA-48L/R/H--was similar in SLE patients and controls. CONCLUSION: In our group of SLE patients, only the distribution of the alleles of the Fc gammaRIIIA-158V/F polymorphism was significantly different from that in the control group. This might indicate that macrophage expression of the Fc gammaRIIIA-158F isoform is involved in the disturbed clearance of immune complexes in patients with SLE.

Alleles↗
PubMed1998

Lack of correlation between impaired T cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes.

Monosomic deletions of chromosome 22q11.2 are the leading cause of DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome. DiGeorge syndrome was originally described as an immunodeficiency disorder secondary to impaired T cell production due to thymic aplasia or hypoplasia; however, the frequency of immunodeficiency in the other clinical syndromes associated with the chromosome 22q11.2 microdeletion has not been previously investigated. This study examines the frequency and severity of impaired T cell production and immunodeficiency in chromosome 22q11.2 deletion syndromes and the relationship of the immunodeficiency to specific phenotypic features. Sixty patients over 6 months of age with the characteristic chromosome 22q11.2 deletion underwent immunologic evaluations. Seventy-seven percent of patients with chromosome 22q11.2 deletions were found to have evidence of immunocompromise. The severity of the immunodeficiency did not correlate with any particular phenotypic feature, nor was it restricted to patients who were categorized as having DiGeorge syndrome. Therefore, impaired T cell production and impaired immunologic function are common in patients with deletions of chromosome 22q11.2. The presence or severity of the immunocompromise cannot be predicted based on other phenotypic features and each child should be individually assessed for immune function.

Abnormalities, Multiple↗
PubMed1998

Successful use of extracorporeal membrane oxygenation (ECMO) during BMT for SCID.

An 8-month-old girl with SCID presented with severe bronchiolitis. She received an HLA-identical sibling BMT without conditioning or GVHD prophylaxis. She deteriorated despite mechanical ventilation but had normal cardiac, hepatic and renal function. ECMO was instituted on day +3 and subsequent improvement was seen concurrently with emergence of CD4+ cells on day +11. She was taken off ECMO on day +18 and suffered a left-sided stroke evidenced by a dense left hemiplegia. She was extubated on day +25 and weaned from supplemental oxygen on day +36 and at day +100 has recovered strength in her extremities. This is the first successful use of ECMO as a bridge to engraftment in a BMT patient.

Bone Marrow Transplantation↗
PubMed1998

Complement deficiency and autoimmunity.

Complete deficiency of one of the early components (C1, C4, or C2) of the classical pathway of the complement cascade is one of the strongest genetic risk factors for systemic lupus erythematosus that has been recognized. The lupus that occurs in complement-deficient individuals typically presents in early childhood. The association of complement deficiency and lupus has been known for over two decades, yet the explanation remains somewhat elusive. Complement component deficiencies may be associated with other rheumatic or autoimmune disorders and both partial and acquired complement component deficiencies are also associated with an increased risk of autoimmune disease. This article reviews the current understanding of the relationship between complement component deficiencies and autoimmunity. Recent data from animal models and new types of genetic analyses are reviewed.

Antibody Formation↗
PubMed1998

Adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency in common variable immunodeficiency.

The clinical presentations of adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency are widely variable and include clinical and immunologic findings compatible with common variable immunodeficiency. The screening of 44 patients with common variable immunodeficiency failed to identify any individuals with deficiencies of these enzymes.

Adenosine Deaminase↗
PubMed1998

Increased prevalence of immunoglobulin A deficiency in patients with the chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).

We wished to determine the prevalence of immunoglobulin A (IgA) deficiency in patients with the chromosome 22q11.2 deletion syndrome. A total of 32 patients with the chromosome 22q11.2 deletion were examined for IgA deficiency. We report a 13% (n = 4) prevalence of IgA deficiency in patients with this syndrome. The odds ratio of IgA deficiency in this population is 14.20 (P < 0.0001). This confirms the occurrence of significant humoral deficits in this predominantly cellular immunodeficiency.

Abnormalities, Multiple↗
PubMed1998

Defective natural killer cell function in patients with hemophagocytic lymphohistiocytosis and in first degree relatives.

Hemophagocytic lymphohistiocytosis (HLH), also referred to as familial erythrophagocytic lymphohistiocytosis, is a rare disorder of infancy associated with proliferation of activated histiocytes and T cells, anemia, thrombocytopenia, and fevers. This disorder appears to be due to the uncontrolled activation of T cells producing IL-2, tumor necrosis factor-alpha, and interferon-gamma. Untreated, the disorder is universally fatal. Various deficits in immune function have been described during acute disease activity including impaired T cell function, impaired monocyte-mediated antibody-dependent cytotoxicity, impaired natural killer cell function, and impaired IL-1 production. We examined natural killer cell function in familial HLH patients to determine whether this finding was consistently associated with the disease. We also examined natural killer cell function in asymptomatic parents and siblings of patients. Impaired natural killer cell function was identified in all patients and in some family members, including obligate carrier parents. This implies that one potential genetic defect in HLH may result in depressed natural killer function, but that this may not be sufficient to reliably predict eventual progression to disease.

Adult↗
PubMed1997

Four conserved promoter motifs regulate transcription of the gene encoding human complement component C2.

The early complement components of the classical activation pathway of the complement cascade include the components C1, C4, C2, and C3. These components act in concert to opsonize bacteria, clear immune complexes, and produce inflammatory mediators. They are not structurally homologous nor are they coordinately regulated. The expression of the early complement components is divergent in terms of cytokine responsiveness and tissue specificity. The only pattern of expression shared by the early complement components is inducibility by gamma-IFN and expression in cells of hepatic or monocytic lineage. Nevertheless, four novel conserved promoter motifs were identified in the 5' flanking region of multiple early complement component promoters. Mutation of these four motifs in the C2 promoter decreased transcription in hepatoma cells in transient transfection analyses, and a synthetic promoter consisting of just the four motifs supported transcription in hepatoma cells. Electrophoretic mobility shift assays demonstrate that three of the four conserved elements bind DNA-binding proteins in a tissue-specific manner. One DNA-binding protein is expressed ubiquitously, but the other three are restricted to cells of monocytic or hepatic lineage. Two of the DNA-binding proteins appear to be members of the zinc-finger family of transcription factors. Therefore, these four motifs appear to bind DNA-binding proteins that may function in the tissue-specific expression of C2. Conservation of these four motifs in multiple early complement component genes suggests that these may represent a conserved transcriptional strategy.

Carcinoma, Hepatocellular↗
PubMed1997

Deciding about mechanical ventilation in end-stage chronic obstructive pulmonary disease: how respirologists perceive their role.

OBJECTIVE: To determine when respirologists approach patients with end-stage chronic obstructive pulmonary disease (COPD) to decide about the use of mechanical ventilation, what information they provide to patients and how they provide it. DESIGN: Self-administered national survey. PARTICIPANTS: All Canadian specialists in respiratory medicine; of 401 eligible respirologists, 279 (69.6%) returned a completed questionnaire. OUTCOME MEASURES: Timing and content of doctor-patient discussions regarding mechanical ventilation; physicians' perception of their level of involvement in the decision-making process; and patient and physician characteristics that may influence decisions. RESULTS: Discussions were reported to occur most often at advanced stages of COPD: when the patient's dyspnea was severe (reported by 235 [84.2%] of the respondents) or when the patient's forced expiratory volume in the first second was 30% or less than predicted value (reported by 210 [75.3%]). A total of 120 respondents (43.0%) stated that they discuss mechanical ventilation with 40% or less of their COPD patients before an exacerbation necessitates ventilatory support. Most (154 [55.2%]) described the decision-making process as a collaboration between patient and physician; 83 (29.7%) reported that the patient decides after he or she has considered the physician's opinion. Over half (148 [53.0%]) of the respondents indicated that they occasionally, often or always modify the information provided to patients in order to influence their decision about mechanical ventilation. CONCLUSIONS: Discussions with COPD patients concerning end-of-life decisions about mechanical ventilation are reported to occur in advanced stages of the disease or not at all, with patients' input where possible. Information presented to patients is often modified in order to influence the decision. Future studies should explore ways to involve patients further in the decision-making process and to improve the process for both patients and physicians.

Adult↗
PubMed1997

Juvenile rheumatoid arthritis-like polyarthritis in chromosome 22q11.2 deletion syndrome (DiGeorge anomalad/velocardiofacial syndrome/conotruncal anomaly face syndrome).

OBJECTIVE: To investigate the association of polyarthritis and chromosome 22q11.2 deletions. METHODS: Eighty patients with chromosome 22q11.2 deletion syndrome followed up at The Children's Hospital of Philadelphia were examined for evidence of arthropathy or arthritis. Patients with chromosome 22q11.2 deletion syndrome and polyarthritis underwent laboratory evaluations of immunologic function to determine the relationship of their immunodeficiency to the polyarthritis. RESULTS: The prevalence of polyarthritis in patients with chromosome 22q11.2 deletion syndrome was markedly increased over the prevalence of polyarticular juvenile rheumatoid arthritis (JRA) in the general population. All 3 patients with polyarthritis had evidence of impaired T cell function. Two of the patients with polyarthritis also had IgA deficiency. CONCLUSION: The chromosome 22q11.2 deletion syndrome represents a primary T cell disorder which can be associated with a JRA-like polyarthritis. All 3 patients with polyarthritis had evidence of more extensive immunoregulatory derangements than those typically seen in patients with chromosome 22q11.2 deletion, and these derangements may have predisposed to the development of polyarthritis.

Arthritis↗
PubMed1997

A promoter polymorphism of tumor necrosis factor alpha associated with systemic lupus erythematosus in African-Americans.

OBJECTIVE: The polymorphic tumor necrosis factor alpha (TNFalpha) gene encodes a cytokine involved in inflammation, angiogenesis, and apoptosis. One polymorphic variant is associated with increased production of TNFalpha. This study examined the frequency of this polymorphic variant in African-American patients with systemic lupus erythematosus (SLE) compared with controls. METHODS: We determined the gene frequency of the polymorphic variant of TNFalpha in an African-American SLE patient population and in a geographically matched African-American control population. RESULTS: The gene frequency of the TNFalpha -308A polymorphism was higher in the African-American SLE population than in the control population. This relationship was independent of major histocompatibility complex DR alleles. CONCLUSION: The TNFalpha -308A polymorphism is associated with an increased risk of SLE in African-Americans.

Adult↗
PubMed1997

Cell cycle checkpoints and DNA repair in Nijmegen breakage syndrome.

Nijmegen breakage syndrome is characterized by a variable T cell and B cell immunodeficiency, growth failure, and an increased risk of malignancy. It is inherited in an autosomal recessive manner and is biochemically related to ataxia-telangiectasia. Cells from a patient with Nijmegen breakage syndrome were unable to arrest cell cycle progression after exposure to ionizing radiation, and BrdU incorporation into newly synthesized DNA was uninhibited, demonstrating that these cells have an aberrant response to radiation exposure. Although gross chromosomal breakage was observed, dinucleotide repeat segments were stable over time, suggesting that other types of DNA stability were not affected. DNA-PK activity, which is mediated by a protein related to the ataxia-telangiectasia gene product and is intimately involved in DNA repair and VDJ recombination, was normal in cells from an NBS patient. Therefore, cells from patients with Nijmegen breakage syndrome have an abnormal response to radiation exposure similar to that seen in ataxia-telangiectasia.

Abnormalities, Multiple↗