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Biomedical subjects

J E Salmon

Publications and source records attributed to J E Salmon.

At least 19 recordsLinked to original sources
PubMed2001

Prevalence and relation to risk factors of carotid atherosclerosis and left ventricular hypertrophy in systemic lupus erythematosus and antiphospholipid antibody syndrome.

The prevalence of preclinical cardiovascular disease was determined in women with systemic lupus erythematosus (SLE) and control subjects matched for traditional risk factors. Compared with control subjects, patients with SLE had a higher prevalence of carotid atherosclerosis (41% vs 9%, p < 0.005) and left ventricular hypertrophy (32% vs 5%, p < 0.005), supporting the possibility that chronic inflammation predisposes to premature cardiovascular disease in SLE.

Adult↗
PubMed2001

Differential modulation of stimulatory and inhibitory Fc gamma receptors on human monocytes by Th1 and Th2 cytokines.

Immune complex-mediated inflammatory responses are initiated by Fc gamma R on phagocytes. We report in this study that an inhibitory receptor, Fc gamma RIIb2, is expressed on circulating human monocytes, and when co-cross-linked with stimulatory Fc gamma R it down-regulates effector function. Fc gamma RIIb2 expression is increased by IL-4 and decreased by IFN-gamma, in contrast to the activating receptor, Fc gamma RIIa, which is increased by IFN-gamma and decreased by IL-4. Thus, Th1 and Th2 cytokines differentially regulate the opposing Fc gamma R systems, altering the balance of activating and inhibiting Fc gamma R. The detection and cytokine modulation of Fc gamma RIIb2 in human myeloid cells provide evidence of a negative regulator of immune complex-mediated responses in human phagocytes and offer a new approach to limit Ab-triggered inflammation in autoimmune disease.

Adjuvants, Immunologic↗
PubMed2001

Low-binding alleles of Fcgamma receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in Hispanic patients.

OBJECTIVE: To examine the relationship between allelic polymorphisms of IgG receptors (FcgammaR) and the development of lupus nephritis in a prospective study, and to determine the distribution of FcgammaR haplotypes (FcgammaRIIA and FcgammaRIIIA genotypes) in lupus patients and disease-free control subjects. METHODS: We studied 67 Hispanic systemic lupus erythematosus (SLE) patients from a prospective study of outcome and 53 disease-free control subjects. Patients were followed up longitudinally for 3 years. FcgammaRIIA and FcgammaRIIIA genotypes were determined using allele-specific polymerase chain reaction. RESULTS: Nephritis was present in 28% of patients at entry into the study and in 69% at the end of 3 years. In the nephritis group (n = 46), as well as the entire SLE cohort, there was a predominance of genotypes with low-binding alleles (FcgammaRIIa-R131 and FcgammaRIIIa-F176) at both loci (SLE nephritis patients 89% versus controls 62%; P < 0.002; odds ratio 0.20 [95% confidence interval 0.05-0.6] for risk of nephritis in individuals homozygous for either FcgammaRIIa-H131 or FcgammaRIIIaV176). The frequency of individuals homozygous for high-binding alleles at either locus decreased as the burden of disease increased (P < 0.002, by Mann-Whitney test). There was no linkage disequilibrium between FcgammaRIIA and FcgammaRIIIA in Hispanics, yet in the SLE patients, there was a clear overrepresentation of the FcgammaRIIa-R131;FcgammaRIIIa-F176 haplotype (SLE patients 48% versus controls 30%) and a decrease in the frequency of the high-binding haplotype (4% versus 23%) (P < 0.002). CONCLUSION: We observed an increase in the frequency of low-binding FcgammaR alleles in an SLE population with a high prevalence of renal disease. The apparent selection for the FcgammaRIIa-R131;FcgammaRIIIa-F176 haplotype in Hispanic patients suggests that low-binding alleles of both FcgammaRIIa and FcgammaRIIIa confer risk for SLE and may act additively in the pathogenesis of disease, whereas the high-binding haplotype FcgammaRIIa-H131;FcgammaRIIIa-V176 is protective, particularly in the homozygous state.

Alleles↗
PubMed2000

Association between FcgammaRIIa-R131 allotype and bacteremic pneumococcal pneumonia.

Human FcgammaRIIa has 2 codominantly expressed allotypes, which differ greatly in their ability to ligate immunoglobulin G2 (IgG2). Whereas FcgammaRIIa-R131 binds only weakly to IgG2, FcgammaRIIa-H131 binds to it efficiently and might be primarily responsible for the phagocytosis of IgG2-opsonized bacteria. IgG2 plays a pivotal role in defense against pneumococcal infection. This prospective study showed that 50% of patients with bacteremic pneumococcal pneumonia were homozygous for FcgammaRIIa-R131, compared with 28% with nonbacteremic pneumococcal pneumonia and 29% of uninfected controls (P<.05). The gene frequency of FcgammaRIIa-R131 was 0.67 in bacteremic patients, significantly higher than in the other groups (P<.05). All bacteremic patients who died within 1 week of hospitalization were homozygous for FcgammaRIIa-R131. Therefore, the severity of pneumococcal infection may, in part, be genetically mediated. Taken together with similar findings in cases of meningococcal disease, these results suggest that such genetic factors may be generalizable to infections caused by encapsulated bacteria.

Alleles↗
PubMed1999

Reactive oxygen intermediates enhance Fc gamma receptor signaling and amplify phagocytic capacity.

Receptors for the Fc region of IgG (Fc gamma R) mediate internalization of opsonized particles by human neutrophils (PMN) and mononuclear phagocytes. Cross-linking of Fc gamma R leads to activation of protein tyrosine kinases and phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) within Fc gamma R subunits, both obligatory early signals for phagocytosis. Human PMN constitutively express two structurally distinct Fc gamma R, Fc gamma RIIa and Fc gamma RIIIb, and can be induced to express Fc gamma RI by IFN-gamma. We have previously shown that stimulation of PMN through Fc gamma RIIIb results in enhanced Fc gamma RIIa-mediated phagocytic activity that is inhibited by catalase. In the present study, we have tested the hypothesis that reactive oxygen intermediates (ROI) have the capacity to regulate Fc gamma R responses and defined a mechanism for this effect. We show that H2O2 augmented phagocytosis mediated by Fc gamma RIIa and Fc gamma RI in PMN and amplified receptor-triggered tyrosine phosphorylation of Fc gamma R-associated ITAMs and signaling elements. Generation of endogenous oxidants in PMN by cross-linking Fc gamma RIIIb similarly enhanced phosphorylation of Fc gamma RIIa and Syk, a tyrosine kinase required for phagocytic function, in a catalase-sensitive manner. Our results provide a mechanism for priming phagocytes for enhanced responses to receptor-driven effects. ROI generated in an inflammatory milieu may stimulate quiescent cells to rapidly increase the magnitude of their effector function. Indeed, human monocytes incubated in the presence of stimulated PMN showed oxidant-induced increases in Fc gamma RIIa-mediated phagocytosis. Definition of the role of oxidants as amplifiers of Fc gamma R signaling identifies a target for therapeutic intervention in immune complex-mediated tissue injury.

Adjuvants, Immunologic↗
PubMed1999

A role for the polymorphism at position 247 of the beta2-glycoprotein I gene in the generation of anti-beta2-glycoprotein I antibodies in the antiphospholipid syndrome.

OBJECTIVE: To determine the frequencies at which either a valine or leucine occurs at position 247 in the beta2-glycoprotein I (beta2GPI) gene of normal individuals of the Caucasian, African American, and Asian ethnic groups and to compare these data with those in patients with the antiphospholipid syndrome (APS), with and without anti-beta2GPI antibodies. METHODS: The DNA segment containing the position-247 polymorphism was amplified by seminested polymerase chain reaction, and the polymorphism was detected by restriction endonuclease digestion. DNA samples from 370 healthy controls of different racial backgrounds were analyzed, and the results were compared with those from 149 APS patients (66 primary; 83 secondary). Allele and genotype frequencies were compared using Fisher's exact test. When significant differences were detected, pairwise comparisons were made using Fisher's exact test with a Bonferroni adjustment. RESULTS: Allele and genotype expression was significantly different (P < 0.0001 for both) among the 3 races, with the V allele and the VV genotype occurring most often among Caucasians, less among African Americans, and least among Asians. Conversely, the V allele and the VV genotype were found more frequently among Asian APS patients than among controls (P = 0.0028 and P = 0.0023, respectively). No significant differences in allele or genotype frequencies were seen in comparisons of the Caucasian or the African American patients with appropriate controls. The differences in allele and genotype frequencies seen in the Asian APS patients were restricted to the anti-beta2GPI-positive patients (P = 0.0018 and P = 0.0005, respectively). CONCLUSION: In Asian patients with APS, expression of a V at position 247, especially in the homozygous state, is significantly associated with the presence of anti-beta2GPI antibodies and, therefore, can be viewed as a major risk factor in this ethnic group (odds ratio 9.19 and 16.33, respectively).

Alleles↗
PubMed1998

Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcgamma receptors (FcgammaR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, lambdas > 10, purported linkage at 1q41-42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log10 of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14-23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26-27, and 12p12-11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcgammaRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.

Animals↗
PubMed1998

A naturally occurring mutation in Fc gamma RIIA: a Q to K127 change confers unique IgG binding properties to the R131 allelic form of the receptor.

Fc gamma RIIa is widely expressed on hematopoietic cells. There are two known allelic polymorphic forms of Fc gamma RIIa, Fc gamma RIIa-R131 and Fc gamma RIIa-H131, which differ in the amino acid at position 131 in the second lg-like domain. In contrast to Fc gamma RIIa-R131, Fc gamma RIIa-H131 binds hlgG2 but not mIgG1, and this differential binding has clinical implications for host defense, autoimmune disease, immunohematologic disease, and response to therapeutic monoclonal antibodies. We identified a novel Fc gamma RIIA genotype in a healthy individual homozygous for Fc gamma RIIA R/R131 in whom a C to A substitution at codon 127 changes glutamine (Q) to lysine (K) in one of the two Fc gamma RIIA genes. This individual's homozygosity for Fc gamma RIIA-R/R131 leads to the prediction that the receptors on her cells would not bind hIgG2. Monocyte and neutrophil phagocytosis of hIgG2-opsonized erythrocytes was significantly higher (P < .05) for cells from this K/Q127, R/R131 individual than for Q/Q127, R/R131 donors. Platelet aggregation stimulated by an mIgG1 anti-CD9 antibody in this individual was significantly different (P < .05) from Q/Q127, H/R131 and Q/Q127, H/H131 donors and similar to Q/Q127, R/R131. Our data show that the K127/R131 receptors have a unique phenotype, binding both hIgG2 and mIgG1. Further functionally significant mutations in human Fc gamma receptors and possible novel mechanisms for inherited differences in disease susceptibility should be sought with unbiased screening methods.

Alleles↗
PubMed1998

Angiotensin I converting enzyme gene polymorphisms in systemic lupus erythematosus: decreased prevalence of DD genotype in African American patients.

The presence of the D (deletion) allele at the angiotensin converting enzyme (ACE) gene has been associated with a) adverse vascular events contributing to early mortality and b) progressive deterioration of renal function in a variety of chronic glomerular diseases. We investigated the potential role of ACE polymorphisms in patients with systemic lupus erythematosus (SLE). Two hundred and sixteen (216) SLE patients (121 Caucasians; 78 African Americans; and 17 other) and 200 normal controls were studied; 134 patients had evidence of renal disease. ACE genotypes were determined by a polymerase chain reaction based assay. The frequency of genotype DD was increased in African American normal controls compared to Caucasians (55% vs. 37%, p = 0.017) and in African American normal controls vs. African American lupus patients (55% vs. 30%, p = 0.008). Trend analysis of the genotype distribution across the three African American groups (renal, non-renal, controls) revealed a trend of increased frequency of I and decreased frequency of D as likelihood of renal disease increases (p = 0.008). No association between any ACE genotype with parameters of renal disease and/or response to therapy was identified. African American patients with lupus have a lower frequency of DD genotype as compared to African American normal controls. Further studies will be necessary to address whether this is due to decreased survival of these patients, a protective effect of DD genotype from developing the disease or a chance sample effect.

Adult↗
PubMed1997

A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease.

A novel polymorphism in the extracellular domain 2 (EC2) of FcgammaRIIIA affects ligand binding by natural killer (NK) cells and monocytes from genotyped homozygous normal donors independently of receptor expression. The nonconservative T to G substitution at nucleotide 559 predicts a change of phenylalanine (F) to valine (V) at amino acid position 176. Compared with F/F homozygotes, FcgammaRIIIa expressed on NK cells and monocytes in V/V homozygotes bound more IgG1 and IgG3 despite identical levels of receptor expression. In response to a standard aggregated human IgG stimulus, FcgammaRIIIa engagement on NK cells from V/V (high-binding) homozygotes led to a larger rise in [Ca2+]i, a greater level of NK cell activation, and a more rapid induction of activation-induced cell death (by apoptosis). Investigation of an independently phenotyped normal cohort revealed that all donors with a low binding phenotype are F/F homozygotes, while all phenotypic high binding donors have at least one V allele. Initial analysis of 200 patients with SLE indicates a strong association of the low binding phenotype with disease, especially in patients with nephritis who have an underrepresentation of the homozygous high binding phenotype. Thus, the FcgammaRIIIa polymorphism at residue 176 appears to impact directly on human biology, an effect which may extend beyond autoimmune disease characterized by immune complexes to host defense mechanisms.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1997

Flow cytometric quantitation of attachment and phagocytosis in phenotypically-defined subpopulations of cells using PKH26-labeled Fc gamma R-specific probes.

Human receptors for IgG (Fc gamma R) are characterized by diverse structure and function. We describe a flow cytometric technique to quantitate receptor-specific Fc gamma R-mediated attachment and phagocytosis in phenotypically-defined subsets of cells using erythrocytes (E) labeled with the lipophilic dye PKH26 and coupled with biotin/avidin to either human IgG (myeloma proteins) or anti-Fc gamma R mAb. Using this technique and Fc gamma RIIa as a model, (1) we demonstrate sensitive and specific quantitation of attached and internalized E coupled to receptor-specific mAb or natural ligand by monocytes within a peripheral blood leukocyte preparation; (2) we show the capacity to detect subtle allelic differences in Fc gamma R function; and (3) we demonstrate oxidant-induced enhancement of binding and internalization.

Cell Adhesion↗
PubMed1997

Anticardiolipin IgG subclasses: association of IgG2 with arterial and/or venous thrombosis.

OBJECTIVE: To determine whether the presence of anticardiolipin antibodies (aCL) of a specific IgG subclass is associated with clinical complications of the antiphospholipid antibody syndrome (APS) and whether polymorphisms of Fc receptors for IgG (FcgammaR) with differential binding preferences contribute to an increased risk of thrombotic complications. METHODS: In 60 patients with IgG aCL, we assessed clinical complications of the APS, measured the level of antibody activity, and determined the IgG subclass distribution of aCL by a modified enzyme-linked immunosorbent assay (ELISA) with murine anti-human IgG subclass monoclonal antibodies. Selective IgG subclass adsorption studies were performed to determine the relative contribution of specific IgG subclasses to overall aCL activity. Fcgamma receptor IIA (FcgammaRIIA) genotypes of aCL patients with thrombosis and of non-systemic lupus erythematosus controls were determined by polymerase chain reaction amplification of genomic DNA and allele-specific probes. RESULTS: IgG2 aCL, detected in 75% of the patients, was the major subclass of aCL. Selective adsorption studies demonstrated that IgG2, in contrast to IgG1, was the predominant subclass responsible for aCL reactivity. IgG2 aCL was the only subclass associated with clinical complications, specifically, arterial and/or venous thrombosis (P < 0.04). The presence of FcgammaRIIA-H131, a receptor expressed on platelets, monocytes, and endothelial cells and the only human FcgammaR which efficiently recognizes IgG2, was associated with thrombosis in aCL patients. Among 45 high-titer (>40 GPL [IgG phospholipid] units) aCL patients with thrombosis, 40% were homozygous for FcgammaRIIA-H131, compared with 25% of disease-free controls (P = 0.042). CONCLUSION: While all 4 IgG subclasses are found in autoimmune aCL, only the presence of IgG2 is significantly associated with thrombotic complications. Reactivity in aCL ELISA is largely due to the presence of IgG2 in high-titer patients. The presence of IgG2 aCL, particularly in association with FcgammaRIIA-H131, may be a useful clinical predictor of increased thrombotic risk in patients with autoimmune IgG aCL. Allelic variants of FcgammaRIIA with distinct capacities to interact with IgG subclasses provide a mechanism for genetic susceptibility to an autoantibody-induced prothrombotic state.

Alleles↗
PubMed1997

Antibodies to C1q in systemic lupus erythematosus: characteristics and relation to Fc gamma RIIA alleles.

Autoantibodies to the collagen-like region of the first complement component (C1qAB) are found in patients with systemic lupus erythematosus (SLE), particularly those with renal disease. In a cohort of 46 SLE patients with diffuse proliferative glomerulonephritis, we found declining C1qAB titers in 77% of treatment responders and in only 38% of treatment non-responders (P < 0.03). To further characterize this autoantibody, we tested 240 SLE patients for the presence of C1qAB. Positive titers were found in 44% of patients with renal disease and 18% of patients without renal disease (chi2 P < 0.0003). Analysis of IgG subclass revealed IgG2 C1qAB alone in 34%, IgG1 C1qAB alone in 20%, and both IgG1 and IgG2 in 46% of patients. Fewer than 10% of patients had measurable titers of IgG3 or IgG4 C1qAB. The pathogenic role of these IgG2-skewed C1qAB may relate to impaired immune complex clearance by the mononuclear phagocyte system: IgG2 antibodies are efficiently recognized by only one IgG receptor, the H131 allele of Fc gamma RIIa (Fc gamma RIIa-H131). In contrast, Fc gamma RIIa-R131, which is characterized by minimal IgG2 binding, has recently been associated with lupus nephritis. In our C1qAB positive patients, the presence of Fc gamma RIIA-R131 was associated with an increased risk for renal disease. Autoantibodies to C1q may have pathogenic significance in SLE patients with genetic defects in the ability to clear IgG2 containing immune complexes.

Adult↗
PubMed1996

Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans.

Allelic variants of Fc gamma R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human Fc gamma RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The Fc gamma RIIa-H131 is the only human Fc gamma R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc gamma RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of Fc gamma RIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc gamma RIIA alleles, with only 9% of SLE patients homozygous for Fc gamma RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P = 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of Fc gamma RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in Fc gamma RIIA-H131 as the likelihood for lupus nephritis increased (P = 0.0004) consistent with a protective effect of the Fc gamma RIIA-H131 gene. The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans.

Alleles↗
PubMed1996

Antiphospholipid antibodies activate vascular endothelial cells.

Antiphospholipid antibodies (aPL) are associated with a syndrome of arterial and venous thrombosis and recurrent fetal loss. We have shown that IgG purified from patients with aPL activate vascular endothelial cells (EC), converting the steady-state, non-thrombotic endothelial surface to a pro-thrombotic state. The aPL-activated EC are characterized by the expression of leukocyte adhesion molecules, including ICAM-1, VCAM, and E-selectin. EC activation is dependent upon the presence of beta 2-GP-I, a cofactor necessary for anticardiolipin reactivity. In addition, EC activation is not attributable to endotoxin contamination, Fc receptor interactions, or immune complexes, but rather is the result of the specific anticardiolipin reactivity of the IgG. Endothelial activation by aPL may be an important mechanism by which these antibodies cause a hypercoagulable state.

Antibodies, Antiphospholipid↗