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C L Anderson

Publications and source records attributed to C L Anderson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Isolation from human placenta of the IgG transporter, FcRn, and localization to the syncytiotrophoblast: implications for maternal-fetal antibody transport.

The IgG transporter responsible for ferrying maternal IgG across the human placenta to fetal circulation has not been identified, although the human homologue of the neonatal rat Fc receptor (FcRn), a heterodimer with pH-dependent IgG affinity, structurally similar to MHC Class I molecules, was recently proposed as a candidate. Affirming this hypothesis, we describe herein the specific copurification from human placenta of 46- and 14-kDa proteins by IgG affinity at acid pH. The larger protein, characterized by its amino acid sequence and by immunoblot, is the alpha-chain of human FcRn (hFcRn). The smaller is beta2-microglobulin. Their coisolation by ligand affinity suggests that they comprise the hFcRn heterodimer. Placenta sections stained immunohistochemically with anti-hFcRn alpha-chain peptide Abs show extensive expression of hFcRn in the syncytiotrophoblast and traces in the endothelium and other unidentified cells of the villus stroma. We find alpha-chain mRNA by Northern analysis in human placenta and in human trophoblast-like cell lines (JEG-3, ED27) but not in a human myelocytic cell line (HL60). We suggest that the placental hFcRn heterodimer may transport IgG to the fetus by a mechanism in which maternal IgG is pinocytosed nonspecifically and then carried to fetal tissues by a pH gradient from acidic endosomes to the pH-neutral basolateral surface of the syncytiotrophoblast. Furthermore, the known characteristics of FcRn suggest a wider function, that it is the receptor postulated by Brambell in the 1960s to regulate tissue and serum IgG concentrations by controlling IgG transport and catabolism.

Amino Acid Sequence↗
PubMed1996

Monocyte IL-8 release is induced by two independent Fc gamma R- mediated pathways.

Cross-linking of PBMC and monocyte Fc gamma R on immobilized IgG stimulates IL-8 release. We used immobilized anti-Fc gamma R Abs to determine which of the three surface Fc gamma R regulated this IL-8 secretion. Fc gamma RIII cross-linking stimulated PBMC to release 5 times more IL-8 than did either Fc gamma RI or Fc gamma RII clustering (p = 0.001) and stimulated 77% more IL-8 release from PBMC than that from purified monocytes (p = 0.001). In contrast, only Fc gamma RI cross-linking significantly induced monocytes to release IL-8 (p = 0.05). Since purified lymphocytes release little IL-8 in response to immobilized IgG or anti-Fc gamma RIII Abs, we hypothesized that lymphocyte Fc gamma R cross-linking augmented monocyte IL-8 release. Supernatants from IgG- or Fc gamma RIII -stimulated lymphocytes induced monocytes to release more IL-8 than lymphocytes incubated on plastic alone (p = 0.002 and p = 0.003, respectively). THP-1 cells, which do not produce IL-8 in response to Fc gamma i]R cross-linking, also released IL-8 in response to supernatants from IgG- or Fc gamma RIII-stimulated lymphocytes, suggesting that the supernatant activity was not soluble immune complexes. The IL-8-stimulating activity was heat labile, suggesting that the activity is a protein. However, we could not reproduce or block this activity using recombinant cytokines or neutralizing anti-cytokine Abs. Thus, monocyte IL-8 is stimulated directly through Fc gamma RI cross-linking and indirectly through an Fc gamma RIII-stimulated soluble lymphocyte factor.

Cross-Linking Reagents↗
PubMed1996

The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor.

More than 30 years ago, Brambell published the hypothesis bearing his name [Brambell, F. W. R., Hemmings, W. A. & Morris, 1. C. (1964) Nature (London) 203, 1352-1355] that remains as the cornerstone for thinking on IgG catabolism. To explain the long survival of IgG relative to other plasma proteins and its pattern of increased fractional catabolism with high concentrations of IgG, Brambell postulated specific IgG "protection receptors" (FcRp) that would bind IgG in pinocytic vacuoles and redirect its transport to the circulation; when the FcRp was saturated, the excess unbound IgG then would pass to unrestricted lysosomal catabolism. Brambell subsequently postulated the neonatal gut transport receptor (FcRn) and showed its similar saturable character. FcRn was recently cloned but FcRp has not been identified. Using a genetic knockout that disrupts the FcRn and intestinal IgG transport, we show that this lesion also disrupts the IgG protection receptor, supporting the identity of these two receptors. IgG catabolism was 10-fold faster and IgG levels were correspondingly lower in mutant than in wild-type mice, whereas IgA was the same between groups, demonstrating the specific effects on the IgG system. Disruption of the FcRp in the mutant mice was also shown to abrogate the classical pattern of decreased IgG survival with higher IgC concentration. Finally, studies in normal mice with monomeric antigen-antibody complexes showed differential catabolism in which antigen dissociates in the endosome and passes to the lysosome, whereas the associated antibody is returned to circulation; in mutant mice, differential catabolism was lost and the whole complex cleared at the same accelerated rate as albumin, showing the central role of the FcRp to the differential catabolism mechanism. Thus, the same receptor protein that mediates the function of the FcRn transiently in the neonate is shown to have its functionally dominant expression as the FcRp throughout life, resolving a longstanding mystery of the identity of the receptor for the protection of IgG. This result also identifies an important new member of the class of recycling surface receptors and enables the design of protein adaptations to exploit this mechanism to improve survivals of other therapeutic proteins in vivo.

Animals↗
PubMed1996

Phosphoinositide 3-kinase and p72syk noncovalently associate with the low affinity Fc gamma receptor on human platelets through an immunoreceptor tyrosine-based activation motif. Reconstitution with synthetic phosphopeptides.

Previously, we have demonstrated that the cytoplasmic tyrosine kinase p72syk is coupled to the platelet Fc receptor for IgG (Fc gamma RIIA) (Chacko, G. W., Duchemin, A. M., Coggeshall, K. M., Osborne, J. M., Brandt, J. T., and Anderson, C. L. (1994) J. Biol. Chem. 269, 32435-32440). Further analysis of the platelet activation by Fc gamma RIIA demonstrated that Fc gamma RIIA is also inducibly coupled to the serine/threonine and lipid kinase, phosphoinositide 3-kinase (PI 3-K). activation of platelets with anti-Fc gamma RIIA antibodies resulted in the noncovalent association of PI 3-K with Fc gamma RIIA as well as an increase in Fc gamma RIIA-associated PI 3-K activity. Binding of both p72syk and PI 3-K to Fc gamma RIIA was reconstituted with synthetic phosphopeptides corresponding to the sequence of the atypical immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic domain of Fc gamma RIIA. Our findings demonstrate that coupling of both p72syk and PI. 3-K activities to Fc gamma RIIA is regulated by tyrosine phosphorylation of the ITAM, and we speculate that p72syk might act as an adapter to recruit PI 3-K to activated Fc gamma RIIA.

Amino Acid Sequence↗
PubMed1996

A novel role for the Fc receptor gamma subunit: enhancement of Fc gamma R ligand affinity.

The Fc receptors (FcR), which belong to the immunoglobulin (Ig) superfamily, bind to specific Ig isotypes with varying affinities triggering complex immune defense responses. Several of the FcR that lack signaling motifs in their cytoplasmic domains rely on associated subunits to transmit signals. Two classes of FcR that bind the Fc portion of IgG, Fc gamma RI, and Fc gamma RIIIa associate with a subunit shared among several FcR, the gamma chain, which is involved in receptor expression and signal transduction. In this report, we propose that a novel role for gamma chain is to enhance the affinity of Fc gamma R for ligand. Our findings demonstrate that Fc gamma RI requires gamma -chain association to attain high affinity binding for monomeric IgG, and suggest that the intermediate binding affinity of the Fc gamma RIIIa isoform results from its association with gamma chain. The affinity increase conferred by gamma chain appears to be mediated through the transmembrane domain of the Fc gamma R, with no requirement for the cytoplasmic domain of the receptor.

3T3 Cells↗
PubMed1996

Pediatric injury hospitalization in Hispanic children and non-Hispanic white children in southern California.

OBJECTIVE: To compare the incidence and causes of injury requiring hospitalization or resulting in death or both between Hispanic children and non-Hispanic white children. DESIGN: Population-based surveillance of children younger than 15 years residing in eight Orange County cities and communities who were hospitalized or died of injuries sustained during 1991 and 1992. SETTING: Eight hospitals and the coroner's office in central Orange County, California. PARTICIPANTS: Study population was 213,906 children residing in the study area. Forty-nine percent were Hispanic, 37% were non-Hispanic white, 12% were Asian or Pacific Islander, and 3% were of other racial origin. RESULTS: A total of 1361 severe injuries were identified (crude annual rate was 318 per 100,000 population). The crude incidence rate ratio comparing Hispanics and non-Hispanic whites was 1.82. After adjustment for census block group, Hispanic children had a 60% higher injury rate and incidence rate ratios of more than 2 for pedestrian injuries, asphyxia, aspirations, foreign-body ingestions, and poisonings. CONCLUSIONS: Hispanic children had higher injury rates than non-Hispanic white children, even when controlling for census block group. These rate differences may be related to differences in exposure to various causes of injury, injury prevention practices, parenting practices, family size, and language. Injury rate differences by ethnicity that address specific injury hazards must be explored to guide prevention efforts. More culturally and linguistically appropriate interventions are needed to provide injury prevention programs to the Hispanic population.

Adolescent↗
PubMed1996

Extremely low-birth-weight children and their peers. A comparison of school-age outcomes.

OBJECTIVE: To document 7-year developmental and educational outcomes in a cohort of predominantly white, middle-class, extremely low-birth-weight (ELBW, < 1000 g) children to address the incidence of increased developmental disability and the need for special educational services. DESIGN: Observational study. PATIENTS: Fifty-four ELBW children and 58 comparison children, who were matched for race, gender, and socio-economic status (30 with low birth weights [1500-2500 g] and 28 with birth weights > 2500 g). The ELBW cohort was drawn from 104 presurfactant survivors born between 1984 and 1986 and cared for in a single hospital. SETTING: Suburban, university-based tertiary referral center. MAIN OUTCOME MEASURES: Teachers' reports of classroom placement and special education services and tests of cognitive, motor, language, and visual-motor integration abilities were studied. RESULTS: Twenty-seven (50%) of 54 ELBW children were in regular classrooms with no special services compared with 21 (70%) of 30 in the low-birth-weight group and 27 (93%) of 28 in the full-term group, indicating a significant trend toward increasing need for special services with decreasing birth weight across the 3 groups (P < .001). The ELBW group scored significantly lower than the comparison groups on all tests, although generally within the average range. Seventy-nine percent of ELBW children had average cognitive scores, but they averaged 14 to 17 points lower than the 2 comparison groups. Twenty percent of the ELBW children had significant disabilities including cerebral palsy, mental retardation, autism, and low intelligence with severe learning problems. CONCLUSIONS: Even with optimal socioeconomic environments, 20% of ELBW children are significantly disabled, and 1 of every 2 ELBW children requires special educational services. Objective testing pinpointed weakness on all measures compared with matched peer groups.

Case-Control Studies↗
PubMed1996

Perinatal nutrition enriched with omega-3 polyunsaturated fatty acids attenuates endotoxic shock in newborn rats.

Sepsis and septic shock continue to have a high mortality and morbidity in the newborn. Eicosanoids are important mediators in Gram negative septic shock. Omega-3 polyunsaturated fatty acids (omega-3) decrease production of biologically active 2-series eicosanoids. Therefore, we hypothesized that omega-3-enriched diet could decrease 2-series eicosanoids and attenuate endotoxic shock in newborn rats. Sprague-Dawley rat dams were fed with either omega-3 polyunsaturated fatty acid-enriched diet (omega-3 PURA) or omega-6 polyunsaturated fatty acid enriched diet (omega-6PUFA; controls) from the 16th day of gestation until 10 days after parturition. In 10 day old rats, shock was induced by an intraperitoneal injection of Salmonella enteritidis lipopolysaccharide. The omega-3PUFA decreased the mortality of endotoxic shock. In omega-6PUFA, lipopolysaccharide induced hyperglycemia at 2 h and hypoglycemia thereafter without an elevation in plasma insulin concentration, omega-3PUFA attenuated the hyperglycemia and hypoglycemia. omega-3PUFA attenuated the decrease of liver phosphoenolpyruvate ca-boxykinase mRNA abundance, suggesting preserved gluconeogenesis. Therefore, perinatal feeding with omega-3PUFA was beneficial in attenuating glucose dyshomeostasis in newborn rats with endotoxic shock and may be a novel approach to the prevention of endotoxic shock in the newborn.

Animal Nutritional Physiological Phenomena↗
PubMed1996

The three genes of the human FCGR1 gene family encoding Fc gamma RI flank the centromere of chromosome 1 at 1p12 and 1q21.

The high-affinity receptor for immunoglobulin G, Fc gamma RI (FCGR1), is encoded by a family of three genes within humans that share over 98% of DNA sequence homology. Efforts to define the location of the FCGR1 genes within chromosome 1 have been made to determine if they are tightly linked to the five other FCGR genes present at 1q23. Our results, obtained through both fluorescence in situ hybridization analysis of human cells and Southern analysis of cell lines containing 1p and 1q, show instead that the three genes flank the centromere of chromosome 1 at bands 1p12 and 1q21. FCGR1B was found at 1p12, whereas both FCGR1A and FCGR1C were localized to 1q21. This places the FCGR1 gene family within a large pericentric linkage group which is conserved between humans and mice. We hypothesize that the three FCGR1 genes were separated by a pericentric inversion known to have occurred on human chromosome 1, which relocated FCGR1A and FCGR1C to the long arm and left FCGR1B positioned on the short arm. We have also performed FCGR1 gene copy number experiments which indicate the existence of three FCGR1 genes within the human genome.

3T3 Cells↗
PubMed1996

The mechanism of platelet aggregation induced by HLA-related antibodies.

Immune-mediated platelet activation is emerging as an important pathogenic mechanism of thrombosis. In vitro studies have suggested two distinct pathways for immune-mediated platelet activation; one involving clustering of platelet Fc gamma RIIa, the other involving platelet-associated complement activation. HLA-related antibodies have been shown to cause platelet aggregation, but the mechanism has not been clarified. We evaluated the mechanism of platelet aggregation induced by HLA-related antibodies from nine patients. Antibody to platelet Fc gamma RIIa failed to block platelet aggregation with 8/9 samples, indicating that engagement of platelet Fc gamma RIIa is not necessary for the platelet aggregation induced by HLA-related antibodies. In contrast, platelet aggregation was blocked by antibodies to human C8 (5/7) or C9 (7/7). F(ab')2 fragments of patient IgG failed to induce platelet activation although they bound to HLA antigen on platelets. Intact patient IgG failed to aggregate washed platelets unless aged serum was added. The activating IgG could be adsorbed by incubation with lymphocytes and eluted from the lymphocytes. These results indicate that complement activation is involved in the aggregation response to HLA-related antibodies. This is the first demonstration of complement-mediated platelet aggregation by clinical samples. Five of the patients developed thrombocytopenia in relationship to blood transfusion and two patients developed acute thromboembolic disease, suggesting that these antibodies and the complement-dependent pathway of platelet aggregation may be of clinical significance.

Adult↗
PubMed1996

The role of the physical and traffic environment in child pedestrian injuries.

OBJECTIVE: To identify environmental risk factors on residential streets for pediatric pedestrian injuries. METHOD: The sample consisted of 39 Latino children 0 to 14 years of age injured as pedestrians on a street in the same block as their home and 62 randomly selected neighborhood control subjects matched to the case by city, age or year of birth, ethnicity, and gender. The cases were identified from a population-based hospital and coroner's office surveillance system established in north-central Orange County, CA. Neighborhood assessments were performed from 3:45 PM to 5 PM, a fairly active time for young pedestrians. The cases were compared with the controls using conditional logistic regressions; in this study design, the odds ratios were interpreted as estimates of the incidence rate ratios. RESULTS: Children living in a multifamily residence had an incidence of injury greater than that of children living in single-family residence on a single lot (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.3-7.6). The ORs in the highest category were several times those in the lowest category for both parked vehicles (OR 9.6, 95% CI 2.6-36) and total number of pedestrians observed (OR 4.7, 95% CI 1.4-16). Vehicle parking, total pedestrians, vehicular traffic volume, and speed were examined in a multivariate model. The association of vehicles parked on the street with pedestrian injury risk remained significant. Unlike the crude results, progressively greater vehicular speed was associated with a marked increase in risk. Progressively higher vehicular traffic volume was associated with a progressively lower adjusted OR. CONCLUSION: The results of this analysis would indicate that residential streets with a high proportion of multifamily residence, over 50% of the curb occupied with parked vehicles, and a large number of pedestrians observed in unenclosed areas should receive high priority for intervention programs to reduce pediatric pedestrian injuries. The analysis suggests that on these streets, measures to reduce the amount of street parking (thus increasing visibility) and reductions in vehicular speed should be considered to decrease pedestrian injuries.

Accidents, Traffic↗
PubMed1995

Interactions in nonnative and truncated forms of staphylococcal nuclease as indicated by mutational free energy changes.

Several mixed disulfide variants of staphylococcal nuclease have been produced by disulfide bond formation between nuclease V23C and methane, ethane, 1-propane, 1-n-butane, and 1-n-pentane thiols. Although CD spectroscopy shows that the native state is largely unperturbed, the stability toward urea-induced unfolding is highly dependent on the nature of the group at this position, with the methyl disulfide protein being the most stable. The variant produced by modification with iodoacetic acid, however, gives a CD spectrum indicative of an unfolded polypeptide. Thiol-disulfide exchange equilibrium constants between nuclease V23C and 2-hydroxyethyl disulfide have been measured as a function of urea concentration. Because thiol-disulfide exchange and unfolding are thermodynamically linked, the effects of a mutation (disulfide exchange) can be partitioned between various conformational states. In the case of unmodified V23C and the 2-hydroxyethyl protein mixed disulfide, significant effects in the nonnative states of nuclease are observed. Truncated forms of staphylococcal nuclease are thought to be partially folded and may be good models for early folding intermediates. We have characterized a truncated form of nuclease comprised of residues 1-135 with a V23C mutation after chemical modification of the cysteine residue. High-resolution size-exclusion chromatography indicates that modification brings about significant changes in the Stokes radius of the protein, and CD spectroscopy indicates considerable differences in the amount of secondary structure present. Measurement of the disulfide exchange equilibrium constant between this truncated protein and 2-hydroxyethyl disulfide indicate significant interactions between position 23 and the rest of the protein when the urea concentration is lower than 1.5 M.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical Phenomena↗
PubMed1995

Who carries passengers in the back of pickup trucks?

This study was designed to compare pickup truck drivers who carried passengers in the back with those who did not, with respect to driving behaviors, sociodemographic features, and issues related to use of the pickup truck. A computerized assisted telephone survey was conducted in Riverside County, California. One thousand ten motor vehicle drivers were interviewed with respect to demographics, restraint use, driving behaviors, and variables related to vehicle use. Thirty-six percent (364) of the households had a pickup truck driver. Pickup drivers were grouped into those who stated that they had carried occupants in the back (n = 119) and those who had not (n = 245). A higher proportion of 16- to 24-year-old and 35- to 44-year-old pickup truck drivers carried passengers in the back of pickup trucks. Those who carried occupants in the back were significantly more likely to be Hispanic, to be students, and to live in a household that included teenagers. They also had a larger mean household size. They were less likely to own the pickup and less likely to be the principal wage earners. They were more likely to report four high-risk driving behaviors. They also used the pickup truck for multiple purposes, i.e. recreation, work, school transportation, and daily transportation. In the multivariate analysis, the presence of teenagers in the household, three high-risk driving behaviors, and three indicators of pickup truck use were independently related to carrying passengers in the back of a pickup. Those who allowed passengers in the back were significantly less likely to agree with statements suggesting restriction of travel in the back. Finally, only 9% of the respondents who carried passengers in the back of a pickup reported that the pickup truck was the only vehicle available in the household.

Adolescent↗
PubMed1995

Surveillance of pediatric injury hospitalizations in Southern California.

OBJECTIVES: This study was designed to determine the incidence and causes of injury hospitalizations/fatalities to children less than 15 years of age. SETTING: Central Orange County, California. DESIGN: Cases were identified through a population based hospital and coroner's office surveillance system. SUBJECTS: The sample consisted of children 0-14 years of age who were residents of the study area and sustained an injury between 1 January 1991 and 31 December 1992 resulting in hospitalization or death. RESULTS: Over the two year study period, 1361 children 0-14 years of age were hospitalized or died as a result of injury. This represents a crude annual injury rate of 318/100,000 children. Rates were highest for children less than 5 years--this age group sustained the highest rate for eight of nine specific causes of injury. Falls were the leading cause of hospitalizations for all ages. Pedestrian injuries were more common among children 1-4 years and 5-9 years, while bicycle injuries were more common among older children. CONCLUSIONS: This study, one of the first population based studies in a Southern California urban/suburban community, found lower rates of injury hospitalization than studies conducted over a decade ago. These lower rates may reflect changes in hospitalization trends and/or injury prevention programs. Comparisons with more recent studies in inner city communities in the north east also show regional differences in rates and causes. Injury prevention efforts should particularly address the higher injury rates among children less than 5 years of age. This study also illustrates the need for regional and local data to guide injury control.

Adolescent↗
PubMed1995

On the role of platelet Fc gamma RIIa phenotype in heparin-induced thrombocytopenia.

Heparin induced thrombocytopenia (HIT) is characterized by the formation of antibodies that activate normal donor platelets in vitro in the presence of heparin. We asked whether the commonly observed donor-specific variation in the platelet aggregation response to HIT antibodies is influenced by the density of Fc gamma RII on platelets or by the Arg/His 131 allelic polymorphism of platelet Fc gamma RII. We found that platelets with His/His 131 Fc gamma RII phenotype were unresponsive to HIT antibody (0/9) whereas platelets with the Arg/Arg 131 phenotype responded well (7/9). His/His 131 platelets were largely unresponsive also to a murine IgG1 antiplatelet monoclonal antibody (UR1) known to activate platelets by Fc gamma RII clustering. We then determined the frequency distribution of Fc gamma RIIa Arg/His 131 phenotypes on a series of 200 patients evaluated for HIT and 100 non-thrombocytopenic hospitalized patients. The frequency of the His/His 131 phenotype was significantly increased (34.4%) in the 96 thrombocytopenic patients with HIT antibody compared to the 104 thrombocytopenic patients without HIT antibody and the 100 non-thrombocytopenic patients (approximately 19%). Thus, the Fc gamma RII phenotype regulates the in vitro activation response of normal platelets to HIT antibody and is a risk factor for the thrombocytopenia of HIT.

Antibodies↗
PubMed1994

Clustering of the platelet Fc gamma receptor induces noncovalent association with the tyrosine kinase p72syk.

The Fc receptor for IgG in platelets was identified as the integral membrane isoform encoded by the Fc gamma RIIA gene. Functional analysis of this molecule determined that activated Fc gamma RIIA is tyrosine phosphorylated and that activation induced the physical association with the protein tyrosine kinase p72syk. Other tyrosine-phosphorylated molecules also co-immunoadsorbed with the activated receptor. Tyrosine kinase activity co-immunoadsorbing with the platelet Fc gamma R was enhanced upon activation and specifically induced the phosphorylation, on tyrosine residues, of a physically associated 72-kDa protein. These data support a model of Fc gamma receptor-mediated platelet activation where signal is transduced through inducible association of the tyrosine kinase p72syk with the low affinity Fc gamma receptor. Thrombin, a potent platelet agonist, has been shown to up-regulate the activity of the tyrosine kinase p72syk in platelets. Consequently, our findings identify a second pathway by which p72syk is activated in platelets.

Antigens, CD↗