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1.
Clin Exp Allergy ; 38(6): 968-76, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18355370

ABSTRACT

BACKGROUND: In past research, children with older siblings were more likely than others to wheeze at age 2 years, but less likely by age 6 years. Higher infection transmission and a down-regulated allergic immune response as a result of these infections, respectively, were suggested as the causes. However, in a study of children aged 0-3 years in a low-income urban community in New York City, USA, with high asthma prevalence, we observed no birth-order effect. OBJECTIVE: To evaluate the association between birth order and atopy and respiratory symptoms in 4-year-old children attending Head Start programs in NYC. METHODS: Respiratory symptoms were assessed by questionnaire for 1005 children (mean age 4.0 years) living in high asthma prevalence neighbourhoods. Serum was collected from a subgroup of the children (n=494) and specific IgE responses to dust mite, cockroach, mouse, and cat allergens were measured. RESULTS: Prevalence of specific IgE (> or =0.35 IU/mL) did not differ significantly among first (35%), second (35%), and later-born children (28%) (P=0.23). Increasing birth order was associated with increasing prevalence of respiratory symptoms in the prior year, including wheeze (first 20%, second 27%, third or later 35%; P<0.001), being awakened at night by cough (28%, 33%, 38%; P=0.005), emergency department visits (14%, 17%, 21%; P=0.02) and hospitalizations for difficulty breathing (6.1%, 6.6%, 10%; P=0.04). The associations of birth order with respiratory symptoms were statistically significant only for the non-seroatopic children and those without an asthmatic parent. CONCLUSIONS: Non-seroatopic children with older siblings were more likely than those without older siblings to have respiratory symptoms at age 4 years. Although the stability of these associations over time remains to be determined, the differences in findings between this study and our previous NYC birth cohort study suggest that patterns of asthma development may vary even among low-income populations within the same city.


Subject(s)
Asthma/epidemiology , Birth Order , Rhinitis, Allergic, Seasonal/epidemiology , Allergens/immunology , Animals , Asthma/blood , Asthma/pathology , Cats , Child, Preschool , Cohort Studies , Family Characteristics , Female , Hospitalization/statistics & numerical data , Humans , Immunoglobulin E/blood , Logistic Models , Male , Mice , Multivariate Analysis , New York City/epidemiology , Otitis Media/epidemiology , Poverty , Prevalence , Rhinitis, Allergic, Seasonal/blood , Rhinitis, Allergic, Seasonal/pathology , Risk Factors , Sex Factors , Siblings , Surveys and Questionnaires , Urban Population
2.
J Immunol ; 163(6): 3430-40, 1999 Sep 15.
Article in English | MEDLINE | ID: mdl-10477615

ABSTRACT

A search for genes expressed in activated T cells revealed that the nonintegrin, 67-kDa laminin binding protein (p67 LBP) is expressed on the surface of a subset (10-15%) of activated peripheral blood T cells. Surface p67 LBP expression is detectable by FACS using the anti-p67 LBP mAb, MLuC5, within 6 h of T cell activation with phorbol dibutyrate and ionomycin, peaks 18-36 h postactivation, and persists for 7-10 days. The subset of T cells expressing p67 LBP is composed of mature, single-positive cells (85% CD4+8-, 15% CD4-8+) of memory cell phenotype (100% CD45 RO+/CD45 RA-). The p67 LBP+ T cells also express the integrin alpha6 chain (CD49f), which is known to associate with p67 LBP on tumor cells. In addition, the p67 LBP+ T cells express the integrin beta1, which associates with alpha6 in the laminin-specific integrin receptor very late activation Ag (VLA)-6 (alpha6beta1). Expression of an exogenous cDNA encoding the 37-kDa LBP precursor (p37 LBPP) confers p67 LBP surface expression on a p67 LBP-negative Jurkat T cell line (B2.7). Expression of p67 LBP induces B2.7 transfectants to adhere to laminin, but avid laminin binding depends on coexpression of VLA-6. Taken together, these data indicate that p67 LBP is an activation-induced surface structure on memory T cells that, together with VLA-6, mediates cellular adherence to laminin.


Subject(s)
Integrins/physiology , Laminin/metabolism , Lymphocyte Activation , Protein Precursors/biosynthesis , Receptors, Laminin/physiology , T-Lymphocyte Subsets/metabolism , Cell Adhesion/immunology , Clone Cells , DNA, Complementary/biosynthesis , Humans , Integrin alpha6beta1 , Jurkat Cells , Molecular Weight , Protein Precursors/physiology , T-Lymphocyte Subsets/physiology , Transfection
3.
Neuroimmunomodulation ; 4(1): 12-8, 1997.
Article in English | MEDLINE | ID: mdl-9326740

ABSTRACT

The cytokine interleukin-1 (IL-1) can act within the brain to induce peripheral endocrine and immune effects. In the rodent intracerebroventricular (i.c.v.) injection of IL-1 activates the hypothalamic-pituitary-adrenal axis and suppresses peripheral immune function by a CRH-dependent mechanism. It is unknown if IL-1 can similarly act within the brain to cause peripheral immunosuppression in the primate and to what extent this could be attributed to the IL-1-induced increase in ACTH and cortisol levels. In this study we have characterized the pituitary-adrenal and peripheral lymphocyte responses to IL-1 alpha (4.2 micrograms) infused over 30 min into the lateral ventricle of ovariectomized monkeys (n = 5) as compared with responses to an intravenous (i.v.) ACTH infusion (1 microgram/h for 7 h; n = 4). Four serial blood samples were obtained for ACTH and cortisol determination and for lymphocyte isolation during a 1-hour baseline and for 7 h after IL-1 or ACTH. Lymphocyte proliferation was measured by 3H-thymidine uptake in response to stimulation with phytohemagglutinin. In all 5 animals, IL-1 alpha caused rapid and profound suppression of lymphocyte mitogen responsiveness for 7 h. Baseline lymphocyte proliferation was 51,800 +/- 9,780 cpm and suppressed to a nadir of 4.5% with a mean of 23% baseline over 7 h (p < 0.001). Mean ACTH and cortisol levels increased from 33 +/- (SEM) 4.6 pg/ml and 43 +/- 4.0 micrograms/dl, respectively, during the control period to 90 +/- 14 pg/ml and 56 +/- 2.6 micrograms/dl, respectively, after IL-1 (p < 0.01). Before i.v. ACTH, baseline lymphocyte proliferation was 49,400 +/- 2,820 cpm, and suppressed to a mean of 64% of baseline during ACTH infusion (p < 0.05). Mean ACTH and cortisol levels increased from 48 +/- 5.0 pg/ml and 43 +/- 2.0 micrograms/dl, respectively, to 170 +/- 34 pg/ml and 66 +/- 2.3 micrograms/dl, respectively, during the ACTH infusion (p < 0.01). Lymphocyte suppression after i.c.v. IL-1 was much more profound than after i.v. ACTH (p < 0.01); the area under the IL-1 response curve was 37% of the area under the ACTH response curve. These studies demonstrate for the first time in the primate that centrally injected IL-1 has a profound suppressive effect on lymphocyte function. They also show for the first time in any species that there appears to be a significant immunosuppressive message produced by i.c.v. IL-1 that is not accounted for by the associated increases in ACTH and cortisol.


Subject(s)
Interleukin-1/pharmacology , Lymphocytes/drug effects , Adrenocorticotropic Hormone/drug effects , Animals , Female , Injections, Intraventricular , Macaca mulatta , Radioligand Assay
4.
J Exp Med ; 173(6): 1483-91, 1991 Jun 01.
Article in English | MEDLINE | ID: mdl-1827828

ABSTRACT

A family of chimeric immunoglobulins (Igs) bearing the murine variable region directed against the hapten dansyl linked to human IgG1, -2, -3, and -4 has been characterized with respect to binding to the human high affinity Fc gamma receptor, Fc gamma RI. Chimeric IgG1 and -3 have the highest affinity association (Ka = 10(9) M-1), IgG4 is 10-fold reduced from this level, and IgG2 displays no detectable binding. A series of genetic manipulations was undertaken in which domains from the strongly binding subclass IgG3 were exchanged with domains from the nonbinding subclass IgG2. The subclass of the CH2 domain was found to be critical for determining IgG receptor affinity. In addition, the hinge region was found to modulate the affinity of the IgG for Fc gamma RI, possibly by determining accessibility of Fc gamma RI to the binding site on Fc. A series of amino acid substitutions were engineered into the CH2 domain of IgG3 and IgG4 at sites considered potentially important to Fc receptor binding based on homology comparisons of binding and nonbinding IgG subclasses. Characterization of these mutants has revealed the importance for Fc gamma RI association of two regions of the genetic CH2 domain separated in primary structure by nearly 100 residues. The first of these is the hinge-link or lower hinge regions, in which two residues, Leu (234) and Leu(235) in IgG1 and -3, are critical to high affinity binding. Substitution at either of these sites reduces the IgG association constant by 10-100-fold. The second region that appears to contribute to receptor binding is in a hinge-proximal bend between two beta strands within the CH2 domain, specifically, Pro(331) in IgG1 and -3. As a result of beta sheet formation within this domain, this residue lies within 11 A of the hinge-link region. Substitution at this site reduces the Fc receptor association constant by 10-fold.


Subject(s)
Antigens, Differentiation/metabolism , Immunoglobulin G/metabolism , Receptors, Fc/metabolism , Amino Acid Sequence , Animals , Binding Sites , Computer Graphics , DNA Mutational Analysis , Humans , Immunoglobulin G/chemistry , Immunoglobulin Isotypes/metabolism , Interferon-gamma/pharmacology , Mice , Models, Molecular , Molecular Sequence Data , Protein Conformation , Receptors, IgG , Recombinant Fusion Proteins/metabolism , Structure-Activity Relationship
5.
J Exp Med ; 173(4): 1025-8, 1991 Apr 01.
Article in English | MEDLINE | ID: mdl-2007852

ABSTRACT

Using domain switch chimeric antibodies, we confirm the important role of CH2 in complement activation. In addition, we demonstrate that the structures responsible for the differential ability of human IgG1 and IgG4 to activate complement are located at the COOH-terminal part (from residue 292 to 340) of the CH2 domain. The amino acids in CH2 that might be involved in complement interaction are discussed. While CH3 contributes to efficient complement activation, CH3 from IgG2 and CH3 IgG3 are equally effective.


Subject(s)
Complement Activation , Immunoglobulin G/immunology , Humans , Immunoglobulin G/genetics , In Vitro Techniques , Models, Molecular , Recombinant Fusion Proteins , Structure-Activity Relationship
6.
J Immunol ; 146(2): 603-10, 1991 Jan 15.
Article in English | MEDLINE | ID: mdl-1702808

ABSTRACT

To localize regions on IgG bound by rheumatoid factors (RF), we studied IgM RF binding to chimeric IgG antibodies consisting of murine V regions fused to human constant regions. Using a modified RF ELISA, we showed that polyclonal RF from rheumatoid arthritis patients bound IgG1, 2, and 4 strongly; IgG3 was also bound, although less well. The majority of 18 monoclonal RF from patients with Waldenstrom's macroglobulinemia bound IgG1, 2, and 4 only. In contrast to RF from RA, 14 of 18 monoclonal RF did not react with IgG3. Only 3 of 18 monoclonal RF bound IgG3 well. By shuffling C region domains between IgG3 and IgG4, we showed that sequence variation in the CH3 domain is responsible for the differential binding of monoclonal RF to IgG3 and IgG4. Hybrid IgG3/IgG4 antibodies containing the CH3 domain of IgG4 were bound by monoclonal RF, whereas those containing the CH3 domain of IgG3 were not. To evaluate the contribution of the N-linked carbohydrate moiety at Asn-297 to RF binding sites on IgG, we measured RF binding to aglycosylated IgG antibodies produced by mutating Asn-297 to another amino acid. Glycosylated and aglycosylated IgG1, 2, and 4 were bound identically by monoclonal and polyclonal RF. Aglycosylated IgG3, however, was bound better than glycosylated IgG3 by polyclonal RF and by IgG3-reactive monoclonal RF.


Subject(s)
Immunoglobulin G/metabolism , Immunoglobulin M/metabolism , Rheumatoid Factor/metabolism , Animals , Antibodies, Monoclonal/metabolism , Antibody Specificity , Arthritis, Rheumatoid/immunology , Dansyl Compounds/metabolism , Enzyme-Linked Immunosorbent Assay , Epitopes/chemistry , Glycosylation , Haptens/metabolism , Humans , Immunoglobulin Heavy Chains/metabolism , Immunoglobulin Isotypes/metabolism , Mice , Mutagenesis, Site-Directed , Recombinant Fusion Proteins/metabolism , Waldenstrom Macroglobulinemia/immunology
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