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J A Winkelstein

Publications and source records attributed to J A Winkelstein.

At least 73 records · Page 4Linked to original sources
PubMed1988

Role of C3 in humoral immunity. Defective antibody production in C3-deficient dogs.

Previous studies have shown that animals pharmacologically depleted of C3 have impaired antibody responses. However, such C depletion is neither complete nor sustained, and the C3 cleavage products generated by C3 depletion can both enhance and inhibit the immune response. To clarify the role of C3 in humoral immunity, the antibody response of dogs with genetically determined total deficiency of C3 (C3D) was examined. Serum IgG levels of the C3D animals were within the normal range, but were significantly lower than levels seen in normal controls or C3D heterozygotes. Specific antibody production was defective: the antibody titers of C3D dogs in response to primary intravenous immunization with two different T cell-dependent Ag (sheep E and bacteriophage phi X-174) were markedly reduced when compared to either normal controls or C3D heterozygotes. After secondary immunization with T-dependent Ag, the total antibody titers were normal, but the C3D dogs made proportionately more IgM and less IgG antibody than did either control group. After i.v. immunization with a T cell-independent Ag (DNP-Ficoll), the C3D dogs had reduced levels of IgM and IgG antibody after primary and secondary immunization. Neither i.m. immunization nor the use of a 20-fold increase in Ag dose i.v. could correct the defect seen in the antibody response of C3D dogs. The results herein demonstrate that C3 plays a critical role in the generation of a normal humoral immune response.

Agammaglobulinemia↗
PubMed1988

Complement levels in dogs with familial canine dermatomyositis.

CH50, C4, C2, and C3 levels were evaluated in 7 dogs affected with dermatomyositis and in 22 control dogs. Dogs with dermatomyositis did not have clinical evidence of active disease at the time of serum collection for complement assays. No absolute complement component deficiency was identified in dermatomyositis-affected dogs in this study; however, a statistical difference in C2 was identified between control dogs of non-collie breeds and control collies, suggesting there may be a breed difference in complement levels.

Animals↗
PubMed1988

Carrier detection in the Wiskott Aldrich syndrome.

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease characterized by immunodeficiency and severe thrombocytopenia in affected males, but no demonstrable clinical abnormalities in carrier females. Through analysis of the methylation patterns of X-linked genes that display restriction fragment length polymorphisms (RFLPs), we studied the pattern of X-chromosome inactivation in various cell populations from female relatives of patients with WAS. The peripheral blood T cells, granulocytes, and B cells of eight obligate WAS carriers were found to display specific patterns of X-chromosome inactivation clearly different from these of normal controls. Thus, carriers of WAS could be accurately identified using this analysis.

B-Lymphocytes↗
PubMed1987

Carrier detection in X-linked agammaglobulinemia by analysis of X-chromosome inactivation.

We used a recently developed strategy to analyze patterns of X-chromosome inactivation in human cell populations in order to study female members of families with X-linked agammaglobulinemia--i.e., to detect the carrier state and to test the hypothesis that the disorder results from a defect intrinsic in the development of B cells. According to this strategy, recombinant-DNA probes simultaneously detect restriction-fragment-length polymorphisms and patterns of methylation of X-chromosome genes. Random X-inactivation patterns were observed in isolated peripheral-blood granulocytes, T lymphocytes, and B lymphocytes of women who were not carriers. In contrast, one of the two X chromosomes was preferentially active in the peripheral B cells, but not the T cells or granulocytes, of three carriers of the disorder. This observation strongly supports the hypothesis that X-linked agammaglobulinemia results from an intrinsic defect in B-cell development. Moreover, the analysis described here can be used for direct identification of carriers in families with this disease.

Agammaglobulinemia↗
PubMed1987

Hereditary partial deficiency of the third component of complement associated with minimal change nephrotic syndrome.

We describe a 10 year old patient admitted to the Children's Hospital of Buffalo with hypocomplementemia associated with steroid responsive minimal change nephrotic syndrome. The sibling also had a low serum C3 concentration and all family members studied had C3 slow phenotypes. Factor I levels were at the lower limit of normal in the patient and his brother. Functional assays for CH50, total hemolytic C3 and serum concentration of C2, C4-C9 and factors B and H were all within normal limits. This case confirms that a depressed serum complement level can occur in minimal change nephrotic syndrome and indicates that this depression could represent a preexisting inherited rather than an acquired deficiency. The findings are consistent with the presence of a null or hypomorphic C3 slow allele in hypocomplementemic family members. Additional studies are needed to resolve the association between the inherited partial C3 deficiency and minimal change nephrotic syndrome.

Child↗
PubMed1987

Reconstitution of T- and B-cell function after T-lymphocyte-depleted haploidentical bone marrow transplantation in severe combined immunodeficiency due to adenosine deaminase deficiency.

A 4-month-old male received a T-lymphocyte-depleted haploidentical bone marrow transplant (BMT) for correction of severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency. Although previous haploidentical bone marrow transplants have been attempted in ADA-deficient SCID, complete reconstitution of both B-lymphocyte and T-lymphocyte function has not been obtained after a single transplant. In this patient, however, rapid, complete, and persistent engraftment occurred. Potential reasons for this successful reconstitution include the use of ablation by chemotherapy (busulfan, cyclophosphamide, and cytosine arabinoside), the in vitro technique of using monoclonal antibody (CT-2) and complement to deplete the donor cells of T lymphocytes, and the relative good health of the patient prior to the transplant. Further trials using this method of haploidentical BMT may prove it to be a successful method of immunologic reconstitution in ADA-deficient SCID patients for whom an HLA-identical marrow is not available.

Adenosine Deaminase↗
PubMed1987

Establishment of central nervous system infection by canine distemper virus: breach of the blood-brain barrier and facilitation by antiviral antibody.

Morphologic, immunologic and virologic data implicating antiviral antibody in promoting entry of canine distemper virus (CDV) into brain and reticuloendothelial tissues are reviewed. Infection of central nervous system (CNS) endothelium precedes invasion of virus-positive and -negative leukocytes into Virchow-Robin spaces and central nervous system (CNS) parenchyma by 1-3 days. Platelets are implicated in initiation of endothelial infection in that: CDV-infected dogs are thrombocytopenic; platelets from CDV-infected dogs contain IgG-virus complexes on their plasma membranes; platelet microthrombi were observed adjacent to foci of endothelial infection, and; CDV-susceptible ferrets rendered thrombocytopenic by antiplatelet antibody exhibit delayed viral entry into CNS tissues. Renal glomerular-bound IgG, IgM and occasionally CDV antigen were demonstrated in CDV-infected dogs by immunocytochemical techniques. Distemper-infected dogs with inherited C3 deficiency exhibited enhanced renal glomerular disease associated chiefly with deposition of IgM in mesengial regions vs. their homozygous normal CDV-infected littermates. Direct infusion of virus-positive leukocytes, plasma and platelets into the CNS capillary bed via the right carotid artery should establish the primacy of each in the initiation of CNS vascular endothelial infection by CDV.

Animals↗
PubMed1987

Indium 111 labeled white blood cell scintigraphy for the diagnosis of upper abdominal abscesses in a child with Wiscott-Aldrich syndrome.

We report on a case of multiple hepatic abscesses in an immunodeficient patient where initial radiologic evaluation by ultrasonography and computed tomography confused early management by failing to demonstrate the abscesses and by suggesting other diagnoses. Indium 111 (In-111) white blood cell (WBC) scanning with Tc-99 liver-spleen scan subtraction accurately demonstrated subcapsular hepatic abscesses in four out of four sequential studies, and later confirmed resolution of the abscesses. We suggest that In-111 WBC scanning may be used as a highly specific method of diagnosing suspected upper abdominal abscesses in children.

Child↗
PubMed1986

Genetic analysis of an inherited deficiency of the third component of complement in Brittany spaniel dogs.

Genetically determined C3 deficiency in Brittany spaniel dogs shares a number of biochemical and clinical characteristics with the human disorder. In humans, the gene for C3 deficiency is a null gene that is allelic to the structural gene for C3 and is not linked to the major histocompatibility locus. The current study used allotype analysis of canine C3 in order to demonstrate that the gene for C3 deficiency in these dogs is also a null gene allelic to the structural gene for C3. In addition, preliminary pedigree analysis suggests that the gene for canine C3 deficiency is apparently not closely linked to the major histocompatibility complex of the dog. Thus, it appears that C3 deficiency in Brittany spaniel dogs not only shares biochemical and clinical features with C3 deficiency in humans, but also shares some genetic characteristics with the human disorder.

Alleles↗
PubMed1986

Activation of the alternative complement pathway by mumps infected cells: relationship to viral neuraminidase activity.

An inverse relationship exists between the sialic acid content of a particle and its ability to activate the alternative complement pathway. The present studies were performed to determine if the neuraminidase (NANase) activities of different mumps virus strains could influence the ability of mumps virus infected cells to activate the alternative pathway. CV-1 cells were infected with three different mumps virus strains (RW, O'Take, and Kilham) and after 24 hours, 10 percent guinea pig serum (GPS) treated with EGTA/MgCl2 or GPS lacking the 4th component of complement (C4DGPS) was added to the cell monolayers. After 30 minutes, the percentage C3 consumed was determined by a functional hemolytic assay. Cells infected with RW (high NANase) consumed significantly more C3 (23.2 per cent) than cells infected with Kilham (5.7 percent, low NANase). Cells infected with O'Take were intermediate in their ability to activate C3. The degree of C3 deposition on the surface of infected cells, detected by fluorescence microscopy, was also greater for cells infected with the RW than the Kilham strain of mumps virus. These studies suggest that the NANase activity of mumps virus can influence the ability of infected cells to activate the alternative pathway and thereby, the ability of complement to participate in host defense against mumps virus infection.

Animals↗
PubMed1986

Dirofilaria immitis: diethylcarbamazine-induced anaphylactoid reactions in infected dogs.

The immunopathogenesis of the anaphylactoid Mazzotti reactions has been studied by comparing physiologic and immunologic aspects of diethylcarbamazine-induced shock in Dirofilaria immitis infected dogs with antigen induced anaphylaxis in infected and uninfected controls. Filarial antigen, specific host IgG antibody, and C1 and C3 complement levels were quantitatively measured over time in relation to the levels of histamine and prostaglandin D2 in the blood and changes in mean blood pressure. D. immitis antigen injected into uninfected dogs having no detectable IgG antibody to D. immitis or Toxocara canis produced a rapid drop in blood pressure that paralleled a drop in C1 and C3 levels and an increase in prostaglandin D2. Antigen injected into infected dogs with IgG antibody produced a similar drop in blood pressure and complement and increase in prostaglandin D2 which differed from the uninfected group only in the slower clearance of antigen from the blood. Diethylcarbamazine alone produced no measurable changes in blood pressure or complement in uninfected hosts. Diethylcarbamazine, however, administered into skin test positive infected dogs, produced a temporally slower but quantitatively similar loss in blood pressure, drop in complement, and increase in prostaglandin D2 and histamine to that induced by antigen injection. Complement activation and immune complex formation are initiated by antigen release, and subsequent vasoactive mediator release leads to shock with prostaglandin D2 being quantitatively higher in blood than is histamine.

Airway Resistance↗
PubMed1986

Impairment of antibacterial defense mechanisms of the lung by extrapulmonary infection.

To determine whether extrapulmonary infection alters antibacterial defenses of the lung, we challenged mice with peritonitis due to Escherichia coli by aerosol inhalation with either Staphylococus aureus or Pseudomonas aeruginosa. In animals without peritonitis, 14% +/- 5% and 11% +/- 1% of the initially deposited viable S. aureus and P. aeruginosa, respectively, remained in the lungs at 4 hr. In contrast, in mice with peritonitis, at 4 hr 45% +/- 9% of the staphylococci were recoved, and the P. aeruginosa had increased to 948% +/- 354% of the initial inoculum. Proliferation of P. aeruginosa in mice with peritonitis was associated with impaired recruitment of polymorphonuclear neutrophils (PMNs) into the lungs. In contrast, a noninfectious stimulus induced more PMNs into the peritoneal cavity than did intraabdominal sepsis but only minimally impaired PMN recruitment into the lungs after aerosol challenge with P. aeruginosa. Sterile intraperitoneal stimulation did not significantly impair intrapulmonary killing of P. aeruginosa. Levels of antigenic C3 and functionally active C5 were significantly depleted in mice with peritonitis due to E. coli. We conclude that the systemic effects of sepsis, including complement depletion, contribute to the decreased pulmonary PMN recruitment and to impaired intrapulmonary bacterial killing of animals with peritonitis due to E. coli.

Animals↗
PubMed1986

The ability to sensitize host cells for destruction by autologous complement is a general property of lipoteichoic acid.

Previous studies have demonstrated that lipoteichoic acid (LTA) from Streptococcus pneumoniae binds to erythrocytes and renders them susceptible to lysis by autologous complement. The present study was performed to determine whether LTA from two other gram-positive bacterial species had the ability to render mammalian cells susceptible to lysis by autologous complement. Human erythrocytes were sensitized with LTA from S. pneumoniae, Streptococcus pyogenes, or Lactobacillus fermentum. Under incubation in normal autologous serum, lysis was observed with each of the LTA-sensitized erythrocyte preparations. When erythrocytes from a C2-deficient patient were sensitized with the LTA preparations and then incubated in autologous, C2-deficient serum, the erythrocytes sensitized with S. pyogenes or L. fermentum LTA demonstrated relatively little lysis, whereas the erythrocytes sensitized with S. pneumoniae LTA yielded near-total lysis. After reconstitution of the C2-deficient serum with purified human C2, lysis was observed with all three LTA preparations. When erythrocytes from an agammaglobulinemic patient were sensitized with either the S. pyogenes or the L. fermentum LTA, they were not lysed in the presence of autologous agammaglobulinemic serum, whereas the erythrocytes sensitized with S. pneumoniae LTA were completely lysed. Serum obtained from the agammaglobulinemic patient after reconstitution with intravenous pooled gamma globulin was able to lyse autologous erythrocytes sensitized with each of the three LTA preparations. These results demonstrate that the ability to render host cells susceptible to lysis by autologous complement is a general property of LTA. Whether activation of the autologous complement occurs by the classical or alternative pathways and whether it is antibody dependent depends on the nature of the bacterial LTA.

Agammaglobulinemia↗