Interferon-gamma upregulates CCR5 expression in cord and adult blood mononuclear phagocytes.

The C-C chemokine receptors CCR5 and CCR3 are fusion coreceptors for human immunodeficiency virus (HIV) entry into macrophages. The regulation of their expression influences infectivity by HIV. We report here that interferon-gamma (IFN-gamma) a cytokine that has bidirectional effects on HIV infection of macrophages, significantly upregulated CCR5 and CCR3 cell surface expression in human mononuclear phagocytes isolated from placental cord blood and adult peripheral blood. Monocytes treated with IFN-gamma showed increased chemotaxis to the CCR5 ligands macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta, confirming the functional relevance of IFN-gamma-induced CCR5 expression. However, IFN-gamma suppressed HIV entry into macrophages. Interestingly, we demonstrated that IFN-gamma inhibited cell surface expression of CD4, the major receptor for HIV. This finding may explain the suppressive effect of IFN-gamma on HIV entry into macrophages, despite its enhancing effect on the expression of CCR5 and CCR3 by these cells. In addition, IFN-gamma-induced secretion of C-C chemokines (RANTES, MIP-1alpha, and MIP-1beta) by mononuclear phagocytes may also suppress HIV entry into macrophages. These data provide further evidence for cytokine-mediated regulation of CCR5 expression and are consistent with a novel paradigm in which cytokines regulate HIV infection and leukocyte migration by reciprocal and opposing effects on the expression of CD4 and chemokine receptors.

Outpatient management with oral corticosteroid therapy for obstructive conditions in chronic granulomatous disease.

We report the outpatient management of three patients with X-linked chronic granulomatous disease, two of whom had episodes of gastric outlet obstruction and another, urinary bladder obstruction. These obstructive conditions were successfully treated with 2-week courses of orally administered corticosteroids with or without the addition of orally administered clindamycin. There were no infectious or other adverse reactions.

Isolation and characterization of human fetal brain-derived microglia in in vitro culture.

Human brain microglia may play a central role in immunopathogenesis of CNS diseases including HIV infection, multiple sclerosis and Alzheimer's disease. In order to investigate the possible relationship between microglia and the mononuclear phagocyte system, human brain microglia were isolated from 14-18-week-old fetal brains, and maintained in in vitro culture. Enriched fetal brain microglia were stained for different monocyte/macrophage and glial cell markers. Fresh dissociated brain cells lacked macrophage surface markers. Isolated microglial cells stained positive for complement receptor C3bi, Class II [human leukocyte antigen-DR (HLA-DR)] antigen and with the lectin Ricinus communis. Microglia also share several functional properties with monocyte/macrophages, which include generation of superoxide anion and histochemically demonstrable intracellular acid phosphatase and non-specific esterase. Primary human dissociated brain cultures were maintained in culture for at least 28 weeks. Although microglia were not observed above the astrocyte cell layer after 5 weeks in culture, microglia-like cells appear below the astrocyte layer after 12 weeks in culture. These cells stained positive for non-specific esterase and displayed oxidative burst activity upon activation with phorbol myristate acetate. Thus, we have successfully isolated an enriched population of microglia from human fetal brain and have demonstrated that these cells possess markers and properties which are characteristics of mononuclear phagocytes.

Childhood common variable immunodeficiency with autoimmune disease.

Clinical and laboratory findings in eight patients with childhood common variable immunodeficiency and autoimmune disease are described. Six of the eight patients had initial signs of the disease, persistent secretory diarrhea, recurrent upper respiratory tract infections, or both, in the first year of life. Autoimmune manifestations included idiopathic thrombocytopenia (4/8), hemolytic anemia (3/8), secretory diarrhea (4/8), arthritis (2/8), chronic active hepatitis (2/8), parotitis (2/8), and Guillain-Barré syndrome (2/8). In addition to the expected sinusitis, otitis, and pneumonia caused by encapsulated bacteria, these patients also had severe infections with viruses of the herpes group. Most of these patients had lymphadenopathy, splenomegaly, growth failure, and failure to develop secondary sexual characteristics. Laboratory studies demonstrated a significant increase in the ratio of T cells expressing the T helper phenotype (OKT4) to T cells expressing the T suppressor-cytotoxic phenotype (OKT8) (T4/T8). This increase could be attributed to a decrease in the absolute number of T8 cells. Additional findings included fluctuating levels of serum immunoglobulins and markedly diminished in vitro antibody production by B cells. The clinical course was relapsing and remitting, and dominated by the autoimmune manifestations of the disease. This group of patients constitutes a distinct subset of children with hypogammaglobulinemia, a subset with a complex, multisystemic disorder associated with significant morbidity and mortality.

Tracheal lavage and plasma fibronectin: relationship to respiratory distress syndrome and development of bronchopulmonary dysplasia.

Plasma for fibronectin determinations was obtained from 39 neonates with uncomplicated respiratory distress syndrome (RDS) and from 15 infants with RDS who developed bronchopulmonary dysplasia (BPD). Tracheal lavage fibronectin and albumin concentrations were measured in 15 infants with RDS and 15 with BPD. Control plasma fibronectin values were obtained from 20 healthy preterm infants on days 1, 2, 3, 14, and 30 of life. Control tracheal lavage fibronectin and albumin concentrations were measured in 17 neonates of various gestational ages who required tracheal intubation for nonpulmonary indications. Mean plasma fibronectin concentrations from patients with RDS was 121 +/- 11 micrograms/ml on days 1, 2, and 3, versus control level of 163 +/- 12 micrograms/ml (P less than 0.01). Mean tracheal lavage fibronectin/albumin ratio was 3.8 +/- 0.6 ng per microgram of albumin on days 1 to 5 for infants with RDS, versus control level of 5.6 +/- 3.6 (P = NS). Tracheal lavage fibronectin/albumin ratio from patients with BPD was elevated at 16.3 +/- 5.0 ng fibronectin per microgram of albumin on days 14 to 21, and 23.6 +/- 7.4 on day 30 (P less than 0.05 versus control and and versus RDS days 1 to 10). Low plasma fibronectin concentrations early in RDS may contribute to the development of pulmonary capillary leak. High tracheal lavage fibronectin levels may foster the development of pulmonary fibrosis in patients with BPD.

Bone marrow transplantation in chronic granulomatous disease.

A 5-month-old Amish infant boy with chronic granulomatous disease underwent bone marrow transplantation from his 5-year-old, histocompatible brother after a preconditioning regimen of busulfan 2 mg/kg/day for 4 days, followed by cyclophosphamide 50 mg/kg/day for 4 days. At the time of bone marrow transplantation, he was free of infection, and remained so throughout the course of the transplant. He was engrafted promptly, with complete reversal of the neutrophil function defect and no sign of graft-versus-host disease. This was followed by loss of the erythroid graft and deterioration in neutrophil function over a period of 9 months. Sixteen months after transplantation, he is free of infection and growing normally, with essentially no evidence for neutrophil engraftment.

A non-x-linked syndrome with susceptibility to severe Epstein-Barr virus infections.

Three siblings developed severe (two) or fatal (one) infectious mononucleosis. This family differed from previously described kindreds with a susceptibility to overwhelming Epstein-Barr virus infections in that: (1) both males and females were affected; (2) they had a history of the recurrent bacterial infections; (3) they produced the full spectrum of antibodies to EBV in the expected range of titers; and (4) survivors recovered completely. Two of these youths, but not their parents or an unaffected sibling with mild IM, had a deficiency of natural killer activity that did not respond to preincubation of their peripheral blood mononuclear cells with interferon. NK activity may have an important role in controlling infections with EBV.

Antigens of the Kell blood group system on neutrophils and monocytes: their relation to chronic granulomatous disease.

KX, an antigen related to the Kell blood group system, is present in trace amounts on normal red cells and is strongly active on the neutrophils of all of 50 persons thus far tested. Normal circulating monocytes are now shown to also bear KX determinants. Absence of neutrophil KX has been associated with all of three previously tested patients with chronic granulomatous disease. In this study two male siblings with CGD also have been shown to have KX negative leukocytes, and white blood cells from their heterozygous mother were found to have a reduced competency to absorb anti-KX. Five CGD boys are known to lack KX; the probability of this occurring by chance is greater 10(-6).