Douglas J. Barrett

Association of class II human histocompatibility leukocyte antigens with rheumatic fever.

The association of class I and II HLA antigens with rheumatic fever and its manifestations was examined in 72 patients, including 48 blacks and 24 Caucasians. No significant association was found between class I antigens and rheumatic fever. In contrast, HLA-DR2 and HLA-DR4 phenotypes were encountered in a significantly higher frequency in black and Caucasian patients with rheumatic fever, respectively, compared with the control populations (P less than 0.005). The most significant association (P less than 0.005) of these DR antigens with a major manifestation of rheumatic fever was found for mitral insufficiency. In addition, a significant association was encountered between persistent elevation of antibody to the group A streptococcal carbohydrate and HLA-DR4 in Caucasian patients (P less than 0.04) or HLA-DR2 in the black patients (P less than 0.001). The frequency of HLA-DR2/4 heterozygotes among patients with rheumatic fever did not differ significantly from controls. These findings support the concept of a genetically determined susceptibility to rheumatic fever and, particularly, to rheumatic heart disease. The association of the clinical manifestations of rheumatic fever and the immune hyperresponsiveness to a streptococcal antigen could be ascribed to a disease-associated immune-response gene which is in linkage disequilibrium with the DR2 and DR4 alleles of HLA-DR locus on chromosome six.

Persistence of multiple maternal genotypes of human immunodeficiency virus type I in infants infected by vertical transmission.

The extent of nucleotide variation within the HIV-1 env hypervariable domains serves as a marker of virus genotypes within infected individuals and as a means to track transmission of the virus between individuals. We analyzed env V1 and V2 sequences in longitudinal samples from two HIV-1-infected mothers, each with three children infected by maternal transmission of the virus. Sequences in samples that were obtained from two infants at 2 d and 4 wk after birth displayed more variation in V1 and V2 than maternal samples obtained at the same times. Multiple HIV-1 genotypes were identified in each mother. In each family, multiple maternal HIV-1 genotypes were transmitted to the infants. Specific amino acid residues in the hypervariable domains were conserved within sequences from each family producing a family-specific amino acid signature pattern in V1 and V2. Viruses that were highly related to maternal viruses in signature pattern persisted for as long as 4 yr in the older children. Results support a model of transmission involving multiple HIV-1 genotypes with development of genetic variation from differential outgrowth and accumulation of genetic changes within each individual.

Spectrum of Sjögren syndrome in children.

Sjögren syndrome, consisting of keratoconjunctivitis sicca and xerostomia with or without another autoimmune disease, is uncommon in children. We describe our retrospective experience with eight pediatric patients with SS. All had recurrent parotid enlargement and abnormal salivary gland biopsies, six had keratoconjunctivitis sicca, and five had other autoimmune manifestations, although only two of these had other clearly defined autoimmune disorders (mixed connective tissue disease and hypergammaglobulinemic purpura). Our patients had a higher incidence of primary SS, parotid enlargement, and hematologic abnormalities than did children previously reported with SS. Children with SS demonstrate a clinical heterogeneity comparable to that seen in adults.

IgG and IgM Pneumococcal Polysaccharide Antibody Responses in Infants

ABSTRACT. The ontogeny of human antibody responses to pneumococcal polysaccharide antigens was studied by determining whether the age at immunization affects the level and/or immunoglobulin isotype of antibody produced. Twenty-nine healthy infants between 2 and 18 months of age and 13 normal adults were studied. Responses were found to vary markedly with the age at the time of immunization and with the pneumococcal serotype tested. Three general patterns of isotype-specific antibody response were observed in the infants: a high response in IgG antibody occurred as early as 2 months of age following immunization with type 3 pneumococcal polysaccharide; little or no response was noted in either IgG or IgM antibody with types 6,18, and 19; and intermediate responses with IgM antibody increases greater than IgG increases were found for type 23. These data suggest that different factors control the immunologic response of infants to various pneumococcal polysaccharide serotypes following immunization at various ages.

Thymosin therapy in the DiGeorge syndrome

Reconstruction of the T-cell immune defect in patients with the DiGeorge syndrome has been accomplished in the past by fetal thymus transplantation. Because of the risk of fatal graft-versus-host reaction with fetal thymus transplantation in patients with abnormal T-cell immunity, we have examined the effects of a thymus tissue extract, thymosin fraction 5, on the in vitro and in vivo immune function in children with the DiGeorge syndrome. T-cell numbers were increased with thymosin F5 in vitro in three of five patients. T-cell number and function was improved in three of four patients treated with thymosin F5 in vivo. Spontaneous improvement in the immune function of these patients cannot be excluded. These results suggest, however, that further trials with thymosin F5 therapy may be indicated in patients with the DiGeorge syndrome.

Immunoregulation in aged humans

Abstract Total B-cell numbers, serum immunoglobulin levels, autoantibody formation, and suppressor/helper cell function were evaluated in a group of well-nourished healthy aged individuals (65–103 years). Total B-cell numbers in the elderly were similar to those in young controls. Mean IgG levels were significantly higher ( P P

Inhibition of human lymphocyte activation by wheat germ agglutinin: a model for saccharide-specific suppressor factors

The suppressive effect of wheat germ agglutinin (WGA) on lectin-stimulated blastogenesis and immunoglobulin production was studied. Addition of WGA at 10 micrograms/ml inhibited phytohemagglutinin (PHA)-, concanavalin-A (Con-A)-, and pokeweed mitogen (PWM)-induced mitogenic responses by 70-80%. PWM-driven immunoglobulin synthesis was suppressed by 45% with WGA. The inhibitory effects of WGA were not due to cell death or to interference with lectin binding at the cell surface. Inhibition was dependent on the presence of WGA in the cell culture during the first 24 hr of mitogen exposure and was observed in cultures of both monocyte-depleted peripheral blood mononuclear cells as well as T-cell-enriched populations. WGA-induced inhibition of blastogenesis was blocked by the addition of N-acetylglucosamine (GluNAc) which prevents WGA binding to the cell surface. WGA was found to mimic the suppressive effect of a soluble immune suppressor supernatant (SISS) derived from Con-A-activated mononuclear cell cultures. PHA responses were inhibited by 80 and 95% with SISS and WGA, respectively. The inhibition by both WGA and SISS was totally reversed with addition of GluNAc. Furthermore, WGA and SISS demonstrated competition for the same cell surface receptor site. WGA may therefore be useful as an in vitro model of a saccharide-specific, biologically relevant, soluble mediator for the investigation of mechanisms of immunologic suppression.

Human anti-pneumococcal polysaccharide antibodies are secreted by the CD5− B cell lineage☆

To determine whether human antibody responses to T cell-independent pneumococcal polysaccharide antigens are derived from CD5+ or CD5- B cells, we utilized an ELISPOT assay to detect individual anti-polysaccharide antibody-secreting cells. Human anti-type IV pneumococcal polysaccharide antibody-secreting cells were found in the CD5- B cell subpopulation. An EBV transformed anti-pneumococcal antibody-secreting B cell line was also CD5-. The ontogeny of CD5 expressing B cells correlated with the age at which polysaccharide responsiveness is acquired (generally around age 2 years in humans). The CD5- B cell subset represents only 25-30% of the B cells in young children, but this fraction increases throughout childhood to a plateau of 70-80% of the B cells in adults. These results support the hypothesis that the developmental change in responsiveness to T cell-independent polysaccharide antigens in humans is associated with maturation of the CD5- B cell subset.

Defective inducer T-cell function before the onset of insulin-dependent diabetes mellitus.

To investigate the possible role of CD4+ T lymphocyte immunoregulatory abnormalities in the pathogenesis of human insulin-dependent diabetes mellitus (IDD), we studied the in vitro function of CD4+ helper/inducer and suppressor/inducer T-cell subpopulations in 25 high risk non-diabetic individuals who tested positive for islet-cell antibodies (ICA). Helper-inducer T-cell function, as measured in the pokeweed mitogen T-B co-culture system, was decreased in the ICA+ subjects in comparison to controls. This abnormality in helper/inducer T-cell function was present for both IgG (P = 0.0001) and IgM (P = 0.004) secretion by B cells. Diminished helper/inducer function correlated with ICA titer (Pearson correlation coefficient -0.44) with subjects having an ICA titer greater than or equal to 40 JDF units demonstrating the most significant disturbances in function (P = 0.01). The helper/inducer T-cell subset percentage was also decreased in ICA+ subjects when compared to matched controls (30 +/- 3% vs 39 +/- 2%; P = 0.02). The abnormality in helper/inducer function was intrinsic to the CD4+ CD45RA+ subset and was not simply due to diminished numbers of helper/inducer T-cells added in the co-culture experiments, since the defect persisted when CD4+ CD45RA+ helper/inducer T-cells were purified and added to B cells as the only source of T-cell help. Our results indicate that ICA+ subjects have functional defects in the helper/inducer subpopulation of CD4+ T-cells. This abnormality may contribute to the pathogenesis of IDD and may provide a novel marker for identifying persons at risk for developing IDD.

Group A Streptococcal Antibodies in Subjects with or without Rheumatic Fever in Areas with High or Low Incidences of Rheumatic Fever

ABSTRACT The levels of streptococcal antibody titers in populations with or without rheumatic fever from an area with a relatively high incidence of rheumatic fever and an area with a low incidence of this disease were compared. Streptococcal antibody titers were determined for two populations, each of which included children without rheumatic fever (nonrheumatic children) and rheumatic fever patients. The two populations were derived from two separate geographic areas, one with a high incidence of rheumatic fever (Grenada) and another with a low incidence of this disease (central Florida). The results revealed an absence of consistent differences in the geometric mean antibody titers between the nonrheumatic subjects and the rheumatic fever patients from Grenada. In the population from Grenada, the mean anti-streptolysin O and anti-DNase B titers were higher in the nonrheumatic controls (P of 0.085 and 0.029, respectively). However, the mean titer of the antibody to the group A streptococcal cell wall carbohydrate was higher in the rheumatic fever patients than in the nonrheumatic controls (P = 0.047). This finding contrasted with the finding that the means of all three streptococcal antibody titers in the patients with rheumatic fever were significantly higher than those in the nonrheumatic subjects from Florida (P = 0.01-<0.001). The reason for this paradoxical finding became evident when the streptococcal antibody titers of the nonrheumatic subjects from Grenada and Florida were compared, revealing significantly higher levels of all three antibodies in the nonrheumatic subjects from Grenada than in the nonrheumatic subjects from Florida (P < 0.001). These results suggest that nonrheumatic individuals in an area with a high incidence of rheumatic fever have inordinately elevated levels of streptococcal antibodies in serum. The presence of elevated streptococcal antibody titers in such a population, which probably reflects a high background prevalence of streptococcal infections, should be taken into consideration when evaluating the role of the group A streptococcus in nonpurulent complications of infections.