Ralph J. Wedgwood

Defective humoral immunity in pediatric acquired immune deficiency syndrome

Specific antibody production was assessed in six young children with the acquired immune deficiency syndrome (AIDS). All patients were immunized with bacteriophage phi X 174, a T cell-dependent neoantigen. In addition, antibody responses to pneumococcal vaccine and tetanus toxoid, lymphocyte responses to mitogens, and serum immunoglobulin levels were determined. Polyclonal hypergammaglobulinemia was documented in three patients. Responses to bacteriophage phi X 174 were abnormal in all patients: primary responses were blunted, secondary responses were markedly decreased, and the class switch (IgM-IgG) was absent in five of six patients. Antibody formation to pneumococcal vaccine and tetanus toxoid was also diminished. Lymphocyte mitogenic responses to phytohemagglutinin, concanavalin A, pokeweed mitogen, and staphylococcal Cowan A were generally decreased. These findings confirm that pediatric patients with AIDS have significant abnormalities in humoral immunity. Dysfunction of both T cells and B cells plays a role in the resultant poor specific antibody production.

Immunologic responses to bacteriophage phi-X 174 in immunodeficiency diseases.

Immunologic responses to bacteriophage varphiX 174 were studied in 26 patients with immunodeficiency diseases. In eight cases of infantile X-linked agammaglobulinemia, there was prolonged circulation of phage and no detectable antibody response. The remaining 18 patients cleared phage normally and produced antibodies. 10 of these patients made only IgM antibody in spite of repeated immunization; all of these have recurrent respiratory tract infections and require treatment with gamma globulin and antibiotics. Eight patients made both IgM and IgG antibody; they experience either milder or no infections, and only one requires treatment with gamma globulin. Prolonged circulation of bacteriophage varphiX 174 and the absence of a detectable antibody response appear to be distinguishing characteristics of X-linked agammaglobulinemia if severe combined immunodeficiency can be excluded.

Severe recurrent bacterial infections associated with defective adherence and chemotaxis in two patients with neutrophils deficient in a cell-associated glycoprotein

We studied two patients with delayed umbilical cord detachment, recurrent bacterial infections, inability to form pus, rapidly progressive periodontitis, and persistent leukocytosis. The phagocytes of both patients were strikingly abnormal in their ability to adhere to surfaces. The adherence of polymorphonuclear leukocytes to endotoxin-coated glass coverslips, glass beads, or nylon wool was markedly reduced. Scanning electron microscopy of the few adherent polymorphonuclear leukocytes from both patients showed a failure to flatten and form fine pseudopods. In vivo polymorphonuclear leukocyte and monocyte chemotaxis assessed by skin window and skin chamber methods was dramatically impaired, and in vitro chemotaxis was severely depressed. Chemiluminescence of zymosan- but not phorbol-stimulated polymorphonuclear leukocytes was markedly reduced. Allogeneic polymorphonuclear leukocytes transfused into these patients functional normally, indicating that the defect is intrinsic to the cells and not a secondary phenomenon. A 180-kilodalton glycoprotein normally present in the particulate fraction of polymorphonuclear leukocytes was found to be completely absent in Patient 1 and present in low concentration in Patient 2. We postulate that the glycoprotein deficiency interferes with the migration of polymorphonuclear leukocytes from the bloodstream into the interstitial space and to the site of infection.

Successful treatment of echovirus meningoencephalitis and myositis-fasciitis with intravenous immune globulin therapy in a patient with X-linked agammaglobulinemia.

PATIENTS with X-linked agammaglobulinemia (X-LA) characteristically have recurrent bacterial infection; they generally have a normal response to viral infection, presumably because cell-mediated im...

Comparison of high-dose and low-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency diseases☆

To assess safety and efficacy of high-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency syndromes we treated a group of 19 patients with a monthly dose of 400 mg/kg of reduced and alkylated, maltose-containing immunoglobulin (Gamimune, Cutter Biological, Berkeley, California) and compared their responses with a group of 16 patients receiving 100 mg/kg per month intravenously. Side effects observed were mild to moderately severe and similar in both groups. In one adult patient receiving the high dose a severe enough reaction developed during the first infusion to exclude her from the study. Serum IgG levels of patients receiving high-dose immunoglobulin showed a stepwise increase in both trough and peak values until a new plateau was reached after four to six infusions. None of the patients receiving the low dose showed such a stepwise increase. On average, serum IgG levels rose by approximately 250 mg/dl for each 100 mg/kg immunoglobulin infused. The mean catabolic rate of the infused IgG was estimated to be 26 days in patients receiving high-dose immunoglobulin infusions. We demonstrated that 400 mg/kg immunoglobulin given intravenously every four weeks to patients with immunodeficiency results in a substantial increase in serum IgG during the postinfusion period, suggesting persistence of specific antibody throughout the interval between infusions.

Immune Response of a Patient with Deficiency of the Fourth Component of Complement and Systemic Lupus Erythematosus

The clinical details of a five-year-old boy with systemic lupus erythematosus and an inherited deficiency of the fourth component of complement (C4) have been reported elsewhere. In this study of his immune responses, immunization with bacteriophage phi X 174 demonstrated diminished antibody formation, abnormal immunologic memory and failure to switch from IgM to IgG during secondary response. We also noted persistent lymphopenia and reductions in peripheral-blood T lymphocytes, lymphocyte responses to mitogens and allogeneic cells and granulocyte chemotaxis. Kinetic studies revealed that delayed activation of the alternative pathway was corrected by purified C4 only if the classical pathway was not blocked. This finding is consistent with the concept that minute amounts of C3b provided through the classical pathway are necessary to prime the properdin system. Inability to activate the classical complement pathway, abnormal kinetics of alternative-pathway activation and depressed antibody responses to a T-cell-dependent antigen may predispose C4-deficient patients to viral infection or immune-complex formation.

Classification of Primary Immunodeficiencies

Primary specific immunodeficiency results from failure to manifest an efficient humoral or cellular immune response. Excluded from the definition are pure hypercatabolic states, such as protein-los...

Combined immunodeficiency and reticuloendotheliosis with eosinophilia.

A generalized erythematous scaly rash, alopecia, lympadenopathy, and hepatosplemonegaly developed in an infant girl during the first 6 weeks of life. Repeated bacterial and fungal infections, persistent diarrhea, and generalized wasting complicated the course of her illness, and death occurred at 5 1/2 months of age. Lymph node architecture was completely obliterated by histiocytes and eosinophils; no plasma cells or germinal centers were present. Both humoral and cellular immune systems were severely but not completely impaired. Familial reticuloendotheliosis with eosinophilia is, in some cases, associated with combined immune deficiency.

Histocompatibility antigens in childhood-onset arthritis

One hundred and twelve well-studied patients with a prior diagnosis of juvenile rheumatoid arthritis were differentiated into seven clinically distinct subgroups, including a group in whom recognizable ankylosing spondylitis had developed by time of follow-up. An apparent increased prevalence of HLA-B27 in the entire series (26%) was clearly related to its increased prevalence in only two subgroups: patients whose disease had progressed to overt ankylosing spondylitis (five of five patients) and boys with pauciarticular arthritis whose disease would be consistent with early ankylosing spondylitis (11 of 18 patients). There were no significant associations of B27 with systemic onset JRA, polyarticular JRA, pauciarticular JRA in girls, or JRA with chronic iridocyclitis. The only other significant alterations found were increased prevalences of HLA-A2 and HLA-BW15 in patients with polyarticular disease without identifiable rheumatoid factor. This study emphasizes that the clinical disorders included under the category of juvenile rheumatoid arthritis represent more than a single disease and that this heterogeneity must be considered in interpreting studies such as those of histocompatibility typing.

Ankylosing spondylitis with childhood onset.

Seven male patients with childhood-onset ankylosing spondylitis are described. Ankylosingspondylitis should be considered in the differential diagnosis of childhood arthritis, especially if the patient is a male with onset of disease in late childhood, if there are any symptoms referable to the sacroiliac joints or lumbodorsal spine, or if there is transient peripheral arthritis affecting only a few joints. Initial symptoms are characteristically fleeting and recurrent. Early diagnosis and therapy are important for preservation of adequate function. The frequency of hip disease may be greater in individuals with early onset of disease.