Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

Specific anti-influenza virus antibody production in vitro by lymphocytes from a subset of patients with hypogammaglobulinemia.

Specific anti-influenza virus antibody production in vitro was studied in peripheral blood mononuclear cells from 17 patients with hypogammaglobulinemia. Cells obtained from 6 of 12 patients with common variable hypogammaglobulinemia produced anti-influenza virus antibody, predominantly of the IgM isotype, when cultured in vitro with type A influenza virus. No antibody was produced in vitro, however, by cells from either of two patients with Bruton's type X-linked hypogammaglobulinemia or by cells from any of three patients with X-linked hypogammaglobulinemia and isolated growth hormone deficiency. These studies demonstrate that peripheral blood mononuclear cells from a subset of patients with common variable hypogammaglobulinemia retain the potential to produce specific antibody in response to antigenic stimulation.

Lack of transmission of human immunodeficiency virus from infected children to their household contacts.

The possibility of transmission of the human immunodeficiency virus (HIV) from infected children to their contacts has been confronted in households, schools, day-care centers, and other child care settings. Cases reported to the Centers for Disease Control and several studies of close contacts of HIV-infected patients suggested that the risk of transmission in these settings is extremely low. However, most of these studies involved infected adults or older children. Younger children, who drool, bite, mouth toys, and are incontinent, may be more likely to transmit HIV in these settings. To assess this possibility, the authors tested 89 members of households in which 25 children with HIV infection, most of whom were preschool-aged, resided. Household members had close personal contact with the infected children. They shared many items likely to be soiled with blood and body fluids, such as toys, toothbrushes, eating utensils, toilets, and bathtubs. Hugging, kissing, sharing a bed, and bathing together were common. Household members were tested no sooner than 4 months after initial contact with the infected child, to allow adequate time for sero-conversion. All 89 participating household members were anti-HIV seronegative, and 78 who were tested were serum p24 antigen negative. It was concluded from this study and other evidence that the risk of transmission from children to their contacts is extremely low and has not been clearly documented in the household setting.

Nephropathy in the Wiskott-Aldrich syndrome.

Nephropathy was detected in five of 32 patients with the Wiskott-Aldrich syndrome who were participating in a study of transfer factor (TF) therapy. In two patients, nephropathy was present before TF and did not appear changed by TF therapy. One of these patients subsequently developed progressive renal failure requiring dialysis beginning 5 1/2 years after TF therapy. In two patients, decreased renal function appeared very soon after the administration of TF. One patient showed gradually decreasing renal function beginning after two years of TF therapy. An additional patient was identified who died with renal failure without having received TF. The results suggest that renal failure occurs in the Wiskott-Aldrich syndrome more frequently than generally recognized and that administration of TF may precipitate or accelerate the renal disease in patients with this syndrome.

Precipitins to an aflatoxin-producing strain of Aspergillus flavus in patients with malignancy.

Serum samples from 121 patients in whom malignant disease had been diagnosed, were assayed for precipitins to fungal isolates from leukemia-associated environments. Control sera were from age-, sex-, and race-matched patients with no history of malignant disease. Sera from 36 (30%) malignancy patients and seven (6%) controls yielded a precipitin band to an aflatoxin-producing Aspergillus flavus isolate from a leukemia-associated house (x2 = 222, p less than 0.05%). No significant numbers of precipitins were obtained to either of the other fungal isolates from that and another such house. Although A. fumigatus has frequently been incriminated as a source of infection in patients with malignancy, only 9% of malignancy patients had a precipitin response to it, as did 1.6% of controls. Also, the presence of the precipitins to A. flavus was not connected with past radiation or immunosuppressive therapy. However, among patients with precipitins to A. fumigatus there was a higher death rate in the year following the study. Precipitins to A. flavus may be related to heavy environmental exposure possibly leading to aflatoxin exposure which may contribute to development of malignancy though immunosuppressive effects.

Mycotoxin-producing fungi from house associated with leukemia.

Fungi were isolated from a house associated with four leukemic patients from three families because of the possibility that mycotoxin-producing strains might be present. Extracts of several of the isolated fungal species produced toxic effects in one or more species of animals. Aflatoxin-producing Aspergillus parasiticus was isolated from non-leukemia-associated houses with the exception of Trichoderma, Verticillium, and Monotospora. We believe that certain mycotoxins may be related to pathogenesis of leukemia, possibly as an expression of their immunosuppressive effects.

Suppression of phytohemagglutinin response by fungi from a "leukemia" house.

Fungal isolates from the house of a husband and wife who both developed acute myelomonocytic leukemia were assayed for effects on the in vivo response to phytohemagglutinin in guinea pigs. Skin responses to intradermal phytohemagglutinin were measured following injections of sterile fungal extracts. Isolates of Penicillium canescens, Curvularia, Fusarium sambucinum, Fusarium equiseti and Trichoderma koningii from the leukemia-associated house depressed the responses to phytohemagglutinin, but none of the fungal isolates obtained from a nearby control house depressed responses to phytohemagglutinin. Such environmental agents may contribute to development of malignancy by suppression of immune responses.

Pharmacologic management of asthma in childhood.

New drugs such as inhalable corticosteroids, disodium chromoglycate, and selective beta2 sympathomimetic agents, as well as new understanding of pathophysiologic mechanisms of older drugs, enable better pharmacologic management of the child with asthma. Emphasis is on educating patient and parents and on using doses calculated for weight of anhydrous theophylline equivalent as well as for beta agonists. Preventive environmental measures should always be used in conjunction with drug therapy.

Asthma: best treatment options.

LEARNING OBJECTIVES: To understand the principles of asthma management in patients of different ages, and to outline major avoidance measures, classes of medications available, and indications for immunotherapy (IT). DATA SOURCES: MEDLINE and major textbooks of allergy and immunology. CONCLUSIONS: There has been an understanding of asthma as a chronic inflammatory disease for many decades but recent information about mediators and cytokines has led to new therapies and better understanding of the effects of IT and other preventive measures. The best treatment for any individual patient depends upon many factors and is a decision to be made between the patient and the physician. It seems that the best response to IT occurs in those who are highly sensitive to unavoidable allergens, and who experienced a late-phase asthmatic response to the allergen initially. New data suggest that IT should be considered early, as it may prevent progression of asthma to more severe, less reversible disease. The best therapy results in the ablation of airway early- and late-phase reactivity.

A prospective study: evaluation of the antibody-dependent cell-mediated cytotoxicity assay in chronic active Epstein-Barr syndrome.

Prospective monitoring of active Chronic Epstein-Barr virally infected patients receiving gammaglobulin therapy was performed using the antibody-dependent cell-mediated cytotoxicity assay (ADCC). Efforts were made to analyze and define with respect to clinical course the autologous immunological parameters (cells and sera). Our data demonstrate that the diagnosis and clinical course of this syndrome proved inconsistent with the assays usefulness in predicting suggestive benefits of gammaglobulin therapy.

Juvenile rheumatoid arthritis.

Juvenile rheumatoid arthritis, the most common connective tissue disease occurring during childhood, is characterized by chronic arthritis and may be associated with disability and blindness. The presentation, laboratory findings and prognosis of the disease differ significantly from those of adult rheumatoid arthritis. Current classification includes systemic, pauciarticular and polyarticular types, each having different therapeutic and prognostic implications.

Sjogren's syndrome in an adolescent.

Sjogren's syndrome is a chronic autoimmune disorder characterized by keratoconjunctivitis sicca, xerostomia, and recurrent enlargement of the salivary glands. Most commonly noted in adults, it rarely affects adolescents. We describe a 15-year-old adolescent with recurrent parotid enlargement as an initial manifestation of this disease.

Metabisulfite sensitivity: case report and literature review.

Sulfiting agents have recently been identified as food and drug additives responsible for adverse reactions. These reactions are not rare and may result in life-threatening asthma and anaphylaxis. We report a 34-year-old female with intractable asthma and urticaria. Sensitivity to sulfites was suspected based on exacerbation after restaurant meals and metaproterenol 5% inhalant solution. Bronchial provocation challenge resulted in a 28% decrease in FEV1 and a 34% decrease in FEF25-75 at the 0.01 mg/ml dose. Thirty-two cases of sulfite sensitivity reported in the literature are reviewed. Foods and drugs containing sulfites are listed. The pathogenic mechanism is unknown. The FDA allows the addition of sulfites to foods and drugs without disclosure. Only recently has this potential hazard been recognized. The FDA is considering a labeling requirement on drugs that do contain sulfites.