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.).

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.

Detection of Epstein-Barr virus and cytomegalovirus in patients with chronic fatigue.

Patients with chronic fatigue as a major complaint frequently present with recurrent sore throat, and on physical examination they have hyperemia and lymphoid hyperplasia of the pharyngeal area. Pharyngeal scrapings were obtained from 41 such patients and analyzed for Epstein-Barr virus or cytomegalovirus DNA by colorimetric in situ hybridization. Results were compared with healthy control subjects matched for age and sex. Epstein-Barr virus-DNA was detected more frequently in male patients, 5/9 (55.6%), than controls, 0/6 (0%), but there was no difference in frequency in female patients, 4/32 (12.5%), than control subjects, 1/29 (3.4%). Cytomegalovirus-DNA was detected infrequently in patients and controls, 13% versus 22% respectively. The presence of EBV-DNA did not correlate with antibody titers nor with the complaint of sore throat. Four of the five males who had positive EBV-DNA in the pharyngeal smears have now recovered.

Cerebral lateralization and histamine skin test asymmetries in humans.

Although asymmetries exist in both cerebral and somatic systems, their relationship is not well understood. One hypothesis suggests that some processes determining cerebral hemispheric dominance also affect immune systems. We employed histamine, a final common mediator for the immediate hypersensitivity immune response, to examine the relationship of skin response to cerebral lateralization (ie, left versus right brain dominance). Histamine skin wheal responses on the left and right forearms were measured using computerized planimetry in 176 consecutive patients undergoing allergy skin testing. Cerebral lateralization was determined by personal and family handedness via questionnaires. Subjects were classified as right handed (RH) with only RH relatives, RH with non-RH relatives, or non-RH (ie, left-handed or ambidextrous). Left/right arm asymmetries in wheal area were demonstrated and were related to cerebral dominance, but could not be explained by simple arm use. Right-handed subjects with only RH relatives had greater wheal size on the right arm, RH subjects with non-RH relatives had no significant left/right difference in wheal size, and non-RH subjects had greater wheal size on the left arm. Further, gender differences in these asymmetries appeared to be present for subjects with mixed cerebral dominance. The results suggest an association between process affecting cerebral and somatic asymmetries, and offer new insight into brain/body interactions.

Evaluation of immunocompetency in juvenile laryngeal papillomatosis.

The morbidity from juvenile laryngeal papillomatosis (JLP), a disease process characterized by recurrent growth of multiple epithelial papillomas, has greatly improved with the advent of immunomodulating agents used in combination with the surgical approach of CO2 laser vaporization. In prospectively evaluating the immunologic status of four pediatric patients with this disorder, one patient repeatedly demonstrated IgG2 subclass deficiency. One of two children found to have subnormal functional natural killer (NK) activity received thrice weekly intramuscular administration of 3,000,000 units/m2 body surface area of human leukocyte (alpha) interferon (IFN). Natural killer function normalized, but therapy was discontinued after 4 months; however, no clinical benefits from IFN administration were observed. Further in vitro evaluation of NK function and lymphokine production is needed, in order eventually to offer more effective immunomodulating agents to such patients. A brief review of the literature concerning JLP is also presented.

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.

Use of transfer factor in a pediatric AIDS patient with disseminated Mycobacterium avium intracellulare.

An 8-year-old male with AIDS and disseminated Mycobacterium avium intracellulare infection was treated with transfer factor (TF) prepared from maternal lymphocytes. Subsequent lymphocyte stimulation studies and repeat cultures failed to demonstrate improvement during treatment. His overall clinical status remained unchanged. No adverse effects of TF were noted.

Effect of interleukin-2 and mitogen on in vitro immunoglobulin production by peripheral blood lymphocytes from patients with selective IgM deficiency.

Immunoglobulin production by mitogen and recombinant interleukin-2-(rIL-2)-stimulated lymphocytes from IgM-deficient patients was studied. The findings were that subnormal serum IgM levels did not necessarily predict defective in vitro IgG or IgM production, lymphocytes from some IgM-deficient patients exhibited defective T cell function, and rIL-2 did not enhance defective in vitro immunoglobulin production.