Immunologic compensation in a patient with a large IgH constant region deletion.

BACKGROUND: Deficiencies of serum Ig of the IgG isotype typically predispose individuals to recurrent infections in some but not all cases. Patients with large deletions of the Ig heavy chain genes are free of recurrent and severe infections. OBJECTIVE: We sought to determine a mechanism of immunologic compensation that would possibly explain the reason for this patient's paucity of infection despite lacking several classes of serum Ig. METHODS: The patient is a 50-year-old white man. Serum Ig levels and specific antibody titers were measured by using various methods, including nephelometry, enzyme immunoassay, and radial immunodiffusion. The status of the Ig heavy chain genes was examined by means of Southern blotting of genomic DNA isolated from EBV-transformed B cells. RESULTS: The patient's serum lacked detectable IgG1, IgG2, IgG4, and IgA1 levels. Southern blot analysis demonstrated a large heavy chain constant (C) region gene deletion that included Cgamma1, Calpha1, psiCgamma, Cgamma2, and Cgamma4. Antibody responses to capsular pneumococcal and hemophilus polysaccharide antigens were essentially absent. However, IgG3 antibodies against the protein antigen tetanus toxoid were present. Relatively high antibody titers were found against pneumococcal surface proteins as well. CONCLUSION: We conclude that our patient's relative freedom from serious infection may be as a result of production of IgG3 antibodies to pneumococcal capsular proteins.

Recurrent Mycobacterium avium osteomyelitis associated with a novel dominant interferon gamma receptor mutation.

Mycobacterium avium causes infections in immunocompromised individuals. Recurrent infection with this organism has been associated with a deletion at the 818 residue of the interferon-gamma receptor (IFN-gammaR). This mutation produces a truncated receptor without an intracytoplasmic tail, resulting in diminished signaling. We describe a substitution at the 832 residue of the IFN-gammaR causing a similar truncated receptor in a 7-year-old girl with recurrent M avium osteomyelitis.

Rubinstein-Taybi syndrome with humoral and cellular defects: a case report.

The first association of Rubinstein-Taybi syndrome with immunodeficiency and the successful prevention of infection with intravenous IgG is reported in a 4 year old boy. This case suggests that immunodeficiency maybe a prominent feature of this syndrome and may predispose these patients to recurrent infections.

Agenesis of the corpus callosum associated with DiGeorge-velocardiofacial syndrome: a case report and review of the literature.

We report a patient with clinical and cytogenetic findings consistent with DiGeorge-velocardiofacial syndrome and agenesis of the corpus callosum. This patient represents the first report of a case of DiGeorge-velocardiofacial syndrome associated with such a central nervous system abnormality. This case, together with previous reports in the literature, suggests that structural brain abnormalities, and in particular abnormalities of the corpus callosum, are part of the complex syndrome associated with the chromosomal microdeletion 22q11.2. We suggest that the diagnosis of DiGeorge-velocardiofacial syndrome be entertained in patients with agenesis of the corpus callosum in the context of other common clinical features of this syndrome.

Selective antipolysaccharide antibody deficiency associated with peripheral blood CD5+ B-cell predominance.

BACKGROUND: Primary humoral deficiencies vary from complete absence of B cells and/or serum immunoglobulin to lacunar deficits involving specific antibody responses to polysaccharides. OBJECTIVES: We compared the B-cell CD5 expression in patients with selective antipolysaccharide antibody deficiencies (SPADs), common variable immunodeficiency (CVID), and IgG subclass deficiency and in normal control subjects. METHODS: Five patient populations were evaluated: (1) patients with severe SPAD (no protective serologic postvaccine response to any of 12 polysaccharide antigens tested); (2) patients with intermediate SPAD (diminished response to polysaccharide antigens and adequate response to 1 to 3 of 12 serotypes tested); (3) patients with IgG subclass deficiency; (4) patients with CVID; and (5) age-matched control subjects. Blood was collected from all patients and evaluated by using flow cytometry. Results were compared by using the Student t test. RESULTS: Patients with severe SPAD deficiencies had a marked predominance of CD5+ B cells in the peripheral blood (93% to 97% of total B cells, n = 2). The intermediate SPAD group had a mean CD5+ B-cell percentage that was significantly higher than that of the age-matched control group (87. 4%, n = 7, vs 52.5%, n = 20; P =.007). Patients with CVID and IgG subclass deficiency had mean CD5+ B-cell percentages that were similar to those of the age-matched control subjects. CONCLUSIONS: Our studies demonstrate that patients with SPAD had a markedly increased percentage of CD5+ B cells in the peripheral blood as compared with age-matched control subjects and patients with other humoral deficiencies. This observation suggests that an association may be present between CD5+ B-cell predominance and SPAD.

Recurrent immune cytopenias in two patients with DiGeorge/velocardiofacial syndrome.

We describe two patients with clinical and cytogenetic findings consistent with DiGeorge/velocardiofacial syndrome who had recurrent cytopenias at presentation. Our observations suggest that recurrent cytopenias may be part of the clinical spectrum of deletion 22q11.2. We also suggest that the diagnosis of DG/VCF syndrome be considered in patients with unexplained recurrent immune cytopenias in association with cardiac lesions, subtle craniofacial dysmorphisms, and/or learning or behavioral impairments.

Parathyroid hormone resistance and B cell lymphopenia in propionic acidemia.

The mechanisms of hypocalcemia, recurrent infections and hypogammaglobulinemia associated with metabolic decompensation of propionic acidemia due to propionyl-CoA carboxylase deficiency have not been defined. A 7-week-old infant with this disorder presented with severe hypocalcemia and B cell lymphopenia during an episode of metabolic acidosis and hyperammonemia. Hypocalcemia (1.1 mmol l-1) was associated with elevated serum intact parathyroid hormone (122 ng l-1), hyperphosphatemia, hypophosphaturia and hypercalcuria, indicating parathyroid hormone resistance. B cell lymphopenia (20 cells microliters-1) was associated with transient neutropenia, anemia and subsequent hypogamma-globulinemia (IgG < 294 mg dl-1, IgM < 8 mg dl-1, IgA < 8 mg dl-1), while T cells were normal. Parathyroid hormone resistance and B cell lymphopenia resolved following treatment with hemodialysis, diet and carnitine. These complications may be due to interference with parathyroid hormone renal tubular action and B cell maturation/proliferation by accumulated organic acids.

Otitis media following tympanostomy tube placement in children with IgG2 deficiency.

Children with IgG2 deficiency commonly develop recurrent acute otitis media. It is believed that these infections are secondary to impaired antibody response rather than eustachian tube dysfunction and are therefore less responsive to treatment with tympanostomy tubes. The authors compared the incidence of acute otitis media in IgG2-deficient patients following tympanostomy tube placement with controls in a retrospective cohort study. The charts of 20 patients (10 with IgG2 deficiency and 10 controls) were reviewed. Episodes of otitis media were recorded for 12 months. IgG2-deficient patients experienced three times as many occurrences of otitis media as did controls. This suggests that otitis media is much more common in these patients following tympanostomy tube placement. We believe that an immunodeficiency workup should be considered in patients with multiple episodes of otitis media following placement of tympanostomy tubes.

Enhancement by tumor necrosis factor-alpha of Fc alpha receptor expression and IgA-mediated superoxide generation and killing of Pseudomonas aeruginosa by polymorphonuclear leukocytes.

Polymorphonuclear leukocytes (PMNL) in bronchoalveolar lavage (BAL) fluid of cystic fibrosis patients express increased levels of receptor for the Fc portion of IgA (Fc alpha R), similar to those found on PMNL stimulated with FMLP in vitro. Since tumor necrosis factor-alpha (TNF alpha) is an activator of PMNL and is found at inflammatory sites, its effects on Fc alpha R expression and IgA-mediated PMNL functions were investigated. Exposure of PMNL to TNF alpha increased surface expression of Fc alpha R 2- to 3-fold, increased superoxide production in response to aggregated IgA 5-fold, and increased phagocytosis of IgA aggregates 3- to 4-fold. Interleukin-8 did not increase Fc alpha R expression and did not enhance IgA-mediated superoxide generation. IgA-dependent PMNL killing of Pseudomonas aeruginosa was enhanced when PMNL were pretreated with TNF alpha. Thus, interactions between phagocytic host defense mechanisms and mucosal IgA may be enhanced by TNF alpha in the inflammatory milieu of the cystic fibrosis lung.

Definition of immunoglobulin A receptors on eosinophils and their enhanced expression in allergic individuals.

Fc alpha receptors (Fc alpha R), detected by the binding of IgA and by anti-Fc alpha R antibodies, were found to be differentially expressed on eosinophils and neutrophils. Neutrophils were the major granulocyte population expressing Fc alpha R, and they expressed much higher levels of Fc alpha R than eosinophils. The expression of Fc alpha R by eosinophils could be upregulated approximately threefold by Ca2+ ionophore treatment in a dose- and time-dependent manner. This effect, which was blocked by a chelating agent, was not duplicated by other cellular stimuli. Eosinophils in allergic individuals displayed enhanced Fc alpha R expression, whereas neutrophils did not. The Fc alpha R on eosinophils had a higher molecular mass (70-100 kD) than those identified on neutrophils (55-75 kD). However, removal of N-linked carbohydrates from Fc alpha R of eosinophils and neutrophils revealed a major protein core of 32 kD for both cell types. The data indicate that expression of Fc alpha R molecules with a characteristic glycosylation pattern is upregulated on eosinophils in allergic individuals.

Pneumocystis carinii pneumonia in a term newborn infant with a transiently depressed T lymphocyte count, primarily of cells carrying the CD4 antigen.

A term infant without infection by human immunodeficiency virus had pneumocystis pneumonia at 17 days of life. Initial counts of T lymphocytes carrying the CD4 antigen were approximately 50% of the lower limits of normal; later the counts of T lymphocytes carrying the CD3 and CD8 antigens decreased as well. By 7 weeks after resolution of the pneumonia, CD3+, CD4+ and CD8+ cell counts had returned to normal. These observations suggest that a primary transient deficiency of T cell production or maturation, especially involving CD4+ cells, may occur in otherwise normal newborn infants.

Increased Fc alpha R expression and IgA-mediated function on neutrophils induced by chemoattractants.

The recent reports of receptors for IgA on blood and mucosal phagocytes suggest a more active role then previously thought for IgA in host defense. Using a mAb and flow cytometry we determined the expression of the Fc alpha R on resting and chemoattractant-stimulated blood neutrophils and compared them with mucosal neutrophils. Fc alpha R expression on blood neutrophils could be rapidly up-regulated in vitro, increasing three to fourfold within minutes of exposure to the chemoattractants FMLP (optimal at 10(-8) M) and zymosan activated serum (a source of C5a). The level of Fc alpha R expression found on neutrophils obtained from bronchoalveolar lavage of cystic fibrosis patients with chronic lung infection was almost identical to that found on blood neutrophils from the same patients maximally activated in vitro. The rise in Fc alpha R expression induced by 10(-8) M FMLP was rapid, with a plateau in 15 to 20 min, and was not inhibited by 10 mg/ml of cycloheximide or puromycin, suggesting that the mechanism of up-regulation involves translocation from intracellular storage pools. Ionomycin (2 mM) plus 1.2 mM CaCl2 also increased expression of Fc alpha R, and its effects were inhibited by EDTA. Trifluoperazine, an inhibitor of calmodulin and/or protein kinase C-dependent processes, blocked the increase in Fc alpha R expression induced by FMLP, but the effects of the chemoattractant were not blocked by EDTA, suggesting that intracellular stores of calcium are important in the physiologic regulation of Fc alpha R expression. Neutrophil superoxide production could be induced by aggregated IgA, and was increased if the neutrophils were pretreated with FMLP, correlating with the increase in Fc alpha R expression. The superoxide response to a suboptimal dose of aggregated IgG was unaffected by FMLP pretreatment, and antibodies to Fc gamma R failed to block the superoxide production induced by IgA. Thus, the increase in phagocyte surface expression of Fc alpha R induced by chemoattractants in vitro and on mucosal cells in vivo, and the concomitant increase in IgA-mediated function may greatly facilitate the defense of mucosal surfaces.

Proposed method of well-child care in a resident's clinic.

Uniformity in a teaching hospital's pediatric outpatient clinic is often inconsistent because of the varying numbers of housestaff involved in patient evaluation. We have developed a flow sheet that defines the appropriate standards of care to be delivered at the Doctors Hospital Pediatric Outpatient Clinic. This flow sheet encompasses a method of rapid assessment of growth, development, physical examination, immunization status, screening laboratory testing, and parental education. We have defined these parameters as the minimal evaluation to be completed at each preschool well-child visit.