Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility.

Autosomal dominant gain of function mutations in the gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. Here we describe three patients in two families who were diagnosed with HIGM at a young age and were recently found to carry heterozygous mutations in PIK3CD. These patients had an abnormal circulating B cell distribution featuring a preponderance of early transitional (T1) B cells and plasmablasts. When stimulated in vitro, PIK3CD mutated B cells were able to secrete class-switched immunoglobulins. This finding implies that the patients' elevated serum IgM levels were unlikely a product of an intrinsic B cell functional inability to class switch. All three patients developed malignant lymphoproliferative syndromes that were not associated with EBV. Thus, we identified a novel subset of patients with PIK3CD mutations associated with HIGM, despite indications of preserved in vitro B cell class switch recombination, as well as susceptibility to non-EBV-associated malignancies.

Serum factor from patients with chronic renal failure enhances polymorphonuclear leukocyte oxidative metabolism.

Sera from patients with chronic renal failure (CRF) contain a factor(s) which enhances the oxidative metabolism of polymorphonuclear leukocytes (PMN) as assessed by chemiluminescence (CL), superoxide anion generation, and hexose monophosphate shunt activity. PMN oxidative metabolic activity was higher in CRF sera than in sera from hospitalized patients with normal renal function or in sera from normal healthy subjects. The enhancement occurred regardless of whether PMN were unstimulated or were stimulated by a nonspecific soluble membrane stimulant (phorbol myristate acetate), or by opsonized Candida albicans. The enhanced CL was significantly reduced in their sera after normal renal function was restored with successful renal transplantation. This CL-enhancing factor was also detected in dialysate fluids from CRF patients and in urine from normal healthy subjects. When serum, urine, dialysate fluids of these CRF patients were fractionated by Sephadex G-25 column chromatography, the specific fraction responsible for enhanced CL was found in the molecular weight range less than 1,000 daltons, and is an ethanol extractable substance with natural fluorescence. Our findings suggest that the enhanced PMN stimulatory activity in CRF serum is specifically associated with renal dysfunction and can be useful, along with other conventional parameters, for monitoring the progression of CRF.

Progressive varicella in three patients with Wiskott-Aldrich syndrome: treatment with adenine arabinoside.

Patients with Wiskott-Aldrich Syndrome have an increased incidence of serious infections, often with microorganisms that usually produce mild disease in immunologically normal subjects. Three patients with Wiskott-Aldrich syndrome complicated by progressive varicella are reported. There have been no previous reports of similar cases. Two of the patients were treated with adenine arabinoside and had rapid recovery.

Long-term survival after bone marrow transplantation: a 15-year follow-up report of a patient with Wiskott-Aldrich syndrome.

In 1968 a 2-year-old boy with Wiskott-Aldrich syndrome was extremely ill with eczema, a series of life-threatening infections, and repeated hemorrhages into his skin, lungs, brain, and other internal organs. He was given high-dose cyclophosphamide therapy for immunosuppression, followed by bone marrow cells from his histocompatible, healthy sister. In the 15 years since bone marrow transplantation, he has had full T cell, partial B cell, and no hematopoietic engraftment. He has weathered the usual infectious diseases of childhood, has had no serious infections, and despite persistent thrombocytopenia has not had serious bleeding episodes.

Adenosine deaminase deficiency with normal immune function. An acidic enzyme mutation.

In most instances, marked deficiency of the purine catabolic enzyme adenosine deaminase results in lymphopenia and severe combined immunodeficiency disease. Over a 2-yr period, we studied a white male child with markedly deficient erythrocyte and lymphocyte adenosine deaminase activity and normal immune function. We have documented that (a) adenosine deaminase activity and immunoreactive protein are undetectable in erythrocytes, 0.9% of normal in lymphocytes, 4% in cultured lymphoblasts, and 14% in skin fibroblasts; (b) plasma adenosine and deoxyadenosine levels are undetectable and deoxy ATP levels are only slightly elevated in lymphocytes and in erythrocytes; (c) no defect in deoxyadenosine metabolism is present in the proband's cultured lymphoblasts; (d) lymphoblast adenosine deaminase has normal enzyme kinetics, absolute specific activity, S20,w, pH optimum, and heat stability; and (e) the proband's adenosine deaminase exhibits a normal apparent subunit molecular weight but an abnormal isoelectric pH. In contrast to the three other adenosine deaminase-deficient healthy subjects who have been described, the proband is unique in demonstrating an acidic, heat-stable protein mutation of the enzyme that is associated with less than 1% lymphocyte adenosine deaminase activity. Residual adenosine deaminase activity in tissues other than lymphocytes may suffice to metabolize the otherwise lymphotoxic enzyme substrate(s) and account for the preservation of normal immune function.

Normal fibronectin levels as a function of age in the pediatric population.

Fibronectin is an important non-immune opsonic protein influencing phagocytic clearance of blood-borne nonbacterial particulates which may arise in association with septic shock, tissue injury, and intravascular coagulation. In the present study, serum fibronectin was measured by both electroimmunoassay as well as rapid immunoturbidimetric assay in healthy children (n = 114) ranging in age from 1 month to 15 years in order to delineate the temporal alterations in fibronectin with age. Normal adult serum fibronectin concentrations are typically 220 micrograms/ml +/- 20 micrograms/ml. Serum concentration is 35-40% lower than normal plasma concentration due to the binding of fibronectin to fibrin during clot formation. Children between 1-12 months of age had significantly (P less than 0.05) lower serum fibronectin levels than children between the ages of 1-15 years. Progressive elevation in fibronectin levels was observed within the last 8 months of the first year of age. Fibronectin levels in children older than 1 year of age remained constant up to 15 years and were within the lower limit of the normal adult concentration. No significant (P greater than 0.05) difference in serum fibronectin was observed between male and female children at all age groups. Fibronectin levels thus, increase during the first year of age and normal levels of this blood protein in the infant are less than the normal range for adults.

Enhancement of granulocyte oxidative metabolism in sera from patients with C2 deficiency and systemic lupus erythematosus.

Serum or plasma from 3 patients with C2 deficiency (C2D) and systemic lupus erythematosus (SLE) significantly enhanced chemiluminescence and superoxide anion production by polymorphonuclear leukocytes (PMN) after stimulation with phorbol myristate acetate or latex beads. PMN from patients and normal individuals were supranormally activated when resuspended in plasma from these patients. No such effect was seen with plasma from a patient with C2D but with no evidence of SLE, from patients with SLE but not C2D, from patients with C1q or C8 deficiency, from C4-deficient guinea pigs, or NZB-NZW mice. Because oxygen-derived free radicals may cause joint or tissue damage, C2D patients who have or develop this activity in their plasma may be more prone to SLE or other collagen-vascular diseases.

Phagocytosis, chemoluminescence, and intracellular killing of fungi by phagocytes from subjects with deficiency of the second component of complement.

The capacity of phagocytes from animals or humans with complement component deficiency to ingest and kill Candida albicans has been much disputed. We show that peripheral blood polymorphonuclear leukocytes and mononuclear phagocytes from subjects with hereditary C2 deficiency (C2D) ingested C. albicans or Saccharomyces cerevisiae at an abnormally slow rate. After preincubating C. albicans in C2D plasma, the slow rate of phagocytosis was corrected and subsequent intracellular killing of C. Albicans was normal. A normal number of C2D phagocytes reduced nitroblue tetrazolium after stimulation with either phorbol myristate acetate or ingestion of C. albicans. The rate at which chemoluminescence was generated in response to C. albicans was abnormally slow, but peak chemoluminescence produced by C2D phagocytes in response to C. albicans was normal.

Regional deficiency of secretory IgA in a patient with combined immunodeficiency of the ADA deficient type.

The IgA system in a patient with SCID and ADA deficiency showed heterogeneity. Serum IgA and stool secretory IgA (SIgA) levels were normal, but with altered kappa/lambda and A1/A2 subclass ratios; IgA in saliva and urine was deficient. Amounts of secretory component were normal. Jejunal and rectal biopsies showed prominent lymphonodular hyperplasia, but no cells containing IgA. A normal serum IgA level therefore does not always predict an intact secretory IgA system.

Characterization of the residual adenosine deaminating activity in the spleen of a patient with combined immunodeficiency disease and adenosine deaminase deficiency.

A number of infants with an autosomal recessive form of combined immunodeficiency disease also lack adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) activity in their erythrocytes. Other tissues from these infants contain only a few percent of the adenosine-deaminating activity present in corresponding normal tissue. The residual adenosine-deaminating activity in extracts from the spleen of a combined immunodeficient, adenosine deaminase-deficient patient was compared with adenosine deaminase from normal spleen. Affinity and immunoadsorbant column chromatography revealed distinct differences between the adenosine-deaminating activity in the patient's spleen and adenosine deaminase from normal spleen. The point of maximum activity and general configuration of the pH optimum curves were also different. erythro-9-(2-Hydroxyl-3-nonyl)adenine, a potent inhibitor of adenosine deaminase from normal spleen, had relatively little effect on the activity from the patient's spleen. In contrast, adenine was a better inhibitor of the activity in the patient's spleen than it was of the enzyme from normal tissue. An adenosine-deaminating activity with the same characteristics and specific activity as that in the patient's spleen was also isolated from normal spleen. These results suggest that the adenosine-deaminating activity in the spleen of this patient is not due to a mutant form of adenosine deaminase.

Successful retransplantation of bone marrow following failure of initial engraftment in a patient with aplastic anemia.

Histobompatible sibling bone marrow was transplanted to a patient withsevere aplastic anemia. The first transplant failed, but a second transplantfrom the same donor was successfully performed with a new and more potentimmunosuppressive regimen. Successful retransplantation after marrow graftrejection is now possible.