The metabolism of IgE in patients with immunodeficiency states and neoplastic conditions.

Serum IgE concentrations were determined and IgE turnover studies were performed in control individuals as well as in patients with several disease states. Patients with common variable hypogammaglobulinemia, thymoma and hypogammaglobulinemia, ataxia telangiectasia, and selective IgA deficiency had significantly decreased mean serum IgE concentrations. In turnover studies, this was found to be due to decreased IgE synthesis. In spite of these depressed mean values, some patients with common variable hypogammaglobulinemia had normal serum IgE concentrations and synthetic rates. Patients with the Wiskott-Aldrich syndrome had a significantly elevated mean serum IgE concentration. In one of four patients studied with the turnover technique, a strikingly high IgE concentration was present and was associated with an elevated IgE synthetic rate. Three other patients had both normal serum IgE concentrations and synthetic rates. Patients with chronic lymphocytic leukemia had significantly decreased mean serum concentrations and synthetic rates for IgE. The depressed IgE synthesis was associated with a significantly prolonged IgE half-life. Patients with Hodgkin's disease had significantly increased serum IgE concentrations. One of three patients studied had a high serum IgE concentration and synthetic rate of IgE. The two other patients had normal serum IgE concentrations associated with normal synthetic rates. Finally patients with protein-losing enteropathy or familial hypercatabolic hypoproteinemia had normal IgE concentrations associated with normal IgE metabolic parameters. In these cases, the disorder in the catabolic rate was not severe enough to affect the total amount of circulating IgE because IgE normally has a very high fractional catabolic rate. In general, IgE levels in a variety of disease states were correlated with IgE synthetic rates and abnormalities in the catabolic rate of IgE in disease did not exert an important effect on IgE concentration.

Impaired culture generated cytotoxicity with preservation of spontaneous natural killer-cell activity in cartilage-hair hypoplasia.

Recent studies of cartilage-hair hypoplasia (CHH), a form of short-limbed dwarfism, have shown that all affected individuals have a cellular proliferation defect that results in a cellular immunodeficiency. However, only a minority of CHH individuals suffer from severe, life-threatening infections. For this reason, relevant immune defense mechanisms that may be responsible for maintaining intact host defenses in the majority of CHH individuals were studied. Spontaneous and allogeneic culture-induced (mixed lymphocyte response-MLR) specific and nonspecific (NK-like) cytotoxic mechanisms were analyzed and correlated with lymphocyte subpopulations present in CHH and normal individuals. Spontaneous natural-killer (NK) activity was present at or above normal levels, but culture-induced specific cytotoxicity and NK-like cytotoxicity as well as NK-like activity by T cell lines were significantly reduced in CHH individuals. The generation of radiation-resistant cytotoxicity, which normally occurs during allogeneic MLR, was markedly diminished in CHH, and was correlated with the decreased proliferation observed in CHH cultures. Preservation of spontaneous NK activity and loss of all forms of culture-induced cytotoxicity was associated with an increase in the proportion of lymphocytes bearing a thymic independent NK phenotype (OKM1+ OKT3- Fc gamma + low-affinity E+), and a significant decrease in thymic derived OKT3+ cytolytic T cell sub-populations in CHH individuals. Therefore, an intact cellular cytotoxic effector mechanism has been identified in CHH (i.e., NK activity). Natural cytotoxicity may be of importance in maintaining host resistance to viral infections despite diminished thymic-derived effector mechanisms in cartilage-hair hypoplasia.

Immunoglobulin E in immunologic deficiency diseases. I. Relation of IgE and IgA to respiratory tract disease in isolated IgE deficiency, IgA deficiency, and ataxia telangiectasia.

Serum immunoglobulin E concentration was studied in normal children and adults, in 25 patients with isolated IgA deficiency, and in 44 patients with ataxia telangiectasia using a double antibody radioimmunoassay. The geometric mean IgE level of the normal adult population studied was 105 ng/ml, with a broad 95% interval (5-2045 ng/ml). Individuals with concentrations less than 15 ng/ml were considered to be IgE deficient. IgE deficiency, defined in this way, was observed in 7 of 73 normal adults and was not found to be associated with respiratory tract disease.80% (35 of 44) of patients with ataxia telangiectasia (AT) were IgE deficient, 66% were IgA deficient, and 57% had combined IgE and IgA deficiencies. Although 45% of the patients with AT had respiratory tract disease, there was no correlation found between IgE deficiency or combined IgE and IgA deficiency and respiratory tract disease in these patients.11 of 25 individuals with isolated IgA deficiency were also IgE deficient. All 11 patients with both IgA and IgE deficiency were uniformly asymptomatic. However, there was an extremely high incidence (71%) of respiratory tract disease in IgA-deficient individuals who were not IgE deficient. These data fail to support the concept of a protective role for IgE in respiratory tract immunity. The possible role of IgE in the pathogenesis of respiratory tract disease in IgA-deficient patients is discussed.

Purine nucleoside metabolism in the erythrocytes of patients with adenosine deaminase deficiency and severe combined immunodeficiency.

Deficiency of erythrocytic and lymphocytic adenosine deaminase (ADA) occurs in some patients with severe combined immunodeficiency disease (SCID). SCID with ADA deficiency is inherited as an autosomal recessive trait. ADA is markedly reduced or undetectable in affected patients (homozygotes), and approximately one-half normal levels are found in individuals heterozygous for ADA deficiency. The metabolism of purine nucleosides was studied in erythrocytes from normal individuals, four ADA-deficiency patients, and two heterozygous individuals. ADA deficiency in intake erythrocytes was confirmed by a very sensitive ammonia-liberation technique. Erythrocytic ADA activity in three heterozygous individuals (0.07,0.08, and 0.14 mumolar units/ml of packed cells) was between that of the four normal controls (0.20-0.37 mumol/ml) and the ADA-deficient patients (no activity). In vitro, adenosine was incorporated principally into IMP in the heterozygous and normal individuals but into the adenosine nucleotides in the ADa-deficient patients. Coformycin (3-beta-D-ribofuranosyl-6,7,8-trihydroimidazo[4,5-4] [1,3] diazepin-8 (R)-ol), a potent inhibitor of ADA, made possible incorporation of adenosine nucleotides in the ADA-deficient patients...

Efficacy and safety of high-dose intravenous immune globulin therapy for antibody deficiency syndromes.

Ten patients with antibody deficiency syndromes were admitted to a treatment protocol in which the dose of intravenous immune serum globulin was increased from 100 mg/kg to a maximum of 250 mg/kg each four weeks. The dose increases were determined by recurrence of infection during treatment and by IgG trough levels of less than 400 mg/dl. Infectious episodes during intravenous immune serum globulin treatment responded well to 10 to 20 day long periods of antibiotic treatment, and prolonged infection-free periods were achieved in all patients. Only one hospital admission was necessary during the entire study period. The increase in intravenous immune serum globulin dose to 200 mg/kg did not significantly reduce the recurrence of infections. Infections also occurred in patients whose IgG trough levels were persistently above 400 mg/dl. High doses of intravenous immune serum globulin were well tolerated, and all patients are still receiving intravenous immune serum globulin treatment. A generalized pruritic rash was observed in two patients. In no patient have clinical or laboratory signs of deficiency in cell-mediated immunity developed.

Use of intravenous immune globulin in pregnant women with common variable hypogammaglobulinemia.

Two patients with common variable hypogammaglobulinemia were treated with immune serum globulin during pregnancy. An intravenous immune serum globulin preparation was used in the last trimester of pregnancy. Both patients tolerated this preparation well and had an uneventful pregnancy. The two term newborns were healthy and had cord blood IgG levels likely to be the result of transplacental transfer of the intravenous immune serum globulin preparation. During pregnancy there is an increase in the IgG distribution space due to plasma volume expansion. Therefore, pregnancy is an indication for these immune serum globulin preparations that can be administered at high doses intravenously in order to confer adequate protection to the mother and the newborn.

Natural cytotoxicity in immunodeficiency diseases: preservation of natural killer activity and the in vivo appearance of radioresistant killing.

We studied spontaneous natural killer (NK) cell activity and radiation-resistant NK mediated cytotoxicity in four patients with clinically documented severe combined immune deficiency disease (SCID), and in one subject each with intestinal lymphangiectasia and cartilage-hair hypoplasia. We observed the preservation of spontaneous NK activity in all patients despite the presence of profound B- and T-lymphocytopenia and clinical immunodeficiency. NK activity was associated with relatively normal circulating numbers of OKM1+ lymphocytes, a population known to contain NK effectors. Spontaneous NK activity resistant to 3000 rad was increased in all patients, indicating the presence of activated natural killer cells in vivo. The concept of a chronically activated immune system in these patients was further supported by the presence of increased Ia positive T cells in all subjects tested, suggesting that radioresistant NK activity may be a useful parameter to measure when assessing in vivo immune activation. Our data, as well as that of others, supports the hypothesis that at least one population of NK cells is a distinct lineage arising at the differentiation level of myeloid and lymphoid stem cells in the bone marrow.

Cytotoxic factors secreted by cells infected by human immunodeficiency virus type I.

Conditioned media from human immunodeficiency virus type I (HIV-1) infected cells were tested for cytotoxic cell-derived factors. The assay used a murine fibroblast cell line which is sensitive to the effects of tumor necrosis factors, but nonpermissive for HIV-1 replication. Cytotoxic activity was detected in cultures of peripheral blood mononuclear cells infected with HIV-1. However, no differences in activity were found in conditioned media from infected lymphoid or monocytoid cell lines compared to their uninfected counterparts. These data suggest that cytotoxic activities of this type are not mediators of cell killing resulting from HIV-1 infection. Thus, this cytotoxic activity is a direct or indirect result of virus replication or cytopathicity. One should consider a role for this cytotoxic factor, secreted by HIV-1 infected mononuclear cells, in various aspects of infection in vivo, such as AIDS encephalopathy or the systemic manifestations accompanying ARC.

Endoscopic ethmoidectomy and maxillary antrostomy in immunodeficient patients.

The efficacy of endoscopic sinus surgery was evaluated in 11 patients with diverse types of primary immunodeficiency disease and symptoms of chronic sinusitis. The postoperative symptoms and ability to eliminate antibiotics were used as outcome parameters. In two patients, the follow-up time was too short to assess therapeutic effectiveness. Five of the remaining nine patients had total or significant resolution of symptoms. Patients with transient immunodeficiency had the best resolution of symptoms. Eight of the total 11 patients were treated with intravenous immunoglobulin preoperatively, and in five patients, the treatment was continued postoperatively. The ability to terminate gamma-globulin reflects not the success of the surgery, but the transient nature of some of the immunodeficiencies.

The role of the immunologist in sinus disease.

The clinical immunologist is playing an increasingly important role in the evaluation and management of sinus disease. Although most patients with sinus disease are not immunodeficient, a significant proportion of patients with chronic sinusitis unresponsive to medical and/or surgical therapy may have an immunodeficiency. Most immunodeficient patients for whom sinusitis is a major clinical problem tend to be those with humoral immunodeficiency diseases. The role of immunoglobulin replacement therapy is well established for patients with global immunoglobulin and antibody deficiencies (e.g., X-linked agammaglobulinemia and common variable immunodeficiency) and may be helpful in controlling refractory sinusitis in patients with more selective immunoglobulin deficiencies (e.g., IgG subclass deficiency and selective antibody deficiencies), but efficacy in these conditions remains to be established by controlled studies. Many immunodeficient patients have a history of repeated sinus surgery before the recognition of their immune defect. Even in immunodeficient patients treated with antibiotics and immunoglobulin replacement therapy, functional endoscopic sinus surgery is successful in only half of the patients.

Enzyme replacement and other biochemical approaches to the therapy of adenosine deaminase deficiency.

Addition of adenosine deaminase (ADA) restored in vitro responses of lymphocytes from a patient with ADA deficiency and severe combined immunodeficiency (SCID). Enzyme replacement therapy, using red blood cells as a source of encapsulated human ADA, restored both T and B cell function in this patient. Ten other ADA--SCID patients have been treated with this form of enzyme replacement and five have responded to therapy. Lymphocytes from ADA--SCID patients treated with enzyme replacement become immunocompetent but remain enzyme deficient. Studies of these cells provide evidence supporting both cyclic AMP- and dATP-mediated immunosuppressive mechanisms in ADA--SCID. These observations suggest that inhibition of cyclic AMP synthesis and/or deoxycytidine (and possibly thymidine) supplementation may be useful new biochemical approaches to the therapy of ADA--SCID.

Cartilage hair hypoplasia: immunological aspects and their clinical implications.

Cartilage hair hypoplasia (CHH) is an autosomal recessive form of short-limbed dwarfism prevalent among the Old Order Amish. Mild to moderately severe cellular immunodeficiency is associated with this disorder. Antibody synthesis is, however, normal in CHH. Individuals affected with CHH were found to have marked impairment of T-lymphocyte function due to an intrinsic defect in cell proliferation. Defective proliferation was also found in B cells and fibroblasts from CHH individuals suggesting that impaired T-cell function reflects a generalized defect in cell proliferation in this syndrome. Studies of cytotoxic mechanisms in CHH patients revealed that proliferation-dependent mechanisms (e.g., cell-mediated cytotoxicity and natural killer [NK]-like activity) were markedly impaired while proliferation-independent NK activity was normal. In spite of impairment of T-cell function, an increased incidence of malignancy was not observed in CHH patients. These observations suggest that NK activity is vital in host defense against malignancies and that marked impairment of T-cell-mediated immunity need not be associated with an increased susceptibility to malignancy if NK function is preserved.

Quantitation of the biosynthesis of immunoglobulin in peripheral blood lymphocytes of normal and immunodeficient patients.

A solid phase radioimmunoassay was applied to the study of biosynthesis of immunoglobulins in lymphocytes cultured from peripheral blood of normal and immunodeficient patients. Total immunoglobulin and IgG were readily detected in lymphocyte culture fluids in studies of all normal individuals (age range 28 weeks, gestation to adulthood). In contrast, synthesis of immunoglobulins was absent or markedly reduced in cultures from patients with humoral immunodeficiencies. Inasmuch as this method requires relatively small amounts of blood, it may be of particular value in the diagnosis of humoral immunodeficiencies in infants and young children.

Lymphocyte dysfunction in cartilage-hair hypoplasia: evidence for an intrinsic defect in cellular proliferation.

Individuals with cartilage-hair hypoplasia (CHH), an autosomal recessive form of short-limbed dwarfism, have markedly reduced lymphocyte proliferative responses and cutaneous delayed hypersensitivity reactions, but normal humoral immunity. In the present study we investigated the cellular basis of the immunodeficiency in CHH. Defective lymphocyte proliferation could be due to a) an imbalance of immunoregulatory lymphocyte subpopulations, b) defective accessory cell function, or c) an intrinsic cellular defect in lymphocytes from CHH individuals. The absolute numbers of B cells and immunoregulatory (OKT4+, OKT8+) T cells were markedly diminished, but the proportions of these populations were the same as in the normal controls. OKM1+ lymphocytes were increased in proportion, and OKM1+ macrophages had normal adherence, helper, and phagocytic properties. Co-culture experiments failed to reveal any evidence of suppression by CHH mononuclear cells. CHH lymphocytes could not be stimulated to proliferate normally with B and T cell activators, mitogenic monoclonal antibody (OKT3), allogeneic cells, or chemical activators (Ca++ ionophore A23187 and phorbol myristate acetate). Fibroblasts from three CHH individuals also proliferated at a significantly decreased rate, compared to two normal lines. These results demonstrate a selective loss of B and T lymphocytes in CHH, as well as an intrinsic proliferative defect in CHH lymphocytes distal to the initial events in the lymphocyte activation sequence. These findings in CHH fibroblasts and lymphocytes may reflect a generalized defect present in multiple cell types in CHH.

Pharmacological modification of immunoregulatory T lymphocytes. I. Effect of adenosine, H1 and H2 histamine agonists upon T lymphocyte regulation of B lymphocyte differentiation in vitro.

Human peripheral blood T lymphocytes were fractionated according to the lability of their sheep red blood cell (E) receptors to theophylline. Theophylline sensitive (Ts) cells function as suppressors of pokeweed mitogen induced B cell differentiation into plasma cells, while theophylline resistant (Tr) cells function as helper/inducer cells in this reaction. The Ts fraction is enriched for cells bearing receptors for the Fc portion of IgG (RFc gamma) while the Tr fraction is depleted of RFc gamma bearing cells. Brief exposure of Tr cells to adenosine or impromidine, an H2 histamine agonist, cause a rapid increase in the number of Tr cells bearing RFc gamma and the development of radioresistant suppressor cell activity. The RFc gamma induced on Tr cells by adenosine or impromidine are more stable in culture than the spontaneously occurring RFc gamma on Ts cells. Ts suppressor activity is radiosensitive and exposure of Ts cells to 2(2-pyridyl)ethylamine, an H1 histamine agonist, results in a marked decrease in RFc gamma on Ts cells as well as loss of Ts suppressor activity. These data indicate that RFc gamma expression and the immunoregulatory function of T lymphocyte subsets may be modified by drugs acting upon adenosine, H1 and H2 histamine receptors.