Imbalances of gamma globulin subgroups and gene defects in patients with primary hypogammaglobulinemia
01 Nov 1970-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 49, Iss: 11, pp 1957-1966
TL;DR: It is concluded that gammaG subgroup imbalances are frequently found in non sex-linked immunoglobulin deficiency disorders and in some instances may be associated with family abnormalities suggesting either regulator or structural gene defects.
Abstract: Analysis of immunoglobulin classes, γG subgroups, and Gm genetic markers from 59 patients with various types of immune deficiencies was undertaken to assess the function of the several cistrons concerned with synthesis of gamma globulins. 13 patients including two sibling pairs were found to have γG subgroup imbalances. All of these patients had non sex-linked disease. 11 of the 13 had preponderance of the γG3 subgroup. In most instances of γG3 preponderance it was the Gm(b) type of γG3 that was selectively retained; the Gm(g) type, controlled by the allelic gene was markedly depressed but not absent in the cases where it could be studied. Other imbalances, either seen concomitantly with γG3 preponderance or independently, included predominance of the γG2 subgroup and selective absence of single γG subgroups.
One family was encountered with probable structural gene abnormalities in the autosomal Gm loci. Both parents had different abnormal gene complexes detectable by absence of specific Gm markers and the propositus received both types from the parents. Similar gene complexes have been seen previously in rare instances through population screening but only in the heterozygous state and were not associated with clinically evident hypogammaglobulinemia. Of several other families of patients with subgroup imbalance, two were informative in that structural gene defects could be excluded. Studies on 22 first degree relatives of patients with subgroup imbalances indicated that the most common abnormality detected was in γA which was absent in 3 and markedly decreased in 2 others; other abnormalities included decreased levels of specific genetic types of γG globulin. It is concluded that γG subgroup imbalances are frequently found in non sex-linked immunoglobulin deficiency disorders and in some instances may be associated with family abnormalities suggesting either regulator or structural gene defects.
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TL;DR: The primary immunodeficiency disorders reflect abnormalities in the development and maturation of cells of the immune system, which result in an increased susceptibility to infection; recurrent pyogenic infections occur with defects of humoral immunity, and opportunistic infections with defect of cell-mediated immunity.
Abstract: The primary immunodeficiency disorders reflect abnormalities in the development and maturation of cells of the immune system. These defects result in an increased susceptibility to infection; recurrent pyogenic infections occur with defects of humoral immunity, and opportunistic infections with defects of cell-mediated immunity. These two broad categories of illness correspond roughly to defects in the two principal types of immunocompetent cells, B lymphocytes and T lymphocytes. Defective development of B cells results in abnormalities in humoral immunity, whereas defects in the development of T cells cause problems with cellular immunity. When pathogens are taken up by macrophages or dendritic cells, . . .
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TL;DR: The clinical and immunologic features of two adolescent boys who had recurrent pyogenic infections are judged to constitute a new syndrome and the explanation for the undue susceptibility to infection, increased IgE production, subnormal antibody formation, and impaired in vivo cell-mediated immunity in these patients remains conjectural.
Abstract: The clinical and immunologic features of two adolescent boys who had recurrent pyogenic infections are judged to constitute a new syndrome. Its characteristics include: recurrent cutaneous, pulmonary, and joint abscesses; growth retardation; coarse facies; chronic dermatitis; exquisite immediate hypersensitivity associated with exceptionally high serum concentrations of IgE and eosinophilia; and depressed in vivo cellular immunity and antibody formation. These patients lacked evidence of respiratory allergy or parasitism. Atopic dermatitis was not present in one boy and the physical characteristics of the other boy9s dermatitis were not typical for that entity. Concentrations of immumnoglobulins G, A, M, D and the various IgG subtypes were normal, as were natural antibody titers to red cell antigens. Nevertheless, depressed anamnestic antibody responses were noted to diphtheria and tetanus antigens and neither patient demonstrated responses to primary immunization with KLH, typhoid, and DNCB antigens. Complement and polymorphonuclear functions were normal. In vitro lymphocyte studies done demonstrated normal DNA synthesis in phytohemagglutinin and staphylococcal antigen-stimulated cultures and MIF production by some antigen-stimulated cultures from each. The explanation for the undue susceptibility to infection, increased IgE production, subnormal antibody formation, and impaired in vivo cell-mediated immunity in these patients remains conjectural.
551 citations
TL;DR: The serum concentration of IgG-2 appears to provide a marker for predicting the ability to produce antibodies to polysaccharide, but not viral protein, antigens, in patients treated with both radiation and chemotherapy.
Abstract: We measured serum concentrations of immunoglobulin classes and IgG subclasses in 53 patients who had completed treatment for Hodgkin's disease and in 10 healthy adults. We wished to determine the relation of these classes and subclasses to the subjects' antibody responses to bacterial polysaccharide and viral protein antigens. Mean levels of the IgG-2 subclass were significantly lower in patients treated with both radiation and chemotherapy than in controls (P<0.05). The level of IgG-2 before immunization correlated directly with the mean antibody response both to 11 pneumococcal antigens (r = 0.71, P<0.001) and to the Haemophilus influenzae Type b antigen (r = 0.40, P<0.01). The correlation between IgG-2 concentration and pneumococcal antibody response was also significant in the 10 healthy adults (r = 0.70, P<0.05). The levels of no immunoglobulin class or subclass correlated significantly with antibody responses to influenza A/Victoria/75 and A/New Jersey/76 hemagglutinins, both of which are p...
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TL;DR: It is speculated that a perinatal or in utero transmission of EBV can induce an "infectious immunodeficiency" and the clinical, histopathologic, and immunologic features resemble those described in adult homosexuals and drug addicts.
Abstract: A new syndrome of acquired immunodeficiency has been identified in seven children who were small for gestational age at birth and subsequently have exhibited failure to thrive, lymphadenopathy, parotitis, hepatosplenomegaly, interstitial pneumonia, and recurrent infections. All have a profound cell-mediated immunodeficiency with reversed T 4 /T 8 ratios. Six are hypergammaglobulinemic and one has low IgG levels. The mothers of five of the seven children are sexually promiscuous and/or drug addicts. Three mothers have an immunodeficiency similar to that found in their infants. One of them died at age 33 years with a diagnosis of acquired immunodeficiency syndrome. In five of the children and in three of their mothers, there is evidence of a persistent Epstein-Barr virus (EBV) infection. We speculate that a perinatal or in utero transmission of EBV can induce an "infectious immunodeficiency." The clinical, histopathologic, and immunologic features resemble those described in adult homosexuals and drug addicts. ( JAMA 1983;249:2350-2356)
385 citations
TL;DR: The immunoglobulin classes and subclasses represent a group of structurally related proteins, and in all instances consist of two pairs of polypeptide chains held together by disulfide bridges and noncovalent forces.
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297 citations
References
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TL;DR: By standardizing the technical conditions of the experiment it is possible to use this principle for the immunochemical determination of antigens, and the lower limit of the method was found to correspond to 0·0025 μg of antigen, and to an antigen concentrations of 1·25 μg per ml.
8,937 citations
2,201 citations
Journal Article•
TL;DR: The results by the antibody-agar plate method are similar to those obtained by the isotopic immune inhibition technique, except for the serum IgA and Type K (I) and Type L (II) immunoglobulin levels.
Abstract: The mean immunoglobulin levels in 20 normal human sera were found to be 12.4 mg/ml for IgG (7 S γ2-globulins); 2.8 mg/ml for IgA (γ1A or β2A-globulins) and 1.23 mg/ml for the IgM (18 S γ1M-globulins). Type K (I) and Type L (II) immunoglobulins were similarly determined. The results by the antibody-agar plate method are similar to those obtained by the isotopic immune inhibition technique, except for the serum IgA and Type K (I) and Type L (II) immunoglobulin levels. With each of these proteins the values obtained by the isotopic immune inhibition test are higher than those found by the antibody-agar plate test. The basis for this difference is discussed.
1,460 citations
TL;DR: Metabolic properties of the four subclasses of human IgG were investigated by performing 47 turnover studies in individuals with normal IgG serum concentrations, as well as in patients with an increased level of one of the subclasses, showing that an elevated serum concentration of any IgG subclass was associated with shortened biologic half-life and increased fractional catabolic rate of all subclasses.
Abstract: Metabolic properties of the four subclasses of human IgG were investigated by performing 47 turnover studies in individuals with normal IgG serum concentrations, as well as in patients with an increased level of one of the subclasses. Studies in 12 subjects with normal IgG serum concentration showed that the average biologic half-life of G(1), G(2), and G(4) was 21 days, while that of G(3) was only 7.1 days. Fractional catabolic rates of G(1), G(2), and G(4) were 6.9 to 8% of the intravascular pool per day. G(3), however, had a higher fractional catabolic rate, amounting to 16.8% of the intravascular pool per day. Distribution of the subclasses was such that the intravascular compartment contained 51-54% of the total body pools of G(1), G(2), and G(4), but 64% of the total body pool of G(3).The short survival and high fractional catabolic rate of G(3) is an inherent property of these molecules, and is not due to denaturation during isolation and radiolabeling. This was demonstrated by studies of a patient with a serum G(3)-myeloma protein. The survival of her own protein, separately labeled either in vivo with guanidoarginine-(14)C or in vitro with (125)I, was determined in the patient. Survivals of the in vivo and in vitro labeled proteins were identical.G(1) and G(3) serum concentrations and synthetic rates were determined. The mean serum concentration of G(1) was 6.8 mg/ml and that of G(3) was 0.7 mg/ml, while their synthetic rates were 25.4 and 3.4 mg/kg per day respectively. The low serum concentration of IgG(2) thus results from a combination of high catabolic and low synthetic rates. Studies in 10 patients with multiple myeloma showed that an elevated serum concentration of any IgG subclass was associated with shortened biologic half-life and increased fractional catabolic rate of all subclasses. The implications of this concentration-catabolism relationship are discussed. The serum concentration of nonmyeloma IgG was usually low in myeloma patients and the synthesis of nonmyeloma IgG was somewhat decreased, suggesting that low serum concentrations of nonmyeloma IgG result from decreased synthesis, as well as from an increased fractional catabolic rate.
488 citations
TL;DR: The composition of various isolated antibodies was determined by quantitative analyses for heavy chain subgroups and light chain types, and one anti-levan antibody studied was uniquely homogeneous, consisting exclusively of γG2-heavy chains and kappa light chains.
Abstract: The composition of various isolated antibodies was determined by quantitative analyses for heavy chain subgroups and light chain types Certain antibodies such as anti-tetanus toxoid and anti-A isoagglutinins were predominantly of the major γG1-type However, a high preponderance of molecules of the minor γG2-subgroup was found for antibodies to dextran, levan, and teichoic acid These findings explain some unusual features previously noted for anti-dextrans such as weak PCA reactions and lack of Gm antigens Studies of several isolated antibodies from single heterozygous individuals showed a selective absence of genetic markers in certain antibodies and their presence in others The "allelic exclusion" principle was clearly evident in the isolated antibodies of two different individuals Large differences in the ratio of kappa to lambda light chains were observed for the same type of antibody from different individuals Subfractionation of dextran antibodies by affinity for specific glycosidic linkage or combining site size produced marked changes in the ratios The isomaltohexaose eluates of the dextran antibodies from two subjects were primarily kappa and the isomaltotriose eluates were predominantly lambda The one anti-levan antibody studied was uniquely homogeneous, consisting exclusively of γG2-heavy chains and kappa light chains By these criteria as well as others, it closely resembled myeloma proteins
410 citations