Silvio Barandun

IgG subclasses: Development of the serum concentrations in “normal” infants and children**

The concentrations of the four recognized subclasses of IgG were measured usingspecific antisera and a radioimmunoadsorbent assay in 38 paired maternal and cord blood samples and in the sera of 95 presumably healthy infants from birth to 2 years of age. Placental transfer of all four subclasses was found to be free. The dramatic changes of the total gamma globulin concentration in the neonatal period were confirmed. However, analysis of the subclasses revealed considerable heterogeneity, leading to the conclusion that for each subgroup there is a different age of onset and speed of synthesis: Within one month after birth IgG 3 values rise to considerable levels and after three months to adult levels. IgG 1 synthesis starts before three months of age and concentrations are close to adult values at 8 months, whereas IgG 2 and IgG 4 synthesis still is far from maturity at age 2 years. Possibly the nature of the stimulating antigens is a determining factor of the resulting IgG subclass responses.

Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy

Immunoglobulin G was given intravenously (IVIgG) to pregnant women (27 to 36 weeks gestation) with signs of chorioamnionitis who were at risk for preterm delivery. Twenty-four patients received antibiotics alone (control group). Twenty-seven patients received the same antibiotics in combination with IVIgG, either 12 gm in 12 hours (low IVIgG dosage) or 24 gm on each of 5 consecutive days (high IVIgG dosage). Transplacental passage of IVIgG was shown to be a function of gestational age and of dose. Up to the thirty-second week of gestation, IgG infusions had no effect on IgG concentrations in cord sera. After that time, cord serum IgG levels were significantly higher in the high-dose group compared with the low-dose and control groups. All four subclasses of IgG, and two different antibodies present in the IVIgG preparation passed from the mother to the fetus. Thus the infused IgG mimicked the transplacental passage of endogenous IgG.

Intravenous immunoglobulin for idiopathic thrombocytopenic purpura (ITP) in childhood.

IgG-SRK (identical with Sandoglobulin) is a polyvalent IgG concentrate obtained by modified alcohol cryoprecipitation, including mild acidification at pH 4. This product was given in high doses intravenously for the treatment of six children with acute ITP, four children with intermittent ITP, and three children with severe chronic idiopathic thrombocytopenic purpura (ITP). An impressive initial response was observed in all patients, the extent of which may be of prognostic significance in acute ITP. Maintenance therapy was required in two of six patients with acute ITP, in three out of four patients with intermittent ITP, and in all of the patients with severe chronic ITP. In the cases of severe chronic ITP, the disease could not be adequately controlled over long periods of time, but bleeding episodes subsided or became considerably less frequent. Although little is known of the effects of IgG-SRK, possible mechanisms were discussed. It is emphasized that a new model has been discovered to study the interrelations between structure and function of human immunoglobulin molecules.

Immunomodulation by intravenous immunoglobulin.

In 1980, it was observed in a child with idiopathic thrombocytopenic purpura (ITP) that intravenous administration of pooled human immunoglobulin-G (IVIG) was followed by a rapid increase of the platelet count. Prompted by this finding, a pilot study and two prospective multi-center studies on children with ITP were organized. Efficacy of this new treatment for ITP was soon confirmed worldwide. In addition to the immediate effect, long-term observations following administration of IVIG suggested the occurrence of modulation of the immune response. Also, concomitant with studies on the mechanism of action of IVIG, the use of IVIG in the treatment of patients with other immune-related disorders was explored.

Serum Concentrations of IgG Subclasses

Publisher Summary The molecules of the immunoglobulin class IgG include 70–80% of the humoral antibodies. Their wide antibody spectrum is a corollary of the enormous heterogeneity of the antigen binding sites and is structurally confined to the variable region of the IgG molecules. Four subclasses of IgG are recognized: IgGl, IgG2, IgG3, and IgG4. The molecules of these subclasses differ in the primary structure of the carboxyterminal three-quarters of their heavy polypeptide chains, number and arrangement of the inter-heavy chain disulfide bridges, and the localization of the disulfide bridges linking the heavy to the light polypeptide chains. There is evidence that subclass-related structural traits are located in all three homology regions of the IgG heavy chains. The determination of the serum concentrations of the four IgG subclasses could offer some insight into the regulatory mechanisms that control subclass serum levels and could bring some new information on their biological significance. This chapter discusses the radioimmunoassay of the four IgG subclasses. In addition to its higher sensitivity, the method allows the scanning of large numbers of sera with minimal quantities of antisera.

Prophylactic and therapeutic use of immunoglobulin for intravenous administration in patients with secondary immunodeficiencies associated with malignancies

Failure of host defense systems associated with malignancies may be attributable to the tumor, to cytoreductive therapy or to combined endogenous and iatrogenic influences. Management of the resulting increased susceptibility to infections may require supplementation of antibiotic therapy with additional forms of treatment, including passive immunization with antibodies. This review discusses the use of immunoglobulin preparations for intravenous administration (IVIG) in patients with secondary immunodeficiencies associated with neoplasia. A suitable model for evaluating the prophylactic effect of IVIG is chronic lymphocytic leukemia. Many observations suggest that IVIG reduces the frequency of acute respiratory infections. Another malignant condition with decreased serum levels of polyclonal immunoglobulins and high frequency of infections is multiple myeloma. A crossover study recently demonstrated that IVIG significantly (P < 0.01) reduced the frequency of respiratory tract infections in these patients. Furthermore the prophylactic effect of IVIG was evaluated in patients with small cell carcinoma of the lung. In a randomized prospective trial it was noticed that IVIG applied during intensive chemotherapy and irradiation courses significantly (P = 0.04) reduced the frequency of infections. Evidence for a therapeutic effect of IVIG was obtained in adult tumor patients and in children with leukemia or non-Hodgkins lymphoma who developed severe varicella-zoster virus infections. The treatment effectively controlled fever, skin lesions and neuralgia and prevented progression of the infection. Therapeutic usefulness of IVIG in bacterial infections is still based on adecdotal evidence. Experimental data suggest that in addition to effects mediated by specific antibodies, nonspecific interactions of IgG molecules with Fc-receptors on macrophages may be clinically important.

IgG Subclass Composition and Immunochemical Characteristics of Plasmin-Treated Human γ-Globulin

Abstract. Plasmin‐treated human IgG preparations were separated on Sephadex G‐100 columns, and proteins of three peaks eluted prior to Fab/Fc fragments were investigated. Determinations of the apparent molecular weight of these peaks revealed that IgG dimers, plasmin‐resistant IgG monomers and additional components with a molecular weight of about 115,000 were eluted. IgG subclasses were measured in individual effluent fractions and χ, Λ and IgG/Fc antigenic determinants were demonstrated. IgG2 and IgG4 were found to be relatively resistant, IgG1 and IgG3 susceptible for cleavage by plasmin. In the components with a molecular weight 115,000, two fragments were characterized and shown to be similar to the papain IgG1‐Fab/c and IgG1‐Fc2 fragments.

Terminal differentiation of PWM-stimulated human B lymphocytes.

Abstract Patterns of surface and cytoplasmic immunoglobulins were simultaneously studied on human B blast cells induced by pokeweed stimulation of peripheral blood lymphocytes. A double-staining immunofluorescent technique was used. After 4 and 7 days of culture, a gradual loss of surface IgD was observed on blast cells whereas numbers of plasmablasts with cytoplasmic immunoglobulin showed a marked increase. After 7 days, 92% of surface IgA positive blasts had passed terminal differentiation to cytoplasmic IgA-producing plasma-blasts. At the same time, 73% of surface IgM positive blasts were found to contain cytoplasmic IgM, and 30% of surface IgG positive cells had cytoplasmic IgG. Only a small fraction of blast cells with surface IgD was able to mature to IgD producing plasmablasts. In general, the class of surface and cytoplasmic immunoglobulin coincided in single blast cells, with the exception of surface IgD which was present on 10% of the cytoplasmic IgM-containing blasts.

Veränderungen des x/λ-Verhältnisses der menschlichen Serumimmunglobuline im Verlaufe der Entwicklung

In sera of normal individuals of different age groups the kappa- and lambda-type immunoglobulins were measured and the kappa/lambda ratio was calculated. The relative concentration of lambda-immunoglobulins in sera of newborns and young children was found to be significantly higher than in the adult sera. The well-known asynchronous maturation of immunoglobulin classes and IgG subclasses in the early childhood is evidently accompagnied by a asynchronous maturation of immunoglobulin types.ZusammenfassungIm Serum von normalen Individuen wurden die Immunglobuline vomx- und λ-Typ quantitativ bestimmt und das x/λ-Verhältnis auf verschiedenen Altersstufen ermittelt. Es hat sich gezeigt, daß die relative Konzentration der λ-Immunglobuline im Serum der Säuglinge signifikant höher ist als im Erwachsenenserum. Die bekannte asynchrone Ausreifung der Immunglobulin-Klassen und IgG-Subklassen im früheren Lebensalter wird offensichtlich durch eine ebenfalls ungleiche Ausreifung der Immunglobulin-Typen überlagert.SummaryIn sera of normal individuals of different age groups thex- and λ-type immunoglobulins were measured and the x/λ ratio was calculated. The relative concentration of λ-immunoglobulins in sera of newborns and young children was found to be significantly higher than in the adult sera. The well-known asynchronous maturation of immunoglobulin classes and IgG subclasses in the early childhood is evidently accompagnied by a asynchronous maturation of immunoglobulin types.

Imbalances of the κ/λ Ratio of Human Immunoglobulins

Publisher Summary The κ/λ light-chain ratio in normal serum is subject to some variations during life. There has not been detected any correlation between the κ/λ light-chain ratio and the concentrations of the various immunoglobulin classes and subclasses in the serum. Therefore, it appears that the synthesis of the two light-chain types is under separate control. A disproportionate synthesis of κ and λ immunoglobulins characterizes a monoclonal proliferation of Ig-producing cells as observed in multiple myeloma, macroglobulinemia, and other paraproteinemias. The light-chain imbalances of variable degree can be observed in humoral immunodeficiencies. The capability of patients with κ- or λ-chain deficiency to respond to antigenic stimuli by producing corresponding antibodies varies. Some antigens triggere a normal or subnormal immune response but others do not. Therefore, a regular response pattern cannot be recognized; however, cellular immunity appears to be intact. The determination of the κ/λ ratio in the serum represents one of the most reliable laboratory methods for the recognition of a homogeneous immunoglobulin characteristic for a monoclonal proliferation of immunoglobulin-producing cells.