Severe Hypogammaglobulinemia Research Articles

Obtention d'une préparation d'immunoglobulines G,A,M (IgGAM) à usage thérapeutique: Etude des conditions d'enrichissement en IgA ou en IgM

Antibodies directed against viruses and bacteria are not equally distributed among the main classes of immunoglobulins, e.g. IgG, IgA and IgM. It has been found that IgM is mostly concerned with certain antibacterial activities (Salmonella, Escherichia coli and Pseudomonas) and IgA with high antibody titers for poliomyelitis virus I whereas antibody activities against many viruses such as influenza and measles virus occur preferentially in the IgG population. Furthermore, isolated immunoglobulin deficiency syndromes are actually well known. In the light of these findings, new concepts of immunotherapy have developed. Massive i.v. IgG-therapy is already widely used in congenital and acquired severe hypogammaglobulinemia. Preparations enriched in IgA and IgM are needed to complete the immunotherapeutical possibilities. Such a fraction called IgGAM has already been prepared in our Institute. Fraction III obtained during large scale fractionation is used as starting material and caprylic acid for the precipitation of most proteins other than the immunoglobulins present in fraction III. The immunoglobulin concentrate is finally obtained by ethanol precipitation of the caprylic acid supernatant. The present study is concerned with various modifications of the initial technique in order to obtain fractions more specially enriched in IgA or in IgM. In some cases the standard IgGAM fraction has been submitted to a further fractionation step, such as adsorption of IgG on DEAE-cellulose or precipitation of certain immunoglobulins achieved by Rivanol or by lowering the salt concentration. In other trials the fractionation procedure starting from fraction III has been modified. Rivanol has been used as a precipitating agent for the subfractionation of fraction III. It is well known that IgG is soluble in the presence of Rivanol. This technique was thus used in order to obtain preparations enriched mainly in IgM and IgA. The precipitate obtained after the addition of Rivanol was dissociated by NaCl and the solution further subfractionated by caprylic acid. In a similar way PEG was associated with the caprylic acid precipitation step. PEG precipitates proteins mainly in function of their molecular weight. However, the enrichment of IgM of the final fraction did not exceed 32% and much IgM was lost under the experimental conditions. It proved easiest to suspend fraction III in distilled water leaving IgM in the precipitate; it is dissolved and the solution submitted to a slightly modified caprylic acid precipitation step. This fraction contains 35-40% IgM, few (2-6%) IgA and about 50% IgG whereas an IgA (35%) enriched fraction is obtained when fraction III is solubilized with acetate at pH 6.2 and then submitted to precipitation by caprylic acid under slightly modified conditions as compared with our standard IgGAM. Thus, simple modifications of the standard procedure allow to prepare fractions enriched more specially in IgM or IgA. Fractions poor or almost devoid of IgG can also be obtained...

Alpha-chain disease with clinical, immunological, and histological recovery.

Clinical, immunological, and histological recovery in a patient with alpha-chain disease is described. The patient, a 27-year-old Greek man, presented with severe steatorrhoea, abdominal pain, oedema, and hypogammaglobulinaemia. Treatment with tetracycline produced only temporary remission. Intermittent therapy with prednisone and cyclophosphamide together with antibiotics was followed by clinical recovery, return of histological appearances of the small intestine to normal, and disappearance of free alpha-chain protein from the serum. The patient remained well one year later without treatment.

Immunoglobulin synthesis in vitro by lymphocytes from patients with immune deficiency: requirements for a special serum factor.

Certain patients with immune deficiency were encountered whose peripheral blood lymphocytes included no immunoglobulin-bearing cells. However, other markers of B type lymphocytes were observed; lymphocytes isolated free of macrophages showed the presence of receptors for the Fc fragment of IgG and for the third component of complement. One patient with a syndrome of thymoma and severe hypogammaglobulinemia was studied in special detail. In vitro the patient's cells were able to develop surface Ig in media supplemented with fetal-calf serum or normal human serum; in media supplemented with autologous serum, the cells developed no surface Ig. During culturing antigenic determinants of immunoglobulin became detectable in the medium, and both medium and cell-surface immunoglobulin underwent a shift from specific IgM determinants early in the culture period to IgG and IgA determinants later. Normal lymphocytes and thymocytes activated by concanavalin A repaired the deficiency in the patient's serum. These data support the concept that a factor possibly derived from T cells is missing from this patient's serum and that this factor is required for the maturation of the B cell for immunoglobulin synthesis.A patient with X-linked agammaglobulinemia had a population of circulating lymphocytes with some surface characteristics that appeared similar to those of the B cells from the patient with thymoma. In contrast, however, no Ig synthesis by this patient's cultured cells could be demonstrated. The possible nature of the lymphocytes reacting with aggregated IgG in this case is discussed.

Immunoglobulin deficiency and regional enteritis.

Two patients combining immune deficiency and an intestinal lesion resembling regional enteritis are presented. One of the patients had severe hypogammaglobulinaemia, the other had selective IgA deficiency. It is concluded that the gastrointestinal lesions presented by our patients represent clinical features that may be associated with immunoglobulin deficiency.

Nongranulomatous Ulcerative Jejunoileitis with Hypogammaglobulinemia

A patient with nongranulomatous ulcerative jejunoileitis with hypogammaglobulinemia was studied. Severe hypogammaglobulinemia was noted to persist despite clinical remission and disappearance of any evidence of protein-losing enteropathy. Despite clinical improvement, the small bowel biopsy continued to demonstrate nonspecific abnormalities. A review of the literature reveals the existence of hypogammaglobulinemia in 4 of 5 cases previously so studied. The persistence of low levels of immunoglobulins raises the possibility that hypogammaglobulinemia may be implicated in the pathogenesis of nongranulomatous ulcerative jejunoileitis.

Surface-bound immunoglobulin on lymphocytes from normal and immunodeficient humans.

By means of immunofluorescence technique, lymphocytes with surface‐bound immunoglobulin were detected in the blood of normal humans F(ab')2, IgM, IgG, IgA, the four IgG subclasses, and the Gm markers Gm(f) and Gm(Z) were demonstrated on cells. IgM was the dominating class, and IgG2 the dominating IgG subclass. The data suggest that the Ig on any one cell belongs to a single class and IgG subclass. Very few lymphocytes stained for antigens on the C‐terminal half of ihe IgG molecule. Ig‐positive lymphocytes were also demonstrated in cord blood and in spleen cell suspensions. An almost total lack of Ig‐positive lymphocytes was demonstrated in the blood of 8 patients with severe hypogammaglobulinemia. The Ig‐positive lymphocytes are thought to be analogous to B‐lymphocytes in other species.

Intestinal nodular lymphoid hyperplasia, hypogammaglobulinemia, and hematologic abnormalities in a child with a ring 18 chromosome

The previously unreported combination of ring 18 chromosome, intestinal nodularlymphoid hyperplasia, severe hypogammaglobulinemia, and bone marrow hypoplasia was found in a deaf and mentally retarded 12-year-old girl. In addition to a quantitative deficiency of platelets, lymphocytes, and neutrophils, functional abnormalities of neutrophils were demonstrated by various recently developed in vitro tests. Defective stem cell maturation and the presence of faulty "bursal-equivalent" tissue are postulated as the basis for the hematologic and immunologic abnormalities.

Correlation between electrophoretic mobility and heavy chain sub-classes of residual IgG from patients with severe hypogammaglobulinaemia.

The correlation between the electrophoretic mobility of residual IgG in hypogammaglobulinaemic sera and the distribution of IgG sub-classes was studied. It was found that IgG from sera with raised levels of IgG2 show fast electrophoretic mobility, and sera with very low or absent IgG2 show a slow moving IgG. IgG3 was absent or just detectable in fast moving IgGs, and present in higher titers in some slow IgGs.

Hypogammaglobulinemia With Nodular Lymphoid Hyperplasia of the Small Bowel

Gastrointestinal symptoms occur frequently in patients with hypogammaglobulinemia. Rosen and Janeway reported that more than half of the patients with acquired hypogammaglobulinemia had diarrhea or steatorrhea.1In contrast, these symptoms occurred rarely in patients with the congenital form of hypogammaglobulinemia. The histology of the small intestine usually has been normal although a spruelike pattern has been noted occasionally. Recently, a syndrome of chronic diarrhea and dysgammaglobulinemia associated with numerous hyperplastic lymphoid nodules in the submucosa of the small bowel has been described.2 We have recently had an opportunity to study an additional example of this disorder and to characterize further the nature of the immunological defect. In the present case, the principal gastrointestinal symptom was bleeding and there was no evidence of malabsorption. The patient had severe hypogammaglobulinemia involving all three major immunoglobulins, without any demonstrable defect in the processes of cellular immunity. Patient Summary A 26-year-old white

A case of vaccinia necrosum (or progressive vaccinia), with severe hypogammaglobulinaemia, treated with n-methyl isatin beta-thiosemicarbazone (33T57).

A fatal case of vaccinia necrosum treated with antivaccinial gamma globulin and N-methyl isatin beta-thiosemicarbazone (33T57) is described. Histological abnormalities found at necropsy included intranuclear as well as cytoplasmic inclusion bodies, absence of lymphoid germinal centres, grey hepatization, and bronchiolar epithelial hyperplasia. Virus titres were highest in the original skin lesion; virus was also found in the lymph node draining it and in the kidney and the brain. No toxic effects could be clearly attributed to the drug used in treatment.

Wheal and erythema allergy in patients with agammaglobulinemia

Atopic diseases have been reported in patients with low gamma globulin levels, associated with demonstrable skin-sensitizing antibodies in some cases. One patient is reported here who lost previous wheal and erythema sensitivity when she developed a severe hypogammaglobulinemia. Typical atopic dermatitis occurred in 4 of 23 boys with congenital, sex-linked, recessive agammaglobulinemia. No wheal and erythema allergy was demontrable in any of these patients. Attempts to induce the development of skin-sensitizing antibodies to an Ascaris extract in 6 congenital agammaglobulinemic patients were uniformly unsuccessful. These patients did, however, all develop delayed sensitivity to the Ascaris.