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Hyper immunoglobulin M immunodeficiency. (Dysgammaglobulinemia). Presence of immunoglobulin M-secreting plasmacytoid cells in peripheral blood and failure of immunoglobulin M-immunoglobulin G switch in B-cell differentiation.

The peripheral blood lymphocytes of nine patients with hyper immunoglobulin (Ig)M immunodeficiency were studied in an attempt to define the cellular basis of this disorder. B cells were normal in number but qualitatively abnormal in all patients. Approximately one-half of the B cell consisted of small lymphocytes (7-9 mum in diameter) bearing surface IgM and IgD, as well as C3 receptors. These cells were driven to secrete IgM but not IgG after in vitro stimulation by pokeweed mitogen. In the blood there were also large lymphocytes (10-14 mum in diameter) that possessed surface as well as intracytoplasmic IgM but lacked C3 receptors. These cells spontaneously secreted large amounts of IgM in vitro and on electron microscopy were found to be rich in rough endoplasmic reticulum. Such a subpopulation of lymphoid cells was not detected in normal peripheral blood and was unique for all patients with hyper IgM immunodeficiency studied.T cells from all patients were normal in number and in function both in vivo and in vitro and were able to generate adequate T-cell help to support IgG synthesis by normal B cells. No evidence was obtained for T cells capable of suppressing normal IgG synthesis in any of the patients after coculture with normal peripheral blood lymphocytes. The defect in hyper IgM immunodeficiency is intrinsic to B cells, which fail to switch from IgM to IgG synthesis.

Adult↗

Intravenous immunoglobulin for treating sepsis and septic shock.

OBJECTIVES: Death from severe sepsis and septic shock is common, and researchers have explored whether antibodies to the endotoxins in some bacteria reduces mortality. This review summarises the effects of intravenous immunoglobulin (IVIG) in patients with bacterial sepsis or septic shock on mortality, bacteriological failure rates, and duration of stay in hospital. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, Medline 1966 to April 1999, EMBASE 1988 to February 1999; we contacted investigators active in the field for unpublished data. SELECTION CRITERIA: Randomised trials comparing intravenous immunoglobulin (monoclonal or polyclonal) with placebo or no intervention, in patients with bacterial sepsis or septic shock. DATA COLLECTION AND ANALYSIS: Inclusion criteria, trial quality assessment, and data abstraction were done in duplicate. We conducted pre-specified subgroup analyses by type of immunoglobulin preparation. MAIN RESULTS: Twenty-three out of 49 studies met our inclusion criteria. Overall mortality was reduced in patients who received polyclonal IVIG (n=413; RR=0.60; 95% CI 0.47 to 0.76). Mortality was not reduced among patients who received monoclonal antibodies such as anti-endotoxins (n=1,736 in 4 good-quality studies; RR=0.98; 95% CI 0.86 to 1.12) or anti-cytokines (n=4,318; RR=0.93; 95% CI 0.86 to 1.01). A few studies measured secondary outcomes (deaths from sepsis or length of hospitalisation) but no differences in the intervention and control groups were identified except among those who received polyclonal IVIG, where sepsis-related mortality was significantly reduced (n=161; RR=0.35; 95% CI 0.18 to 0.69). REVIEWER'S CONCLUSIONS: In our opinion, polyclonal IVIG significantly reduces mortality and can be used as an adjuvant treatment for sepsis and septic shock. Adjunctive therapy with monoclonal IVIGs remains experimental.

Humans↗

Effect of colostral immunoglobulin G1 and immunoglobulin M concentrations on immunoglobulin absorption in calves.

Twenty-three calves were fed colostrum at 110 ml/kg body weight divided into two feedings at 1 and 13 h of age. The concentrations of immunoglobulins were measured in the colostrum fed and in the calves' sera following colostrum feeding. Apparent efficiency of immunoglobulin absorption was calculated for each calf. Significant negative correlations between efficiency of absorption and mass of immunoglobulin fed were observed for both immunoglobulins. A separate group of 225 calves born on a commercial dairy were fed 2.84 L of colostrum by 4 h of age. Concentrations of immunoglobulin G1 in the colostrum fed and in the calves' sera at 48 h were measured. Negative correlation was observed between the efficiency of absorption and the mass of immunoglobulin G1 fed. These results suggest a physiologic limitation to the mass of immunoglobulin that can be absorbed to serum from a given volume of colostrum. No indication of a selective immunoglobulin absorption mechanism was observed.

Animals↗

Receptor-mediated maternofetal transfer of immunoglobulins. Inhibition of transport of anti-HIV-1 immunoglobulin by generic immunoglobulins in the in vitro perfused placenta.

OBJECTIVES: The passage of immunoglobulin G (IgG) across the placenta is thought to involve Fc' receptors on the syncytiotrophoblast. To confirm the receptor dependency of this process we have studied the changes in the tissue content and transfer kinetics of immunoglobulins and hyperimmune serum to HIV (HIVIG) during in vitro dual placental perfusion. METHODS: Isolated lobules of term placentae from normal pregnancies were perfused in a model of maternal and fetal circulation. The perfused tissue was compared to fresh tissue samples from the same placenta for the content of IgG, IgG subclasses, IgM, cytokeratin, human placental lactogen and SP1 antigen by immunohistochemistry and by protein elution. RESULTS: The immunoglobulin staining faded by an average of 40% during the 1st hour of perfusion. In contrast, staining for cytokeratin, human placental lactogen and SP1 remained unchanged. During a 4-hour recycling of endogenous immunoglobulins in the maternal circulation, IgG and HIVIG crossed to the fetal side in a steady rate. The transport of HIVIG could be inhibited by preperfusion with an intravenous gammaglobulin preparation (IVIG). DISCUSSION: The transfer of IgG across the placenta occurs in a steady state rate consistent with a receptor-mediated mechanism. Furthermore, inhibition of HIVIG maternofetal transfer by IVIG further establishes the receptor-mediated transfer of immunoglobulins through the placenta.

Female↗

Cells and mediators which participate in immunoglobulin synthesis by human mononuclear cells. III. Null cells secrete a factor(s) (human immunoglobulin synthesis/secretion-facilitating factor) that can replace the null cells in the synthesis of immunoglobulin by cultured B cells.

In the accompanying communication, it was demonstrated that the null cells, the TM cells, monocytes and PWM are all obligatory participants in the synthesis and secretion of immunoglobulins by human B cells in culture. Here we demonstrate that the null cells secrete a factor, referred to as human immunoglobulin synthesis/secretion-facilitating factor (HISFF) that can replace the null cells in the cultures. HISFF is distinct from the known T cell-derived interleukins. HISFF functions in an HLA-unrestricted fashion since it can facilitate the synthesis and secretion of immunoglobulins by allogeneic B cells. The null cells cultured with TM helper cells and PWM required monocytes in the culture in order to secrete HISFF. Furthermore, B cells cultured with TM cells in medium containing HISFF, monocyte-derived factors and PWM nevertheless required monocytes in order to respond to the HISFF signal. Thus, the monocyte plays a pivotal role in the secretion of and response to HISFF. Normal levels of immunoglobulin were synthesized even when HISFF was added to the cultures of B cells, TM cells and monocytes, in the presence of PWM, as late as day 6 of the 7 day culture. We conclude that the null cells participate in immunoglobulin synthesis by the B cells by secreting a soluble mediator, HISFF, capable of replacing the null cells in the culture; and that the HISFF signal is the last signal received by the B cell before it begins to synthesize and secrete immunoglobulins.

B-Lymphocytes↗

Neutralization of disease associated autoantibodies by an immunoglobulin M- and immunoglobulin A-enriched human intravenous immunoglobulin preparation.

Immunoglobulin preparations enriched with IgM and IgA are used in the therapy of severe bacterial infections and for the treatment of acute graft-versus-host disease, but not as yet, in the treatment of autoimmune diseases. We investigated the potential of an IgM- and IgA-enriched immunoglobulin preparation to neutralize activity autoantibodies from patients with autoimmune diseases. We demonstrate that Pentaglobin(R) was at least as effective as intravenous immunoglobulin (Sandoglobulin(R)) in inhibiting autoantibody activity. Each of the immunoglobulin isotypes present in Pentaglobin(R) may be responsible for the inhibitory effect. Pentaglobin(R) immobilized on an affinity matrix retained the disease associated autoantibodies and interacted with F(ab')2 fragments of IgG autoantibodies. Suppression of autoantibody activity is dependent, at least in part, on idiotypic interactions. The present findings provide a rationale for considering these preparations for the immunomodulation of autoimmune disease.

Autoantibodies↗

Polyclonal hyper-immunoglobulin G1(A1) syndrome. Evidence for a dominant immunoglobulin production regulator within the human immunoglobulin heavy chain gene complex.

The hyper-IgG1(A1) syndrome entails a polyclonal selective increase of the serum levels of immunoglobulin (Ig) G1 and to a lesser extent of IgA1; this is not mediated by malignancy, infectious or autoimmune diseases or environmental agents. In three generations of a family, all the affected individuals carried an immunoglobulin heavy chain (IgH) allele distinguished by restriction fragment length polymorphism analysis; the IgH allele was not present in non-affected family members. A 32:1 chance for the linkage of this rare IgH haplotype with the hyper-IgG1(A1) syndrome in the family argues for a dominant regulator located at the human IgH locus having a selective influence on the production of IgG1 and IgA1.

Female↗

Immunoglobulin deficiency with increased immunoglobulin M in three siblings: effect of long-term immunoglobulin therapy.

Diagnosis of immunoglobulin deficiency with increased IgM (hyper-IgM syndrome) was made in three siblings (two girls and a boy) on the basis of history, physical findings, and laboratory data. The prominent clinical findings were recurrent viral and bacterial infections of the respiratory tract. The most severe infections affected the male patient, who died at the age of 8 years. Family history and the lack of clinical signs in the parents and relatives indicated no immunodeficiency which, together with the occurrence of the disease in both sexes, indicated an autosomal recessive inheritance. The two female patients (18 years old and 3 years old) have been treated with intravenous acid-treated immunoglobulin for 2 years, resulting in significant clinical improvement with respect to the frequency and severity of infections.

Adolescent↗

Measurement of immunoglobulin M, immunoglobulin G, and immunoglobulin A antibodies against Yersinia enterocolitica by enzyme-linked immunosorbent assay: comparison of lipopolysaccharide and whole bacterium as antigen.

An enzyme-linked immunosorbent assay (ELISA) for the detection and quantitation of human immunoglobulin M (IgM), IgG, and IgA antibodies against Yersinia enterocolitica by using lipopolysaccharides as antigens is described. The results obtained with the lipopolysaccharide ELISA were compared with the results of the whole bacterium ELISA. The correlations observed were good for each immunoglobulin class. Cross-reactions between Y. enterocolitica serotypes O:3 and O:9, Yersinia pseudotuberculosis IA, and Brucella abortus were studied by human and rabbit antisera in the whole bacterium and lipopolysaccharide ELISAs and by rabbit antisera using ELISA inhibition. The greatest cross-reactivity observed was that of the anti-Brucella serum with Y. enterocolitica O:9 in the whole bacterium ELISA. In the lipopolysaccharide ELISA this cross-reaction was not demonstrable with the rabbit antiserum, but it was strong with the human antiserum. However, differential diagnosis was possible with ELISA inhibition. On the basis of our experience, we are now routinely using whole bacterium ELISA for the determination of class-specific Yersinia antibodies, and potential cross-reactions are controlled by the ELISA inhibition.

Antibodies, Bacterial↗

Immunoglobulins in NZB-BL mice. I. Serum immunoglobulin levels and immunoglobulin class of erythrocyte autoantibody.

Determination of serum immunoglobulin levels in NZB and normal mice has indicated that an elevation of the gammaM-globulin level occurs in NZB mice. This can be demonstrated in young NZB mice well before other autoimmune manifestations are observed. A slight elevation of gammaM-globulin was also observed in NZB hybrid mice. Erythrocyte autoantibodies were analyzed by the direct Coombs' test with specific antiimmunoglobulin reagents. Autoantibodies in NZB mice can be of all immunoglobulin classes, although predominantly of gammaG(1)-class. In (NZB x NZC)F(1) hybrid mice, although Coombs' positivity develops around the same age as in NZB mice, there is a greater restriction of the autoantibodies into gammaM- and gammaG(1)-classes. Preliminary attempts to quantitate immunoglobulins coating NZB red cells have shown that there are approximately 400 molecules of gammaM and 5000 molecules of gammaG-globulin per NZB mouse red cell.

Animals↗

Cell-associated immunoglobulin in human non-Hodgkin lymphomas. A comparative study of surface immunoglobulin on cells in suspension and cytoplasmic immunoglobulin by immunohistochemistry.

Eighty-three non-Hodgkin lymphomas classified according to the Kiel classification have been studied with regard to surface immunoglobulin (sIg) on cells in suspension and cytoplasmic immunoglobulin (cIg) by the peroxidase anti-peroxidase method (PAP) on formaline-fixed tissue sections. Fifty-six out of 66 examined (i.e. 85%) revealed a monoclonal staining pattern for sIg, whereas 37/70 (53%) gave a monoclonal staining pattern for cIg by PAP. The methods combined gave a monoclonal staining pattern in 73/83, i.e. in 88%, of the biopsies tested. The discrepancies between the two methods were largest in centroblastic/centrocytic and lymphocytic lymphomas. With regard to the light chain staining patterns, complete agreement between the two methods was obtained in the 20 cases that allowed such analysis to be made. This suggests that the specificity of PAP, as carried out in this study with reagents purified by immunoabsorbent techniques, is satisfactory. On a basis of heavy chain isotypes centroblastic/centrocytic, lymphoplasmacytoid, and immunoblastic lymphomas could be divided into distinct immunological subgroups. In four biopsies the sIg heavy chains were mu + delta, whereas mu + gamma chains were detected by PAP. This finding may be relevant to the mu leads to gamma switch known to occur during normal B-cell differentiation. Immunoglobulin inclusions were found in 8 cases--3 belonging to the immunoblastic group, and 5 to the lymphoplasmacytoid group.

Adult↗

Immunoglobulin Fc gamma receptor promotes immunoglobulin uptake, immunoglobulin-mediated calcium increase, and neurotransmitter release in motor neurons.

Receptors for the Fc portion of immunoglobulin G (IgG; FcgammaRs) facilitate IgG uptake by effector cells as well as cellular responses initiated by IgG binding. In earlier studies, we demonstrated that amyotrophic lateral sclerosis (ALS) patient IgG can be taken up by motor neuron terminals and transported retrogradely to the cell body and can alter the function of neuromuscular synapses, such as increasing intracellular calcium and spontaneous transmitter release from motor axon terminals after passive transfer. In the present study, we examined whether FcgammaR-mediated processes can contribute to these effects of ALS patient immunoglobulins. F(ab')(2) fragments (which lack the Fc portion) of ALS patient IgG were not taken up by motor axon terminals and were not retrogradely transported. Furthermore, in a genetically modified mouse lacking the gamma subunit of the FcR, the uptake of whole ALS IgG and its ability to enhance intracellular calcium and acetylcholine release were markedly attenuated. These data suggest that FcgammaRs appear to participate in IgG uptake into motor neurons as well as IgG-mediated increases in intracellular calcium and acetylcholine release from motor axon terminals.

Acetylcholine↗

Screening of a large number of dyes for the separation of human immunoglobulin G2 from the other immunoglobulin G subclasses immunoglobulin G2 enrichment on immobilized Procion Yellow HE-4R.

Human immunoglobulins (IgG) are produced on a multi-ton scale for therapeutic applications. There is presently no available method to manufacture IgG preparations enriched with immunoglobulins from the IgG2 subclass although they might be useful for therapeutic purposes. By frontal chromatography, we have screened 69 immobilized dyes, among which, six display a different affinity for IgG2 and other subclasses. One (Procion Yellow HE-4R) was studied further. The screening of various mobile phase conditions allowed us to devise a procedure to prepare IgG2 enriched IgG solutions: The cumulative yield for IgG2 was 43% and IgG2/total IgG ratio in the final product was 67%.

Affinity Labels↗

Immunoglobulin A nephropathy. Quantitative immunohistomorphometry of the tonsillar plasma cells evidences an inversion of the immunoglobulin A versus immunoglobulin G secreting cell balance.

Primary IgA nephropathy (Berger's disease) is characterized by renal deposits of IgA, the origin of which is still unknown. However, several clinical and biological findings suggest that these immunoglobulins might have a mucosal origin, and that such patients should present mucosal abnormalities. This paper reports the results of the immunohistomorphometrical analysis of tonsillar plasma cells from seven patients suffering from Berger's disease and seven controls also with recurrent tonsillitis. IgG, IgA, and IgM-secreting cells were enumerated after immunofluorescent staining of serial frozen-cut sections from 20 tonsils. In controls, a predominance of the IgG-secreting population, similar to this reported in the literature was observed (65% of IgG secreting cells and 29% of IgA plasma cells), while an inversion in the patients' plasma cells percentages was evidenced (IgG:37%, IgA:56%). This increment in the IgA population was paralleled by an augmentation of the number of dimeric IgA-secreting cells (75% of IgA plasma cells), stained both for cytoplasmic IgA and J chain. In controls, the latter cells were in similar proportions as previously reported by others (45% of IgA plasma cells). These results demonstrate an imbalance in the IgA-producing system of patients with Berger's disease, which is in keeping with the hypothesis favoring a mucosal origin for the mesangial IgA present in their kidneys.

Adolescent↗

Persistence of rubellavirus-specific immunoglobulin M and immunoglobulin A antibodies: investigation of successive serum samples with lowered immunoglobulin G concentration.

The persistence of rubellavirus-specific immunoglobulin (Ig) M and IgA antibodies has been studied in seven patients with primary postnatal rubella infections. Successive blood samples obtained over a period of several years after the onset of disease have been investigated, employing the fluorescent antibody technique and the sucrose gradient centrifugation method. IgM antibodies were found to persist for 4 to 5 weeks after the onset of disease, with only moderate variation being observed with respect to the different patients and the method of investigation being studied. The persistence of IgA antibodies (as examined by the fluorescent antibody technique) varied from a few weeks to several years after the onset of the disease. The detection of IgA antibodies cannot be considered as conclusive for the diagnosis of recent rubella infections.

Adolescent↗

Structural studies of the Xenopus 19S immunoglobulin and 7S immunoglobulin and two immunoglobulin-like proteins.

Xenopus laevis 19S and 7S immunoglobulins (Ig) were extensively reduced and alkylated, their H and L chains spearated and their molecular weights determined. Two kinds of L chains of molecular weight 25,000 and 27,000 were revealed by SDS-polyacrylamide gel electrophoresis. In addition two Ig-like proteins consisting of heavy chains only, of 19S H-type and with similar molecular weight, were detected in Xenopus serum ans isolated. These proteins share common antigenic determinants with Xenopus 19S Ig heavy chains and are devoid of light chain determinants.

Alkylation↗

Monoclonal antibodies against goldfish (Carassius auratus) immunoglobulin: application to the quantification of immunoglobulin and antibody-secreting cells by ELISPOT and seric immunoglobulin and antibody levels by ELISA in carp (Cyprinus carpio).

Monoclonal antibodies (mAbs) raised against heavy and light chains of goldfish immunoglobulin (Ig) were characterized by a Western blot technique. A complete cross-reactivity was observed between carp and goldfish Ig. These mAbs were used for the quantification of carp Ig and anti-Yersinia ruckeri antibodies by ELISA. An ELISPOT assay was also developed in carp to quantify Ig-secreting cells (ISC) and antibody-secreting cells (ASC). The number of ASC was maximum on day 18 post-vaccination and decreased to the basal level on day 28. The antibody levels in sera were maximum on day 18 and slowly decreased until day 28.

Animals↗

Distinct interethnic differences in immunoglobulin G class/subclass and immunoglobulin M antibody responses to malaria antigens but not in immunoglobulin G responses to nonmalarial antigens in sympatric tribes living in West Africa.

The well-established relative resistance to malaria observed in the Fulani as compared with other sympatric tribes in West Africa has been attributed to their higher levels of serum immunoglobulin (Ig) G antibodies to malarial antigens. In this study, we confirm and extend the previous findings by analyses of the levels of IgM, IgG and IgG subclasses of anti-malarial antibodies in asymptomatic individuals of different sympatric tribes in Burkina Faso (Fulani/Mossi) and Mali (Fulani/Dogon). The Fulani showed significantly higher median concentrations of anti-malarial IgG and IgM antibodies than the sympatric tribes at both locations. Although the overall subclass pattern of antibodies did not differ between the tribes, with IgG1 and IgG3 as dominant, the Fulani showed consistently significantly higher levels of these subclasses as compared with those of the non-Fulani individuals. No significant differences were seen in the levels of total IgG between the tribes, but the Fulani showed significantly higher levels of total IgM than their neighbours in both countries. While the antibody levels to some nonmalarial antigens showed the same pattern of differences seen for antibody levels to malaria antigens, no significant such differences were seen with antibodies to other nonmalarial antigens. In conclusion, our results show that the Fulani in two different countries show higher levels of anti-malarial antibodies than sympatric tribes, and this appears not to be a reflection of a general hyper-reactivity in the Fulani.

Adolescent↗