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C M Roifman

Publications and source records attributed to C M Roifman.

87 records · Page 5Linked to original sources
PubMed1988

Functional differences between immunoglobulins M and D expressed on the surface of an immature B-cell line.

Crosslinked IgM molecules expressed on the surface of immature B cells mediate responses that inhibit further development, in contrast to the activational and proliferative events that follow crosslinking of the mu heavy chain in mature B cells. Concomitant with this change in IgM signaling capacity is the appearance of surface IgD, which has been proposed to modulate the response elicited by the mu heavy chain. In an attempt to gain insight into the mechanism(s) by which surface IgM is able to generate such disparate responses, delta heavy chain gene transfectants of the murine B-cell lymphoma line WEHI-231 were established. WEHI-231 cells resemble phenotypically immature B cells, in addition to being highly susceptible to the growth-inhibitory effect of surface IgM cross-linking. Endogenous mu and exogenous delta heavy chains expressed on the surface of the transfectants were compared for their role in cell proliferation and on gene expression. Our results indicate that the growth-inhibitory response is associated only with the mu heavy chain and that surface IgD does not mediate such a response. Furthermore, in contrast to IgM, IgD molecules appear to have an inductive effect on the expression of Myc and the endogenous mu and exogenous delta Ig heavy chain genes but not on the expression of the housekeeping gene encoding beta 2-microglobulin. These findings suggest that IgM and IgD are functionally distinct when expressed on the surface of an immature B cell.

Animals↗
PubMed1988

Replacement therapy with high dose intravenous gamma-globulin improves chronic sinopulmonary disease in patients with hypogammaglobulinemia.

In the last 30 years patients with antibody deficiency have benefited remarkably from regular replacement therapy with intramuscular immune serum globulin. In a proportion of patients this approach has not been successful in preventing sinopulmonary infections and progressive deterioration. The introduction of preparations of immune serum globulin suitable for intravenous administration provided the potential for examining the effects of achieving higher serum IgG levels. We have therefore evaluated and compared high vs low dose therapy in patients with hypogammaglobulinemia and sinopulmonary disease. To achieve minimum trough serum IgG levels of 500 mg/dl, we administered 0.6 g/kg every 4 weeks. High dose therapy proved efficacious in reducing symptoms, decreasing the frequency of major and minor infections and significantly improving pulmonary function. The improvement appeared to correlate with a marked reduction in the isolation of Mycoplasma, particularly Urea-plasma urealyticum, an important cause of infection in patients with hypogammaglobulinemia. High dose therapy with immune serum globulin suitable for intravenous administration appears to be the treatment of choice in patients with sinopulmonary disease.

Adolescent↗
PubMed1987

High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease.

In a randomised cross-over study 12 patients with antibody deficiency and chronic lung disease received monthly infusions of either 0.6 g/kg or 0.2 g/kg intravenous immunoglobulin for six months, and were then switched to the alternative dose for a further six months. Although the incidence of infections did not differ greatly in the high-dose and low-dose phases, the frequency of acute infection was substantially reduced in those periods when serum IgG was 500 mg/dl or more. Pulmonary function worsened on the low-dose regimen and improved on the high-dose regimen.

Acute Disease↗
PubMed1987

Induction of human B cell proliferation and differentiation by the combination of phorbol ester and ionomycin.

Phorbol esters and Ca2+ ionophores are known to mimic intracellular messengers involved in cell activation. We studied the effects of 12-O-tetradecanoylphorbol 13-acetate (TPA) and ionomycin on tonsil and peripheral blood-derived B lymphocytes. We show that TPA and ionomycin are co-mitogenic and induce B lymphocyte differentiation. Although TPA in high concentrations is mitogenic to B lymphocytes by itself, submitogenic concentrations of TPA in combination with ionomycin trigger 50% of B lymphocytes to synthesize DNA. Stimulation of B lymphocytes with TPA plus ionomycin resulted in increased magnitude and a shift in the kinetics of c-fos and c-myc expression compared with either agent used alone. Activation markers such as the transferrin and interleukin 2 (IL2) receptors were markedly increased after 24 h incubation with TPA and ionomycin. In parallel to the rapid proliferative burst, we observed evidence for B lymphocyte differentiation with an increase in the number of cells expressing cytoplasmic immunoglobulin (Ig) and the disappearance of the B1 surface marker. Since the cells remained surface Ig+ and secreted only small quantities of Ig, our results suggest that the combination of TPA and ionomycin is a potent inducer of B cell proliferation and early differentiation; terminal differentiation to an Ig-secreting state, however, is not achieved.

Antigens, Surface↗
PubMed1987

Response of human B cells to different anti-immunoglobulin isotypes: absence of a correlation between early activation events and cell proliferation.

Cross-linking of surface immunoglobulin (sIg) by antibodies against IgM, IgG and IgD activates B cells and in some circumstances can induce cell proliferation. We studied the potential link between anti-Ig-induced changes in the cytosolic free Ca2+ concentration ([Ca2+]i), inositol phosphate production and the ability to induce cell proliferation in the presence or absence of the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Anti-IgM, but not anti-IgD or anti-IgG, induced cell proliferation in the presence but not the absence of TPA. Each of the antibodies induced a rapid increase in [Ca2+]i which appeared to be due to release of Ca2+ from internal stores. This was followed by a sustained increase in [Ca2+]i, apparently due to Ca2+ uptake from the extracellular medium. Anti-IgD induced the greatest increase in [Ca2+]i, anti-IgM induced intermediate changes and anti-IgG the lowest change. Since inositol 1,3,5-trisphosphate (IP3) can release Ca2+ from internal stores, we tested the ability of each anti-Ig isotype to increase concentrations of IP3. In contrast to the change in [Ca2+]i and proliferation, anti-IgG induced the most significant increase in IP3 concentrations. Taken together these data indicate that changes in [Ca2+]i, inositol phosphate production and anti-Ig-induced human B cell proliferation are not directly linked. They also demonstrate that changes in [Ca2+]i, inositol phosphate production and activation of protein kinase C are not sufficient to induce proliferation of human B cells. It appears that anti-IgM induces an additional Ca2+-independent, inositol phosphate-independent and protein kinase C-independent activation signal which can collaborate with TPA to induce B cell proliferation. The molecular events involved in this signal remain to be identified.

Antibodies, Anti-Idiotypic↗
PubMed1986

Corticosteroids for prevention of adverse reactions to intravenous immune serum globulin infusions in hypogammaglobulinemic patients.

Severe adverse reactions to intravenous immune serum globulin occurred repeatedly in four of 10 hypogammaglobulinemic patients. Treatment-limiting symptoms included fever, chills, headache, hypertension, and chest pain. Pretreatment of patients with hydrocortisone immediately prior to infusion prevented subsequent adverse reactions and permitted these patients to receive immune serum globulin intravenously.

Adult↗
PubMed1986

Increased susceptibility to Mycoplasma infection in patients with hypogammaglobulinemia.

The incidence and morbidity of Mycoplasma infections were examined in a group of 23 patients with hypogammaglobulinemia. Among this group of patients, 18 had one or more episodes of acute respiratory illness during which Ureaplasma urealyticum, Mycoplasma orale, or Mycoplasma pneumoniae were isolated from sputum. Resolution only followed institution of specific antibiotic therapy and elimination of the Mycoplasma. In addition to respiratory illness, U. urealyticum was isolated from the urine of two patients with urinary tract infection and from an area of cellulitis in another patient. M. pneumoniae was isolated from the joint of a patient with arthritis. In six patients with chronic lung disease, Mycoplasma was frequently isolated and clinical improvement, albeit transient, coincided with negative Mycoplasma culture results. These findings emphasize the unique susceptibility to Mycoplasma infection in patients with hypogammaglobulinemia.

Adolescent↗
PubMed1986

Mitogenic response of human thymocytes: identification of functional Ca2+-dependent and independent signals.

In contrast to peripheral blood mononuclear cells (PBMC), human thymocytes do not exhibit a proliferative response to the T cell mitogens phytohaemagglutinin (PHA), concanavalin A (Con A), or Staphylococcal protein A (SPA). In thymocytes and PBMC, Con A and PHA induce increases in free cytosolic calcium concentrations [( Ca2+]i). Since both Con A and PHA induce similar increases in [Ca2+]i in thymocytes and PBMC, the absence of thymocyte proliferation was not due to an inability to induce an increase in [Ca2+]i. The lack of proliferative response was secondary to the failure of the mitogens to induce interleukin 2 (IL-2) production. Incubation of mitogen-treated thymocytes with phorbol esters reconstituted IL-2 production and the proliferative response indicating that the cells were indeed activated by the mitogens. Similarly, addition of exogenous recombinant IL-2 also induced mitogen-treated thymocytes to proliferate. This IL-2-dependent proliferation established that SPA, Con A, and PHA triggered the expression of biologically active IL-2 receptors. Since an increase in [Ca2+]i is a prerequisite, and possibly a trigger, for IL-2 production, the failure of PHA, Con A, or SPA to result in thymocyte proliferation may be due to an inability of thymocytes to respond to increases in [Ca2+]i with subsequent IL-2 production.

Calcium↗
PubMed1985

Functional comparison of recombinant interleukin 2 (IL-2) with IL-2-containing preparations derived from cultured cells.

Due to its purity and potential availability in large amounts, human recombinant interleukin 2 (IL-2) expressed in Escherichia coli is an important source of IL-2 for experimentation and possible therapy. To date, very few comparisons between the activity of recombinant IL-2 and conventional cell-derived preparations of IL-2 have been made. This is particularly important since the use of recombinant IL-2 may have some specific limitations. For example, recombinant IL-2 is not post-translationally modified as are cell-derived preparations. Lack of modifications such as glycosylation of threonine 3 may alter efficacy or stability. Comparative studies are necessary to demonstrate the efficacy, species specificity, and stability of recombinant IL-2. By comparing IL-2 activity of recombinant IL-2 to that of cell-derived IL-2, we have demonstrated that each of the preparations are equally active in several murine and human IL-2 proliferation assays and that IL-2 is the active moiety in these assays. In contrast to previous reports, we also show that recombinant IL-2 is sufficient to establish and maintain long-term cell lines. Additionally, by using "synthetic" recombinant IL-2 of defined protein sequence, we have demonstrated that this amino acid-defined structure is indeed responsible for the functions attributed to IL-2.

Animals↗
PubMed1985

Benefit of intravenous IgG replacement in hypogammaglobulinemic patients with chronic sinopulmonary disease.

Seven patients with hypogammaglobulinemia and chronic sinopulmonary infections were treated with a preparation of intravenous gammaglobulin. In order to maintain levels of serum IgG at greater than 500 to 750 mg/dl four weeks after infusion, 0.6 g/kg was administered every month. Stable serum levels were achieved after three to eight months. After six to 12 months of this regimen, there was significant reduction in acute infections requiring hospitalization, amelioration of clinical and radiographic evidence of chronic maxillary sinusitis, and improvement in pulmonary symptoms and pulmonary function test results. The administration of increased amounts of IgG intravenously is of benefit in patients with chronic sinopulmonary infections.

Adolescent↗