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Biomedical subjects

R S Geha

Publications and source records attributed to R S Geha.

At least 181 records · Page 10Linked to original sources
PubMed1988

Fatal varicella in steroid-dependent asthma.

Disseminated varicella infection is a potentially life-threatening complication of chronic high-dose corticosteroid (CS) or immunosuppressive therapy. A review of the literature indicates that, with one possible exception, this complication has not occurred in a CS-dependent subject with asthma. We present in this article the clinical features and autopsy findings of a steroid-dependent subject with asthma who died of acute, disseminated varicella. A 16-year-old poorly compliant, steroid-dependent subject with asthma received two courses of high-dose intravenous methylprednisolone during a 3-week period, followed by a tapering schedule of oral prednisone. During this time, she was exposed to chickenpox. She subsequently developed a classic varicella rash, sever back pain, rapidly progressive hepatic failure, pneumonitis, and encephalopathy. Death ensued 3 days after the onset of the rash. Evidence of disseminated varicella infection was confirmed at autopsy. This case illustrates that a small number of subjects with severe asthma receiving high-dose CS need to be considered as a separate, high-risk group for developing disseminated varicella. We recommend that the immune status of these patients to varicella-zoster virus be assessed by a serum titer. If these patients are nonimmune, they would be candidates for varicella-zoster immune globulin on exposure, and for acyclovir therapy should varicella dissemination occur.

Adolescent↗
PubMed1988

Impaired antibody responses in the hyperimmunoglobulin E syndrome.

Patients with the hyper-IgE (HIE) syndrome have recurrent bacterial infections with Staphylococcus aureus and other polysaccharide encapsulated organisms. To determine whether an impairment of the antibody response to polysaccharide antigens contributes to infections in this syndrome, we measured serum antibody to the teichoic acid of S. aureus and to the capsular polysaccharide of Haemophilus influenzae type b. Compared to control subjects who had no history of S. aureus infections (N = 14), sera from patients with HIE (N = 9) lacked the expected elevation of serum antibody to teichoic acid (p greater than 0.05) and had significantly lower levels of this antibody than sera from 14 patients with atopic dermatitis, complicated by recurrent cutaneous S. aureus infections (p less than 0.01). After immunization with the capsular polysaccharide of Haemophilus influenzae type of vaccine, the antibody response of patients with HIE was significantly impaired compared to that of age-matched control subjects (p = 0.01). Although patients with HIE syndrome had normal total IgG levels, most patients with HIE but not patients with atopic dermatitis had IgG2 subclass deficiency. Defective antibody responses in patients with HIE were not restricted to polysaccharide antigens because the serum levels of antitetanus toxoid antibody in these patients were significantly lower than that of control subjects (p less than 0.001). Impaired antigen-specific antibody responses in patients with HIE syndrome may contribute to their increased susceptibility to infection.

Adolescent↗
PubMed1988

IgE response and its regulation in allergic diseases.

The distinguishing feature of the allergic person is his or her elevation of serum IgE. This propensity to develop a sustained IgE response is determined genetically. The biologic effects of IgE are mediated via Fc receptors (Fc epsilon R) present on mast cells and basophils (Fc epsilon R type 1) and subpopulations of monocytes, macrophages, eosinophils, and platelets (Fc epsilon R type 2). Interaction of allergen with IgE on these cells results in receptor "bridging" and the release of histamine and other inflammatory mediators. Fc epsilon R type 2 on lymphocytes and monocytes are upregulated in atopic disease and may play a role in the allergic inflammatory reaction. The activation of B cells to synthesize IgE requires several stages (see Fig. 2). T cells play an important role in the regulation of IgE synthesis. In vitro activation of resting B cells to synthesize IgE requires direct cellular interaction with T cells or the presence of IL4 for activation. The latter effect is inhibited by alpha-interferon. Preactivated B cells are influenced in an isotype-specific manner by T-cell-derived IgE binding factors (IgE-BF), which may act as IgE-potentiating or IgE-suppressive factors, depending on their degree of glycosylation. The regulation of IgE synthesis is an important area of investigation. It provides us with an understanding of the basis of the human allergic response and ultimately may provide the basis for novel strategies in the treatment of allergic diseases.

Antibodies, Anti-Idiotypic↗
PubMed1988

Antibody deficiency syndromes and novel immunodeficiencies.

Antibody deficiency syndromes can be quantitative or qualitative. The major categories of antibody deficiency syndrome are: (1) X-linked agammaglobulinemia, involving the maturation arrest in the development of the B cells; (2) transient agammaglobulinemia, which affects both sexes is often associated with defective T helper function for immunoglobulin production; (3) acquired agammaglobulinemia, a heterogeneous disorder caused by a primary B cell defect, absence of B cells, presence of B cells but with an activation defect, failure of helper factor production by T cells or increase in suppressor cells; (4) IgG2 and IgG3 subclass deficiencies, causing significant and recurrent infections and, with IgG2, a significant impairment of the ability to respond to carbohydrate antigens such as Haemophilus influenzae, pneumococcus and meningococcus; (5) qualitative antibody deficiency syndrome in the response to carbohydrate antigens, presenting as recurrent infection and involving the inability of the patient to respond to immunization with polysaccharide antigens such as Haemophilus influenzae type b; (6) antibody deficiency states associated with T cell dysfunction. Impairment of T cell function, which is required for B cell activation, presents often as antibody deficiency syndrome. In these cases, total gamma-globulin level is normal, but the quality of the antibody is very poor.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Clinical and immunologic aspects of the hyperimmunoglobulin E syndrome.

The HIE syndrome is a rare disorder characterized by extremely high serum IgE levels; recurrent serious infections, primarily involving the skin and sinopulmonary tract; and chronic eczematoid dermatitis dating from early infancy. The most common organisms that infect these patients are S. aureus and C. albicans. In addition, they have increased susceptibility to infection with H. influenzae, S. pneumoniae, enteric gram-negative rods, herpesviruses, and a variety of fungal organisms. The infections are frequently deep-seated, with abscess formation in the case of skin infection and pneumatocele formation in the case of pneumonias. Osteomyelitis, septic arthritis, and visceral abscesses are also seen but less frequently. Associated features of this syndrome are coarse facies, growth retardation, osteoporosis, keratoconjunctivitis, and eosinophilia. The immunologic basis of the HIE syndrome is still speculative. It is believed that the elevated IgE levels reflect a T-cell imbalance characterized by T-cell activation and a deficiency of suppressor T cells to inhibit IgE production. The propensity for recurrent infection may be related to a unique abnormality in the humoral immune system: excessive production of IgE directed to S. aureus and other infectious organisms with a concurrent deficit in their ability to synthesize protective IgG antibody against the same organisms. The fluctuating neutrophil chemotactic abnormality found in these patients may be secondary to the underlying T-cell defect with secretion of chemotactic inhibitor substances from mononuclear cells. Alternatively, the interaction of infectious agents with IgE on the surface of Fc epsilon R-bearing immune effector cells results in the release of inflammatory mediators that impair local host immune response. Activation of the immune system may also contribute to the associated features in this syndrome via the secretion of mediators that regulate connective tissue production and bone mineralization. Further studies will be needed before we completely understand the pathogenesis of HIE syndrome. Therapy primarily involves use of prophylactic anti-S. aureus antibiotics and the use of intravenous antibiotics, antifungal agents, or antiviral agents during acute infections. Surgical drainage or resection of deep-seated infections are frequently indicated. In patients who do not respond to conservative management, there may be a role for intravenous gammaglobulin and/or plasmapheresis.

Antibody Formation↗
PubMed1988

IgG antibody response to polysaccharides in children with recurrent infections.

IgG2 subclass deficiency associated with poor antibody response to polysaccharide antigen is a now well-described entity. A newer entity which appears to be at least as common is the recurrent infection with a selective deficiency in the antibody response. At the present time, the antibody response to Haemophilus influenzae type b (Hib) is a good marker for the selective antibody deficiency in these children, as the vast majority of such children made a very poor antibody response to Hib. The data suggest that treatment of these children with prophylactic antibiotics and/or with IV gamma-globulin, depending on the clinical situation, is beneficial. This reinforces the view that the observed abnormality in the antibody response may be causally related to the recurrent infections. Prospective studies of the 10% of 'normal' children who fail to respond to soluble polysaccharide antigen would reveal if there is within this group a higher incidence of recurrent infections. The result of such studies will be important in our understanding of normal as well as abnormal selective antigen-specific antibody deficiencies in children.

Antibody Formation↗
PubMed1987

The presence of IgE on macrophages and dendritic cells infiltrating into the skin lesion of atopic dermatitis.

Monoclonal antibodies reactive with human IgE were used to investigate the presence of surface IgE in situ on mononuclear cells infiltrating into the skin lesion of atopic dermatitis (A.D.) by application of the immunoperoxidase technique to tissue sections for light and electron microscopic examination. A substantial proportion of infiltrating macrophages but not of lymphocytes were found to bear IgE on their cell surfaces. These observations raise the possibility that IgE may contribute to the skin inflammation associated with A.D. via non-mast-cell-mediated immune mechanisms. We hypothesize that allergens introduced into the skin lesion of A.D. are potentially capable of interacting not only with IgE-bearing mast cells but also with IgE-bearing macrophages and dendritic cells to cause the release of inflammatory mediators.

Adolescent↗
PubMed1987

Requirement for mitogen, T cell-accessory cell contact, and interleukin 1 in the induction of resting T-cell proliferation.

The role of interleukin 1 (IL-1) and accessory cells (AC) in mitogen-driven, resting human peripheral blood T lymphocyte proliferation was examined utilizing highly purified T-cell preparations. Such preparations fail to respond to optimal concentrations of the lectin phytohemagglutin (PHA) or interleukin 2 (IL-2), indicating the functional depletion of monocytes (Mo.) and of activated T cells, respectively. The requirement for Mo. and IL-1 was quantitatively determined by adding known loads of Mo. and of recombinant human IL-1 alpha or beta forms (r-hIL-1, alpha/beta) to T-cell preparations and monitoring the resultant proliferative responses to the mitogens PHA, concanavalin A (Con A), the anti-CD3 monoclonal antibody (mAb) Leu 4, and Sepharose beads-linked Leu 4. Although some mitogens induced IL-2r gene transcription and surface expression in T cells, all mitogens tested failed to drive T cells to proliferate in the absence of Mo. r-h IL-1, as well as Mo.-conditioned media, failed to support the proliferation of mitogen-treated T cells. However, r-h IL-1 significantly amplified the proliferative responses of mitogen-treated T cells when suboptimal loads of Mo. were added. Both r-h IL-1 alpha and beta forms behaved identically in all the aforementioned experiments. The necessity of T cell-Mo. contact for T-cell proliferation was established by demonstrating that T cells separated from Mo. by a semipermeable membrane which allowed free diffusion macromolecules failed to proliferate to the mitogens tested. In contrast to lectins and anti-CD3 mAb phorbol-12-myristate-13-acetate (PMA) induced on its own a modest proliferative response which was greatly enhanced by r-h IL-1 independent of the addition of monocytes. The mechanism of r-h IL-1 action in supporting PMA-primed, T-cell proliferation involved the induction of IL-2 synthesis. We conclude that IL-1 does not substitute for the need for Mo. in supporting mitogen-driven T-cell proliferation. Mitogens, direct accessory-T-cell contact, and IL-1 each act, in this order, to bring about resting T-cell proliferation. The distinct behavior of PMA might relate to its ability to substitute for monocyte contact in promoting the progress of T cells through the cell cycle.

Antigen-Presenting Cells↗
PubMed1987

Requirements for activation of human peripheral blood T cells by mouse monoclonal antibodies to CD3.

The present study was undertaken in an attempt to reconcile the conflicting results concerning the signals required for the activation of human resting T cells by antibodies to the T-cell receptor/CD3 complex (Ti/CD3). For this purpose we have used highly purified peripheral blood T cells, depleted of monocytes and of preactivated Ia + T cells, to the extent that they were unable to proliferate to interleukin 2 (IL-2) alone or to optimal doses of phytohemagglutinin (PHA). To further minimize the contribution of contaminating monocytes, we used the anti-CD3 mAb, Leu-4, and cells from Leu-4 nonresponder subjects, whose monocytes we show completely fail to bind the Leu-4 mAb. The parameters of T-cell activation which we measured were rises in intracellular free calcium ion [Ca2+]i, IL-2 receptor expression IL-2 production, and cell proliferation. Our results indicate that induction of proliferation of resting T cells requires at least two signals. Signal one is best delivered by multivalent anti-CD3 mAb, such as Leu-4 mAb covalently linked to Sepharose 4B (Seph-Leu-4), or with Leu-4 mAb and anti-mouse IgG. These reagents crosslink the CD3 receptor complex on the T cell, and result in a rise in intracellular [Ca2+]i, in expression of receptors for IL-2, and in proliferation upon addition of IL-2. In contrast, purified T cells exposed to soluble Leu-4 mAb do not exhibit a rise in intracellular [Ca2+]i, do not express receptors for IL-2, and do not proliferate upon addition of IL-2, indicating that the valency of anti-CD3 mAb is critical for the delivery of the first activation signal to the T cell. The essential step of crosslinking of CD3 antigens on T cells by anti-CD3 mAb is normally mediated by monocytes which have bound anti-CD3 mAbs via their Fc receptors. Monocytes from Leu-4 nonresponder subjects, which we show fail to bind Leu-4 mAb, fail to crosslink CD3 antigens on T cells, resulting in failure of T-cell activation. The second signal needed for the proliferation of T cells whose Ti/CD3 complexes are crosslinked is IL-2. IL-2 production by such T cells required a monocyte delivered signal, which must be delivered to these T cells simultaneously with the crosslinking of their Ti/CD3 antigens. This IL-2-inductive signal can be delivered by both Leu-4 nonresponder and Leu-4 responder monocytes, indicating that delivery of this IL-2 inductive signal is independent of anti-CD3 mAb binding by monocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1987

Regulation of the human allergic response.

Over the last several years our laboratory has been engaged in the in vitro study of the regulation of IgE synthesis. We have found that polyclonal B cell activators fail to induce IgE synthesis in human B cells. Alloreactive T cell helper clones induced synthesis in B cells only under conditions of interaction and in B cells from allergic donors under cognate conditions of bystander stimulation as well. Isotype-specific regulation of the IgE response was mediated in the secretion of IgE-binding factors by T cells suppressing Fc receptors for IgE. Finally, IgE immune complexes in sera from patients with hyper-IgE states were shown to downregulate T cell proliferation to antigen and to stimulate monocytes to resorb 45Ca-labelled bone and to release prostaglandins. The implications of these in vitro findings for disease states in which IgE is elevated are discussed.

B-Lymphocytes↗
PubMed1987

Recombinant human IgE.

The gene for a human epsilon chain Fc fragment has been cloned and expressed at a high level in Escherichia coli, and its biological activity in binding to the high-affinity receptors on mast cells and basophils and mediating histamine release has been examined in a variety of assays, including the inhibition of passive cutaneous anaphylaxis in human skin, which was induced by ragweed immunoglobulin IgE antibody and antigen. The positive results obtained in these assays encouraged us to try to analyse the binding site on IgE by site-directed mutagenesis. We describe deletion mutants here that narrow down the binding site on IgE for the mast cell receptor to a stretch of 76 amino acids (residues 301-376 on the ND epsilon chain) spanning the CH2 and CH3 domains. This peptide displays activity in the human skin test indistinguishable from that of a myeloma IgE.

Basophils↗
PubMed1987

Reversal of lymphocyte activation in vivo in the Kawasaki syndrome by intravenous gammaglobulin.

The effect of intravenous gammaglobulin (IVGG) on the immunoregulatory abnormalities found during acute Kawasaki syndrome (KS) was studied in a randomized trial of IVGG plus aspirin (ASA) versus ASA alone. Before therapy, patients in each treatment group had increased numbers of circulating HLA-DR-bearing Leu 3+ helper T cells, a deficiency of Leu 2+ suppressor/cytotoxic T cells, and increased levels of spontaneous IgG and IgM synthesis by peripheral blood mononuclear cells. There were no significant differences (P greater than 0.1) between immunologic parameters measured on day 1 and day 4 in the ASA-treated group. In contrast, patients treated with ASA plus IVGG had by day 4 a highly significant decrease in HLA-Dr+ Leu 3+ helper T cells (P less than 0.001), an increase in Leu 2+ suppressor/cytotoxic T cells (P less than 0.01), and a decrease in spontaneous IgG (P less than 0.01) and IgM synthesis (P less than 0.001). These changes were associated with a reduction in the secretion of T cell-derived B cell helper factors (P less than 0.001). These findings indicate that treatment with IVGG suppresses the marked T and B cell activation found in patients with acute KS.

Antibodies, Monoclonal↗
PubMed1987

Crossreactivity and inheritance of idiotypes restricted to human anti-tetanus toxoid antibodies.

The presence of cross-reactive idiotypes on human IgG antibodies of tetanus toxoid (TT) antigen was assessed by examining the capacity of two anti-idiotypic (ID) antisera raised against IgG (Fab')2 anti-TT (idiotype) from two subjects to bind radiolabeled "idiotype" and to inhibit the binding of radiolabeled TT to IgG from unrelated subjects and from family members of the idiotype donors. Idiotypic crossreactivity with unrelated individuals was infrequent and weak but was frequent and stronger among siblings. The strongest idiotypic crossreactivity was seen between identical twins in studies using four anti-ID raised against the anti-TT idiotypes of two sets of twins. The results of the present study suggest that idiotypic determinants restricted to human anti-TT antibodies are, at least in part, encoded by inherited genes, which are infrequently shared among unrelated individuals.

Antibodies↗
PubMed1987

Regulation of the human IgE antibody response.

The frequent association of elevated serum IgE in patients with T cell immunodeficiencies suggest a role for T cells in the regulation of the human IgE antibody response. Unlike the situation with other isotypes the polyclonal B cells activators, pokeweed mitogen and Epstein Barr virus, do not routinely induce IgE synthesis in normal B cells. However, B cells from normal donors will synthesize immunoglobulins of all isotypes (including IgE) when cultured with T cell clones that recognize determinants expressed on the B cells (cognate stimulation). T cells with Fc receptors for IgE can be isolated from patients with hyper IgE syndrome and maintained as long term continuous T cell lines. These cells secrete IgE binding factors which enhance IgE synthesis but not IgG synthesis by preactivated IgE bearing B cells from allergic subjects but not resting B cells from normal donors. IgE binding factors isolated from sera of normal donors selectively suppress IgE synthesis. In contrast, IgE binding factors isolated from sera of patients with hyper IgE syndrome contain IgE potentiating activity as well as IgE suppressor activity. These results suggest that IgE synthesis in man is activated by T cells and isotype specific secretion of this immunoglobulin is modulated by IgE binding factors.

B-Lymphocytes↗