Biomedical subjects
D C Adelman
Publications and source records attributed to D C Adelman.
Elevated serum interleukin-6 associated with a failure in B cell differentiation in common variable immunodeficiency.
Interleukin-6 (IL-6/B cell stimulatory factor 2) has been found to drive activated human B-lymphocytes through the final stages of differentiation to become immunoglobulin-producing cells. Most patients with common variable immunodeficiency (CVI) have B-lymphocytes that fail to differentiate into high-rate immunoglobulin-secreting cells in vivo and in vitro. In view of (1) the known effects of IL-6 to promote B-lymphocyte terminal differentiation and (2) the defect in differentiation in B-lymphocytes of patients with CVI, we believed that it was important to analyze the role of this cytokine in patients with CVI. Using an IL-6-dependent murine hybridoma cell line in a bioassay, serum IL-6 levels were determined in 17 patients with CVI and in eight normal control subjects. Thirteen of the 17 patients with CVI exhibited serum IL-6 levels that were twofold to 18-fold higher than the range (mean, +2 SD) of normal control subjects. Spontaneous IL-6 production by peripheral blood mononuclear cells (PBMC) of patients with CVI was significantly higher than that from normal control subjects, whereas lipopolysaccharide maximally stimulated IL-6 production by PBMCs of patients with CVI or PBMCs of normal control subjects was equivalent. A substance inhibitory of IL-6 bioactivity was found in equivalent amounts in sera of both patients and normal control subjects. Sera from patients with CVI with high IL-6 bioactivity were found to have saturated this IL-6 inhibitory substance, thus resulting in large amounts of free IL-6 in the sera. These studies suggest that the failure of B cells from patients with CVI to terminally differentiate into high-rate immunoglobulin-secreting cells cannot be attributed to a decrease in the serum levels of IL-6 and that the increased circulating IL-6 levels in patients with CVI result from hyperproduction rather than decreased use of IL-6. The persistently elevated levels of IL-6 observed in some patients with CVI may secondarily result in the induction of the neoplastic and autoimmune phenomena associated with this disease.
Neuropeptides, mast cells and allergy: novel mechanisms and therapeutic possibilities.
Diverse neuropeptides are released by neuroendocrine and immune cells at the sites of allergic and inflammatory reactions. The neuropeptides and other neuromediators affect functions of smooth muscle, microvasculature and secretory cells, and are potent stimuli of mast cell, lymphocyte and other leucocyte contributions to such reactions. The distinctive immune sources, structures and cellular receptors for neuromediators suggest the possibility of novel pathogenetic mechanisms and levels of pharmacological intervention specific for neuroregulation of immunity and hypersensitivity.
Role of lymphotoxin in expression of interleukin 6 in human fibroblasts. Stimulation and regulation.
IL-6 is a cytokine with a number of biological functions, including stimulation of immunoglobulin synthesis and proliferation of early hematopoietic stem cells. We showed that lymphotoxin stimulated accumulation of IL-6 mRNA in human fibroblasts (W138) in a dose-responsive fashion; tumor necrosis factor-alpha (TNF-alpha) was about threefold more potent than lymphotoxin. Further experiments suggested that stimulation by lymphotoxin was independent of protein kinase C activity, did not require new protein synthesis, and was at least in part a result of increased stabilization of IL-6 mRNA. t1/2 of the IL-6 transcripts increased from 0.3 h in unstimulated cells to 0.85 h in cells stimulated with lymphotoxin. In addition, stimulators of protein kinase C, including phorbol esters and teleocidin, enhanced accumulation of IL-6 mRNA. Cycloheximide (CHX), inhibitor of protein synthesis, also markedly increased levels of IL-6 mRNA. Both CHX and activators of protein kinase C increased by greater than 16-fold the stability of IL-6 mRNA. Further, dose-response studies showed that sodium fluoride (NaF), activator of G-binding proteins, and ouabain, inhibitor of Na+/H+ pump, increased levels of IL-6 mRNA. NaF stimulated IL-6 mRNA levels independent of protein kinase C activity. These results suggest that stimulators of several pathways of signal transduction increase levels of IL-6 mRNA and posttranscriptional stabilization is, in part, the mechanism that many of these signals, including lymphotoxin, use to increase levels of IL-6 RNA.
Acute respiratory emergencies in emergency treatment of the injured athlete.
Exercise and physical fitness are becoming increasingly popular in our society. As a result there are more individuals who are at risk for the development of acute respiratory emergencies associated with sports and athletics. EIB is a common feature of asthma and is characterized by a postexercise fall in FEV1 of more than 10 per cent. Although a variety of medications have been used for the prevention of EIB, cromolyn sodium and inhaled adrenergic agonists have been shown to be the most effective. EIA and cholinergic urticaria are two physical allergies in which hypotension can be brought on by exercise. In some individuals, EIA develops only in association with the ingestion of a particular food. Associated with sports and recreational activities in alpine areas is the risk of developing acute high-altitude medical problems. One of the most dramatic and potentially life threatening is high-altitude pulmonary edema. The management of this condition can be problematic, particularly if rapid descent to lower elevations is not possible. Although rare, spontaneous pneumothorax and pulmonary emboli do develop in the otherwise well-conditioned athlete. These entities must be considered when the physician evaluates any athlete in whom acute cough and dyspnea develop.
Abnormal T-cell subsets in normal persons.
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Retinoic acid induces the differentiation of B cell hybridomas from patients with common variable immunodeficiency.
Human-human B cell hybridomas constructed from B lymphocytes of common variable immunodeficiency (CVI) patients and the nonsecreting cell line WIL2/729 HF consistently secrete low levels of Ig and appear to retain a defect characteristic of the CVI patient's B cells. We assessed the differentiative capacity of retinoic acid (RA) on these hybridomas, as well as on hybridomas constructed from normal B cells and from patients with selective IgA deficiency. RA at concentrations varying between 10(-5) and 10(-9) M augmented IgM secretion 4-20-fold from four of four CVI hybridomas tested, but did not affect Ig secretion from normal or IgA-deficiency hybridomas. In support of this elevated Ig secretion, RA enhanced the de novo synthesis of biosynthetically labeled light (kappa) and heavy (mu) Ig (up to 4- and 15-fold, respectively) in the CVI hybridoma line JK32.1. The increase in IgM synthesis/secretion could not be accounted for by RA-induced alteration in the cell cycle. In inducing this increase in IgM production, RA was found to affect two aspects of Ig gene expression: (a) the steady-state levels of heavy and light chain mRNAs were enhanced, and (b) the processing of mu heavy chain transcripts to the secreted mRNA form became favored over the membrane mRNA form. We also show that expression of Leu-17 (CD38), a surface marker that is re-expressed in the late pre-plasma stage of B cell development, was increased by RA from less than 20% to greater than 90% of the total cell population, with a concomitant 4-10-fold augmentation in the mean fluorescence intensity. Changes in both Leu-17 expression and de novo Ig synthesis were prominent by 24 h, but could be observed as early as 8 h after induction. Taken together, our study demonstrates that RA affects a marked alteration in the differentiated state of the CVI hybridoma clones. This finding suggests that retinoids can enhance the functional capabilities of B cells with defects in maturation and support further studies to evaluate their clinical potential in CVI.
Imipenem cross-reactivity with penicillin in humans.
We examined the potential for IgE-mediated cross-reactivity between the carbepenems, a new class of beta-lactam antibiotics, represented by imipenem, and penicillins. In vivo skin testing with the relevant imipenem and penicillin determinants was undertaken. Having determined the concentrations of imipenem materials that did not induce false positive skin tests in nonpenicillin-allergic control subjects, we tested 40 subjects with a history of penicillin-allergic reactions. Twenty of these subjects were found to be nonallergic to penicillin on skin testing, and none of these subjects reacted to the imipendem determinants. In contrast, half the 20 subjects who were positive to one or more penicillin determinants also reacted to imipenem reagents. There was a good correlation between the penicillin and imipenem reagents to which the patients reacted. Imipenem should only be administered to penicillin-allergic subjects with similar precautions of penicillin administration to such patients.
Fixed cutaneous eruptions to seminal-plasma challenge: a case report.
Reactions to human seminal plasma may present as immediate hypersensitivity, cell-mediated hypersensitivity, or fixed eruptions. There are no typical responses to semen. An abnormal skin lesion or systemic response after intercourse may be the only clue to identifying those who are reacting to semen. The use of condoms has proven to be the most consistent preventive modality. However, the use of condoms is unacceptable to some regardless of the relief provided. Although conventional therapy for hypersensitivity reactions to human seminal plasma is suboptimal, one should be aware of MA in the treatment of an atypical cause of human seminal plasma induced reactions.
Update on asthma therapy.
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Thirty-four-year delayed-onset lupus nephritis: a case report.
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Immediate hypersensitivity reactions to beta-lactam antibiotics.
Allergic reactions to the beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) are a major factor limiting their use. Immediate hypersensitivity reactions to penicillins depend on the presence of preformed allergic (IgE) antibodies to several penicillin determinants. These materials can be used in in-vivo skin testing to exclude those patients at risk for immediate or accelerated allergic reactions. The cephalosporins have not had their relevant determinants defined as related to allergic reactions. The results of in-vivo challenges of patients with IgE to penicillin suggest the incidence of reactivity of cephalosporins in patients allergic to penicillin is less than generally appreciated. The monocyclic beta-lactam antibiotic, aztreonam (a monobactam), failed to show cross-reactivity with penicillin antibodies, because immune reactivity toward the monobactam was directed against side chain rather than nuclear determinants. On the other hand, the new bicyclic carbapenem beta-lactam drugs, represented by imipenem, showed extensive in-vivo cross-reactivity with penicillins.
Recurrent bacterial infections and cellulitis in a 29-year-old woman with a history of hypogammaglobulinemia.
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The neuropsychiatric manifestations of systemic lupus erythematosus: an overview.
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Generalized motor seizure following metrizamide cisternography.
Metrizamide is a water-soluble contrast medium used as a diagnostic tool in myelography and cisternography. Despite its accepted safety, its use has been associated with generalized motor seizures, and several cases of this toxicity have been reported. Risk factors include phenothiazine ingestion, seizure history, and large doses of the contrast material. Abnormal electroencephalographic wave patterns, as well as seizure activity, are less frequent after cisternography than myelography. A case of a metrizamide-induced generalized motor seizure following cisternography is reported in a patient with none of the above risk factors. The need for a thorough medication history and the use of prophylactic anticonvulsants in selected patients is discussed.
Macrophage-mediated inhibition of melanoma cell growth in nude mice.
The effects of macrophages or sera from tumor-transplanted or control syngeneic and allogeneic mice on the latency and growth rate of P51 murine melanoma cells were determined after transplantation into congenitally athymic (nude) mice (tumor neutralization test). Syngeneic macrophages from tumor-bearing mice (TBM) inhibited melanoma growth in the nude mouse more than control macrophages, additionally macrophages from sensitized allogeneic mice inhibited melanoma growth to a greater degree than did allogeneic control macrophages. Sera from TBM inhibited melanoma growth as compared to control cells alone. Macrophages obtained after 14 days were also cytolytic towards the melanoma target in vitro. Despite the growth of large local masses, no evidence of distant metastases was found. The nude mouse thus provides an appropriate model for this tumor to portray in vivo immunotherapy.
Humoral immune responses to human lymphoma cell heterotransplants in the central nervous system of athymic, nude mice.
Human malignant lymphoma cells may be readily heterotransplanted into the brains of athymic nude mice. We have examined humoral immune responses to these lymphoma cells and have found a primary cytotoxic IgM and a late cytotoxic IgG response. Nude mice with tumors growing intracerebrally were injected intravenously with fractionated IgM or IgG anti-lymphoma cell antibody obtained from heterozygous immunocompetent animals. Frozen brain sections from these mice stained with fluoresceinated antibodies to mouse IgG and IgM revealed the presence of IgG but no IgM. Thus, IgM could not cross the blood-brain barrier to react with the heterotransplanted lymphoma cells. It is proposed that xenogeneic tumor cells grow readily within the brains of nude mice because these cells are protected from a primary host cytotoxic IgM response by the blood-brain barrier. The blood-brain barrier renders the brain an immune sanctuary within which the impaired cell-mediated immune responses of nude mice are further compromised by the exclusion of a major component of the humoral immune response.
Serum IgE level drives basophil and mast cell IgE receptor display.
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