Immunology and immunopathology of trimellitic anhydride pulmonary reactions

Inhaled trimellitic anhydride (TMA) reacts with airway proteins to produce trimellityl (TM) proteins. The TM-proteins result in both systemic and local immune responses, of which various proteins present in the airway can be used for markers. Thus TM-human serum albumin (HSA), TM-IgG, and TM-IgA can be used as hapten-protein complexes for immunologic studies in sera of humans exposed to TMA by inhalation. Various immunologic assays have been established to measure antibodies against TM-proteins and have various purposes. With TM-HSA as a model antigen, total serum antibody may be measured by the ammonium sulfate technique of coprecipitation of TM-¹²⁵I HSA. By solid-phase radioimmunoassays, IgE, IgG, IgA, and IgM antibodies can be measured. Lymphocyte reactivity can be measured by ³H thymidine uptake of TM-protein-stimulated lymphocytes. Biologic effects of IgE antibody can be measured by allergy skin tests and leukocyte histamine release with TM-proteins such as TM-HSA. The reaction of TMA with proteins results in alteration of those proteins that include changes in charge and physical conformation, the latter resulting in an apparent change in molecular size. These changes may relate to the observations that human antibody is not merely directed against the hapten in the hapten-human protein complex but also against new antigenic determinants formed by the TM-protein complex. Correlations have been made with certain human immunologic responses and lung disease after TMA inhalation, as follows: IgE antibody against TM-proteins correlates with TMA-induced rhinitis, conjunctivitis, and asthma; high levels of total antibody, IgG, and IgA antibody appear to correlate with the late respiratory systemic syndrome, probably a variant of hypersensitivity pneumonitis; workers exposed to TMA fumes (rather than TMA powder) have the highest levels of antibody, and this may correlate with occurrence of the hemorrhagic pneumonitis seen in this group of workers; patients with no symptoms or mild irritative symptoms have the lowest or no antibody levels. The immunopathogenetic relationships may be better understood with the further development of animal models of TMA lung disease now available.     

Cytotoxicity of ionophore A23187 for basophils and other human blood cells.

The calcium ionophore A23187(A23) at concentrations exceeding 1 microgram/ml has been shown to be progressively cytotoxic for human blood basophils, neutrophils, lymphocytes, and erythrocytes. Toxicity to basophils was considered to be manifested by the increasing inability of 2-deoxyglucose (2DG) to inhibit histamine release (HR) at increasing concentrations of A23. The toxicity to neutrophils and lymphocytes was demonstrated by decreased lactate production (LP) after incubation with A23 of Ficoll-Hypaque fractions greatly enriched in each respective cell type. Red cells present in dextran-sedimented leukocytes were increasingly susceptible to lysis during washing subsequent to exposure to increasing concentrations of A23. A concentration of 4 microgram A23/ml, which is cytotoxic at 37 degrees C, produced optimal and noncytotoxic HR at 22 degrees C. It was possible to reduce A23 concentrations required for optimal HR by increasing Ca++ from 0.6 to 3 mM.     

Skin testing in farmers' lung disease

Intradermal skin tests with a culture filtrate antigen of Micropolyspora faeni grown on a synthetic medium were performed on patients with farmers' lung disease (FLD) and well farmers with and without antibodies to a panel of FLD antigens. Seventy-five percent of the FLD patients, 79% of the well farmers with M. faeni antibody, and 5% of well farmers without M. faeni antibody had a 2+ or greater intradermal immediate skin-test reaction. Prausnitz-Küstner (P-K) reactions were positive using serum of M. faeni immediate skin test-positive FLD patients. IgG-rich fractions from a staphylococcal protein A-Sepharose column of such serum contained the sensitizing factor whereas IgG-depleted fractions did not. M. faeni—specific IgE could not be detected in serum by a polystyrene radioimmunoassay. Positive late-onset (6-hr) skin tests occurred only in FLD patients and farmers with precipitating antibody. Biopsy specimens of the 6-hr reactions revealed a generalized dermal and perivascular polymorphonuclear infiltrate with deposits of immunoglobulin and complement about blood vessels. The skin-sensitizing factor noted in FLD patients and well farmers with antibody is not disease specific. This factor appears to be associated with the IgG-rich fraction of serum, and its role in the pathogenesis of FLD is unclear.     

Long-term corticosteroid effect on lymphocyte and polymorphonuclear cell function in asthmatics

The effect of long-term alternate-day steroid administration on lymphocyte and polymorphonuclear cell (PMN) functions was studied in 10 steroid-dependent adult asthmatic patients. The duration of alternate-day prednisone usage ranged from 3 to 12 yr with an average of 6.7 ± 3.6 yr. Maintenance steroid dosage at the time of study ranged from 20 to 50 mg on alternate days, averaging 31 ± 8 mg. Prednisone caused marked lymphopenia, suppression of phytohemagglutin (PHA) lymphocyte transformation and PMN adherence 4 hr after ingestion. By 24 hr these measurements returned to normal or higher. These effects appeared at all doses between 20 and 50 mg of prednisone. In contrast, there was no statistically significant suppression of the total leukocyte count, total and active erythrocyte (E) rosette-forming lymphocytes, serum immunoglobulin concentrations, polymorphonuclear cell (PMN) phagocytosis, or delayed skin reactivity. We conclude that the acute effects of prednisone on lymphocyte and PMN function are transient and return to normal levels by 24 hr. The continued administration of beclomethasone dipropionate by inhalation did not interfere with the recovery of the transient leukocyte abnormalities induced by oral prednisone.     

Tranexamic acid: Preoperative prophylactic therapy for patients with hereditary angioneurotic edema

Short-term therapy of 96-hr duration with tranexamic acid was prophylactically effective as defined by the absence of attacks of angioedema in 14 patients with hereditary angioedema undergoing 10 dental and 4 general surgical procedures. Eight of the 14 patients had previously undergone dental extractions without prophylactic therapy with antifibrinolytic agents and each had experienced one or more attacks of angioedema. Seven of these 8 patients had a cumulative experience of 13 episodes of laryngeal edema after dental extractions and the eighth had a bout of cutaneous angioedema. Although the number of dental extractions conducted without prophylactic antifibrinolytic therapy cannot be accurately defined in retrospect, the prominence of laryngeal edema in this circumstance is striking when compared with the absence of attacks in the presence of prophylaxis with tranexamic acid. Methyltestosterone and impeded androgens are now known to be effective prophylaxis for spontaneous and, presumably, postoperative attacks when employed chronically because their administration is associated with correction of the biochemical defect of hereditary angioneurotic edema, but their chronic administration to children and women of childbearing age requires further definition because of their potential pituitary suppressive action. Tranexamic acid prophylaxis makes it possible to offer to untreated patients with hereditary angioneurotic edema dental work and other operative procedures that in the past were withheld or conducted with considerable risk.     

Effect of prostaglandin D2 and I2 on the airways of rhesus monkeys

Prostaglandin (PG) D2 and PGI2 were evaluated to determine their effect on pulmonary function parameters when aerosolized in anesthetized rhesus monkeys. PGD2 resulted in an increase in frequency (f) and pulmonary resistance (rl) and a decrease in peak expiratory flow rate (PEFR), tidal volume (VT), and dynamic compliance (Cdyn), with the major effect on RL. PGI2 primarily effected an increase in f and a decrease in PEFR and VT. PGI2 had a variable effect, generally a decrease, on RL. The metabolite of PGI2, 6-keto-PGF 1 alpha, had no effect on the rhesus airway. PGF 2 alpha responses were similar to PGD2 except that the PGF 2 alpha produced a less strikingly consistent increase in RL. When PGI2 and PGD2 were aerosolized simultaneously, they simulated previously described antigen responses. Further, PGI2 plus PGD2 produced an airway response at 1/10 the concentration of either agent alone.     

The biopsychosocial approach: Clinical examples from a consultation-liaison service

In this second of three articles exploring Engel's biopsychosocial model, five case histories illustrate how psychological factors, sometimes related to organic trauma or illness, may precipitate psychiatric conditions. The patients’ disorders, and their management by a consultation-liaison team, demonstrate the interaction of biologic, psychological, and social systems in assessment and treatment of disease.     

Plasma steroid concentrations during alternate-day treatment with prednisone

Plasma steroid concentrations were measured in asthmatic children 24 and 48 hours after administration of alternate-day treatment with prednisone, and the results were compared with those of control patients who did not receive corticosteroid treatment as well as those of patients who were treated with prednisone each day. It was found that 24 hours after administration of prednisone in any dose, plasma steroid concentrations were significantly lower than those of the control group. The degree of suppression in plasma steroid concentration was less marked in patients who received treatment on alternate days than in those who received the same doses of prednisone each day. Within 48 hours after administration of alternate-day treatment, plasma steroid concentrations approached the values observed in the control group and were independent of the magnitude of the prednisone dose. Although alternateday steroid treatment was associated with transient and incomplete suppression of pituitary-adrenal function, patients whose therapy was changed from a daily to an alternate-day regimen sometimes exhibited prolonged suppression of adrenal cortical function.