Allen P. Kaplan

In vivo studies of mediator release in cold urticaria and cholinergic urticaria

Six patients with cold urticaria were found to possess elevated plasma histamine levels after cold challenge by placing one hand in ice water for 4 minutes. A single patient became hypotensive during the procedure and had a level of 260 ng/ml. histamine in the venous effluent from his hand. No elevation of plasma serotonin or bradykinin was observed. Two patients with cholinergic urticaria possessed elevated plasma histamine levels during and after vigorous exercise for 10 minutes; these patients also gave a positive test for vibration-induced angioedema. A single patient with cholinergic urticaria possessed elevated baseline serotonin levels and elevated levels during and after exercise but no elevation of plasma histamine or bradykinin. The results suggest that histamine is the major mediator of urticaria and hypotension in cold urticaria. Histamine also appears to be released coincident with the development of urticaria in some patients with cholinergic urticaria, while elevated serotonin levels in a single atypical patient suggest that a subpopulation of patients with cholinergic urticaria possess a different pathogenesis.

Assessment of tissue fluid histamine levels in patients with urticaria.

Abstract Tissue fluid histamine in lesions and normal skin sites of patients with various forms of physically induced urticaria and chronic idiopathic urticaria was assessed utilizing suction-induced blisters. Histamine levels were elevated over challenged sites in cold urticaria, solar urticaria, and delayed pressure urticaria. Histamine levels were elevated in both challenged and control sites in patients with immediate-pressure urticaria and local heat urticaria in whom the apparatus provoked lesions. In 5 of 13 patients with chronic idiopathic urticaria, the blister fluid histamine levels were elevated in lesions but not in normal-appearing skin, while in 7 patients the blister fluid histamine levels were elevated in lesions as well as in normal-appearing skin. Although the pathogenesis of chronic idiopathic urticaria is unknown, a clear abnormality related to skin histamine has been identified.

Immunologic reactivity in the hypereosinophilic syndrome.

Because previous studies have suggested an important link between eosinophilia and immunologic reactivity, we investigated various components of the immune system in a large number of patients with the idiopathic hypereosinophilic syndrome (HES) to elucidate a possible role for immunologic phenomena in the etiology and pathogenesis of this disease. Immunoglobulin G, A, or M levels were only rarely abnormal. However, in 8 of 21 (38%) patients with HES, IgE levels were markedly elevated suggesting an association of an IgE-mediated mechanism with eosinophilia in this subgroup. Severe dermatographism was present in three fourths of patients, and 2 patients with intermittently elevated histamine levels manifested an unusual form of immediate-pressure urticaria. Serum complement determinations showed elevated C4 and C3 levels in 27% and 77% of patients, respectively. Antigen-antibody complexlike material measured by C1q binding was elevated in the serum of 7 of 22 (32%) patients; this finding may relate to the known ability of eosinophils to avidly phagocytose antigen-antibody complexes. When compared with normals, lymphocytes from patients with HES showed a variety of abnormalities of lymphocyte surface receptors and lymphocyte function. Thus, patients with HES demonstrate a variety of immunologic abnormalities which may be related primarily or secondarily to the pathogenesis of this syndrome.

Evaluation of a patient with cold and cholinergic urticaria

A-20-year-old male Army paratrooper presented with a history of inducible urticaria associated with exercise as well as cold exposure. Upon evaluation, he not only had a positive ice cube test, but also had a positive mecholyl skin test with numberous satellite lesions and generalized punctate urticaria following exercise challenge. Thus, he appeared to have combined cold and cholinergic urticaria. When mediator release was examined during cold and exercise challenge, histamine release was observed in each instance; a rapid rise and fall of plasma histamine was seen after cold challenge, while a lag phase followed by sustained elevation of plasma histamine was associated with exercise challenge. This represents the fourth reported case of combined cold and cholinergic urticaria and is the first in whom mediator release was assessed. The time-course of histamine release was characteristic of each disorder.

The role of cyproheptadine in the treatment of cold urticaria

Histamine release in cold urticaria was studied before and after therapy with cyproheptadine to determine whether any effect upon histamine release could be distinguished from end-organ receptor-site blockade. Patients were asymptomatic while taking cyproheptadine, their ice cube test reverted to normal, and only one of six patients had any swelling upon ice-water submersion of one hand for 5 min. Histamine-release curves were obtained following ice-water submersion before and after cyproheptadine therapy. All patients had significant histamine release and in five of six patients there was no evident difference in the magnitude of histamine release before or after therapy. A single patient did have diminished histamine release after therapy, but could not be restudied to be sure this was not a spurious result. Our data demonstrated that cyproheptadine is extremely effective in ameliorating the symptoms and signs of cold urticaria and that its principal effect is that of an H1 receptor antagonist, thereby blocking the effects of histamine. These data further suggest that a sufficient dose of any standard antihistamine should be similarly effective and that patients who do not tolerate cyproheptadine or do not appear to respond to it should be tried on other antihistamines of the H1 type.

A search for conformational change on ligand binding in a human γM macroglobulin—I: Circular dichroism and hydrogen exchange

Abstract We have sought evidence for conformational changes in a nitrophenyl-binding human γM macroglobulin upon binding the ligand N-(4-nitrophenyl)-ϵ-NH 2 -caproate (4NP-EAC). Circular dichroism spectra of the γM pentamer and its tryptic Fab fragments were unaffected by concentrations of 4NP-EAC sufficient to saturate 91 per cent of the combining sites. Hydrogen exchange studies revealed that 98 per cent site saturation with 4NP-EAC trapped about 17 hydrogens per site. Although the standard deviations were too large to exclude absolutely ligand-induced trapping in the Fc and hinge regions, the data suggest that most or all of the trapping occurred in the Fab domains. This trapping of hydrogens could have resulted from a stabilization of thermal segmental motion or a small conformational change. The slow rate of release of the trapped hydrogens makes shielding of residues by the bound ligand a somewhat less likely explanation.

Tropical eosinophilia: A human model of parasitic immunopathology, with observations on serum IgE levels before and after treatment

The diverse clinical syndromes characterized by asthmatic symptoms, transient pulmonary infiltrates, and eosinophilia have tended to obscure the specific association of one such entity with filarial infections. Serum IgE levels were determined before and after therapy in a group of well-characterized patients with tropical eosinophilia (TE), studied earlier in Singapore. The mean serum IgE level in 14 cases before treatment with diethylcarbamazine was 2,355 ng. per milliliter, with a trend but statistically nonsignificant decrease in levels to 600-1,000 ng. occurring 8 to 12 weeks after therapy. Leukocyte and eosinophil counts showed a rapid reduction after treatment, and although mean complement-fixing (cf) titers to Dirofilarial antigen tended to decrease, they were not significantly reduced until 5 to 6 weeks. The historical development of evidence supporting the filarial etiology of TE was reviewed. Many basic questions engendered by the clinical syndrome of tropical eosinophilia make it an excellent model for study of the immunopathology of parasitic infections.

Renal arteriography following systemic reaction to contrast material

Abstract A 15-year-old atopic female with severe hypertension (B.P. 220/160) was evaluated for evidence of renal arterial disease with equivocal results, and the performance of renal arteriography was considered essential. However, she had a history of two well-documented anaphylaxis-like reactions to contrast materials, considered to be an absolute contraindication to the performance of such a study. When the etiology of this sensitivity was investigated, an IgE-dependent mechanism was not evident. However, the patients leukocytes released significantly greater quantities of histamine upon incubation with contrast materials than did 7 of 9 normal volunteers. The 2 hyperresponsive normal subjects were not atopic and had no prior exposure to contrast materials. Pretreatment with 80 mg prednisone and 200 mg diphenhydramine daily for 3 days prior to arteriography and challenge with increasing quantities of intravenous iothalamate meglumine (Conray) at the time of the study resulted in successful performance of arteriography and identification of fibromuscular dysplasia of the right renal artery. Placement of an aortorenal bypass graft corrected her hypertension. Thus, arteriography can be safely performed in selected patients with severe previous reactions to contrast materials when the alternatives provide no lesser risk by pretreatment with a steroid-antihistamine regimen and gradual administration of increasing doses of the contrast agent.

Amino terminal sequences of human immunoglobulin heavy chains

Abstract Partial amino-terminal sequences of 6γ, 5μ and 2α human Ig heavy chains not previously described, are presented. These sequences in conjunction with data on 28 other heavy chains permit further definition of heavy chain variable region subgroups. The most frequently studied subgroup (I) appears to be associated with all or most classes of heavy chains for which there are sufficient data. There is one subgroup (IV) which seems only to be associated with μ chains.

Mediator release from basophil granulocytes in chronic myelogenous leukemia: Demonstration of the eosinophil chemotactic activity of histamine

Mediator release from the leukocytes of two patients with chronic myelogenous leukemia and basophilia was studied using rabbit antihuman IgE antibody. The release of histamine, slow reacting substance of anaphylaxis (SRS-A), platelet activating factor (PAF), chemotactic activity for neutrophils and eosinophils, and an inhibitor of eosinophil migration was observed. However, the release of SRS-A from the basophils of one patient and the release of chemotactic activity from both patients displayed unusual properties. During acceleration of the disease process, the basophils of one patient released maximal SRS-A activity at progressively lower concentrations of anti-IgE. Both patients released a high molecular weight factor (M.W. greater than 20,000) which enhanced the migration of neutrophils and eosinophils and a low molecular weight chemotactic factor (M.W. less than 500) which selectively attracted eosinophils. A double peak of eosinophil chemotactic activity was routinely observed for the low molecular weight factor; this was shown to represent the eosinophil chemotactic activity of histamine with relative inhibition of migration at the histamine peak. There was little release of the tetrapeptides, ECF-A, in these patients which facilitated demonstration of this eosinophilotactic activity of histamine. These results suggest that the eosinophil chemotactic activity observed in acute allergic reactions is the net effect of the release of multiple chemotactic factors.