Vasculitis in chronic urticaria

We have explored the problem of the histologic basis of chronic urticaria and its relation to vasculitis and immune complex disease. In a prospective study, 42 consecutive patients with chronic urticaria (from twice weekly to daily episodes lasting more than 6 wk) had skin biopsies and were studied for immunologic variables. Twenty-two patients (52%) had vasculitis on biopsy as defined by the presence of cellular infiltrates within the vessel wall. The other 20 patients (48%) had either edema only or perivascular infiltrates with mononuclear cells (perivasculitis). The group with vasculitis could be subdivided into seven patients with neutrophilic venulitis including three with fibrinoid change, seven with mixed-cellular vasculitis, four with lymphol monocytic vasculitis, and four with eosinophilic vasculitis. Vascular deposits of immunoreactants were found in only four (18%) of the vasculitis patients, compared with 65% of concurrently studied patients who had cutaneous venulitis manifested as palpable purpura, i.e., Henoch-Schönlein syndrome. Urticarial patients with vasculitis were more often male and had a longer mean duration of hives compared with the nonvasculitis group. We saw no differences between the vasculitis and nonvasculitis cases of urticaria with regard to the incidence of arthralgia, elevated erythrocyte sedimentation rate (ESR), or hypocomplementemia. The group with vasculitis did not have more generalized disease nor were the hives more resistant to therapy. We have discussed the definition and histologic criteria for the diagnosis of vasculitis when it occurs in very small blood vessels.     

Skin histamine in chronic urticaria

To further study the role of histamine in the pathogenesis of chronic urticaria, the concentration of histamine in tissue extracts from skin biopsy samples and in plasma from patients with chronic urticaria was measured by a sensitive radioenzymatic assay. Tissue histamine levels from urticarial lesions and uninvolved skin were compared with extracts of biopsy samples taken from normal controls. The average tissue histamine content in 15 biopsy samples from the chronic urticaria patients was significantly higher than in those of 15 normal controls. Forty percent of the patients had levels 2 SD greater than the mean of the control group. Elevated histamine levels were also found in biopsy samples of uninvolved skin from some urticaria patients. Circulating histamine levels from chronic urticaria patients were rarely elevated and did not correlate with skin concentration. No correlation was noted between tissue histamine concentration and estimated mast cell concentration on Giemsa-stained sections of five biopsy samples. These results indicate that tissue histamine levels are increased in some patients with chronic urticaria. This suggests that local histamine elevations may be important in the pathogenesis of many patients with this disease. In addition, increased tissue histamine in these patients is not reflected by elevated circulating levels.     

The effect of H1 and H2 blockade on cutaneous histamine response in man

Histamine-induced cutaneous wheal responses were measured in 10 healthy subjects. The effect of the potent H1 blocker, hydroxyzine HCl, the H2 blocker, cimetidine, and the two drugs in combination was determined. The H1 blocker alone produced a mean wheal suppression of 75% (p less than 0.001). The H1 plus H2 blocker produced 84% suppression. The augmented suppression of H1 plus H2 blocker vs H1 blocker was statistically significant (p less than 0.02). The H2 blocker alone produced suppression that was not statistically significant. The results provide additional evidence that H2 receptors are present in the human cutaneous microcirculation, and add support to the clinical observation of therapeutic efficacy of H1 plus H2 blockers seen in some patients with chronic urticaria.     

A comparison of the actions of H1 and H2 antihistamines on histamine-induced bronchoconstriction and cutaneous wheal response in asthmatic patients

The effect of an H1 antihistamine, an H2 antihistamine, and the combination of the two drugs on both histamine-induced bronchoconstriction and dermal whealing was examined in five patients with mild asthma. Chlorpheniramine 8 mg, cimetidine 300 mg, the combination of both, and placebo were administered orally to each patient for a single dose and for seven consecutive doses given every 6 hr after a double-blind, randomized protocol. The airway response to inhaled histamine and the wheal size induced by the intradermal injection of histamine were determined in every patient 2 hr after the final drug dose. The results indicate that a single dose of chlorpheniramine produces a significant increase in the threshold of histamine-induced bronchoconstriction as measured by the provocative histamine dose producing 20% decrease in 1-sec forced expiratory volume (PD20-FEV1), and this effect was significantly enhanced after seven doses. Cimetidine caused a significant decrease in the threshold of histamine-induced bronchoconstriction, but this was not augmented by seven doses. Only chlorpheniramine, when given for seven doses, improved the baseline FEV1 and forced expiratory flow during middle half of forced vital capacity (FEF25%-75%). Chlorpheniramine in both single and multiple doses and the combination of chlorpheniramine and cimetidine given for seven doses produced a significant inhibition of histamine-induced dermal wheals, whereas cimetidine alone had no effect. These results confirm our previous observation that both H1 and H2 receptors are present in the airways of asthmatic patients and that they mediate opposite effects. We also demonstrated a cumulative effect with the repeated administration of chlorpheniramine but not with cimetidine. Finally, the results suggest that the role of H1 and H2 receptors differs in the bronchi from that seen in the dermal vessels of asthmatic patients and are in contrast to those of normals. The H2 receptor effect on histamine-induced skin wheals appears deficient, further supporting earlier suggestions of the presence of an H2 receptor defect in asthmatic patients.     

A controlled trial of therapy in chronic urticaria

Nineteen patients with chronic idiopathic urticaria (duration 2 to 192 mo) referred to our clinic as therapeutic failures were treated sequentially with five regimens. These were administered orally in a double-blind random sequence and included hydroxyzine pamoate (25 mg q.i.d.) plus one of the following: (1) placebo, (2) terbutaline (2.5 mg q.i.d.), (3) cyproheptadine (4 mg q.i.d.), (4) chlorpheniramine (4 mig q.i.d.), (5) cimetidine (300 mg q.i.d.). Therapeutic response was assessed by patient's subjective choice, symptom diary scores, and suppression of wheal response to intradermal injections of histamine and compound 48/80. At least 35% improvement was noted in all patients with an average optimal response of 70%. The hydroxyzine-cimetidine combination was favored by 11 of 19 (58%) patients, in addition to producing the lowest symptom scores and the greatest histamine-48/80 wheal suppression. These results support the efficacy of combination H1 and H2 antihistamines in the management of some patients with difficult chronic urticaria.     

Lymphocyte subpopulations in the skin of patients with chronic urticaria

In order to characterize the nature of the mononuclear cells in the perivascular infiltrates in the skin of 11 patients with CU, skin biopsy specimens were analyzed in situ by an avidin-biotin immunoperoxidase technique. Serial frozen sections were stained for total T cells, helper-inducer T cells, suppressor-cytotoxic T cells, B cells, monocytes/macrophages, and HLA-DR antigen. The infiltrates were found to consist mainly of T cells, whereas B cells and macrophages were rarely seen. Most of the T cells possessed the T4+ helper phenotypes, whereas smaller numbers of infiltrating cells were defined as suppressor-cytotoxic cells. Most of the helper-inducer T cells coexpressed the Ia (HLA-DR) antigen. Several potential pathogenic mechanisms could be implicated in CU based on these observations.     

How corticosteroids work

Corticosteroids are widely used in the treatment of allergic and inflammatory conditions. It is important to recognize that there are great species differences in the responses to glucocorticoids and that man is a “steroid-resistant” species. Steroids affect metabolism and distribution of T and B lymphocytes, but do not significantly affect antibody production in man. Steroids profoundly affect the inflammatory response by way of vasoconstriction, decreased chemotaxis, and interference with macrophages. Steroids affect types I, III, and IV mechanisms of immunologic injury. There are still enormous gaps in our knowledge of the actions of glucocorticosteroids.     

Small vessel vasculitis caused by hepatitis B virus immune complexes: Small vessel vasculitis and HBsAg

In a comprehensive study of 80 patients with vasculitis, 4 had concurrent hepatitis B virus (HBV) infection. Polyarteritis nodosa was present in 2 and in the other 2, cutaneous vasculitis, presenting clinically as palpable or Henoch-Schönlein purpura. In one of these patients skin biopsies demonstrated granular deposits of IgM, C3, C4, and the hepatitis B surface antigen (HBsAg) and electron-dense deposits of aggregated 20-nm particles resembling HBsAg in postcapillary venules. Evidence for circulating HBsAg-immune complexes included increased serum C1q binding activity, decreased serum complement, and a cryoprecipitate containing both HBsAg and IgM anti-HBs. Aggregated 20-nm particles resembling intact HBsAg were also seen by negative staining electron microscopy of the serum cryoprecipitate. This patient fulfills all the criteria for a specific immune complex vasculitis caused by his immune response to a chronic HBV infection. These findings emphasize that HBV infection may be associated with small vessel vasculitis as well as polyarteritis nodosa, mixed cryoglobulinemia, and glomerulonephritis. A similar immune response to other viral infections may be expressed as palpable (Henoch-Schönlein) purpura also.     

Tartrazine and the prostaglandin system.

The effect of tartrazine on prostaglandin production was evaluated in several in vitro systems in order to elucidate the interrelationship between aspirin-sensitive asthma and tartrazine. Unlike the nonsteroidal anti-inflammatory drugs, tartrazine did not inhibit cyclooxygenase activity in sheep seminal vesicles, guinea pig lung microsomes, and human platelets. Tartrazine had no effect on the activation of acyl hydrolase, which is the rate-limiting step in prostaglandin production. The major metabolite of tartrazine, sulfanilic acid, also had no inhibitory effect on the sheep seminal vesicle cyclooxygenase. In view of these findings, if there is a cross-sensitivity between tartrazine and aspirin in aspirin-sensitive asthmatics, it is unlikely to be on the basis of prostaglandin inhibition.     

Activation of the complement system by radiographic contrast media: studies in vivo and in vitro.

The effect of radiographic contrast media (RCM) on the complement system was studied in vivo and in vitro. In 65 patients undergoing intravenous pyelography, plasma was obtained before and 3, 5, 10, 20, 30, and 60 min postinfusion. Nine patients experienced immediate generalized reactions (IGR) post-RCM infusions. Six patients developed urticaria, 1 developed angioedema, and 2 developed nausea and hypotension. A significant decrease in CH50 occurred in 29 patients, including 6 with IGR. Split products of C3 were detected in 24 of these patients. Six patients without change in CH50 had detectable C3 split products. There was a statistically significant decrease in hemolytically active C3 and factor B, but not C1q or C4 in the group with decreased CH50 when compared to the group without CH50 change. All patients had normal levels of C1 esterase inhibitor, C3aI (serum carboxypeptidase B), C3bI, and βIH. Neither anti-RCM antibodies nor immune complexes were detected in any patient's plasma. In vitro, decreased CH50 and hemolytically active C4, C3, properdin, and factor B were found with incubation of plasma with RCM. These changes occurred independent of the buffer used (EDTA/EGTA). Finally, C3 split products were detected in the reaction mixtures. These data indicate that RCM is associated with decreased hemolytic complement activity, both in vivo and in vitro. Furthermore, the in vitro changes occurred without the presence of calcium or magnesium, indicating that complement activation by RCM may occur in a nonsequential manner.     

Monocyte cellular function in asthmatic patients on alternate-day steroid therapy

Monocyte cellular function in 15 asthmatics on alternate-day steroid therapy (mean dose of prednisone, 45.4 +/- 17.45 mg qod) was studied at 8 A.M. and noon after receiving an 8 A.M. steroid dose and at 8 A.M. the following day, and was contrasted to function in 16 healthy controls. Monocyte chemotaxis, bacterial killing and phagocytosis, and oil phagocytosis were not significantly altered by the steroid dose. On the other hand, all the patients experienced monocytopenia, lymphopenia, and neutrophilia 4 hr following the administration of steroid. The lack of functional impairment on this clinically relevant steroid regimen is consistent with the lack of serious infections seen in patients on such regimens. This study re-enforces the need to differentiate the effect of even small doses of steroid on circulating cell populations from direct effects on cell function which occur only with very high or frequent steroid dose regimens.     

Exercise-induced anaphylactic reaction to shellfish

The syndrome of immediate type I food hypersensitivity, mediated by tissue-bound IgE antibody and mast cell histamine release, is well recorded in the medical literature. This case study represents a previously undescribed late food hypersensitivity, induced only by strenuous exercise. Identification of this new syndrome illustrates classical epidemiologic analysis, improves medical advice for the allergic and athletically inclined, and raises new questions in the areas of allergy and immunology.     

A hyperimmunoglobulin E syndrome with normal chemotaxis in vitro and defective leukotaxis in vivo.

A 26-yr-old male with a lifelong history of atopic dermatitis and recurrent severe staphylococcal abscesses was found to have hyperimmunoglobulinemia E. Evaluation of both the humoral and cellular aspects of chemotaxis in vitro showed both neutrophils and monocytes to be normal. However, quantitative neutrophil migration in vivo was significantly suppressed using the patient's own serum as the attractant. This defective migration in vivo was partially corrected by serum from normal donors as the attractant and also partially corrected following plasma infusion in this patient. Evaluation of quantitative leukocyte migration in vivo may be most useful in patients suspected of defects of leukocyte mobility.     

T cell rosette formation in primates, pigs, and guinea pigs. The influence of immunosuppresive agents

Out of 144 combinations of lymphocytes from 8 species and erythrocytes from 18, significant numbers of rosettes were found in only 14. Human and chimpanzee lymphocytes formed rosettes in the greatest number of combinations (5), pig lymphocytes with 3, and guinea pig lymphocytes with only one erythrocyte (rabbit). In all positive combinations tested, the percentage of rosette-forming cells was highest in the thymus, intermediate with lymph node and peripheral blood lymphocytes, and lowest in the spleen. Using the guinea pig rosette-forming cell as an experimental test for T lymphocytes, the effect of several immunosuppressive drugs on the percentage of lymphocytes that are T cells was measured. Cyclophosphamide injected into guinea pigs increased this percentage the most, cortisone and tilorone increased the percentage of rosette-forming cells slightly, and azathioprine and vinblastine caused no change. After in vitro incubation with the lymphocytes, cyclophosphamide, azathioprine, and tilorone increased the percentage of rosette-forming cells and vinblastine reduced this percentage.     

4;11 translocation in acute lymphoblastic leukemia: A specific syndrome

Three patients with acute lymphoblastic leukemia (ALL) having t(4;11) (q21;q23) are described. Their clinical characteristics are compared with ten other published cases all involving similar histories and poor prognoses.     

Induction of delayed hypersensitivity to protein antigens in mice without Freund adjuvants

Three ways for inducing tuberculin-type delayed hypersensitivity (DH) in mice to purified protein antigens without Freund adjuvant are described. Four strains of mice compared for susceptibility to sensitization with several antigens ranked SJL > CF-1 > CAF₁ = C57B1. Females were more easily sensitized than males. The first way of sensitizing without Freund adjuvant was simply to inject antigen intradermally in saline, but it could be used only with the potent antigen methylated human serum albumin (HSA). Six-mercaptopurine injections during the first 5 days of sensitization enhanced such sensitization in CF-1 but inhibited it in CAF₁ mice. The second way sensitized with a weaker antigen, chicken conalbumin (CA), and thus is more versatile. It consisted of injecting a saline solution of antigen into a 24-hr strong DH dermal reaction to an unrelated antigen (dextran). The third way was simplest and best: Freund adjuvant was replaced with aqueous Evans blue dye. Thus, distilled water solutions of antigen (CA or chicken ovalbumin) and dye injected subcutaneously induced DH indistinguishable from that induced with the same antigens in Freund adjuvant. Neither antigen in distilled water alone sensitized. The dye also intensified Arthus sensitization. This diazo dye therefore may be a practical, harmless water-soluble substitute for Freund adjuvant for inducing DH or cell-mediated immunity and for intensifying Arthus sensitization.     

Thymocytes, macrophages, and erythrocytes

Lymphocyte-macrophage and lymphocyte erythrocyte interactions were examined in the 4 homologous and 12 heterologous combinations of mice, rats, guinea pigs, and rabbits. There was a highly species-specific interaction between thymic lymphocytes (T cells) and homologous peritoneal macrophages. Distinct red cell rosettes were formed only between thymus-derived cells of the guinea pig and rabbit erythrocytes.