• cold urticaria;
  • histamine releasing factors;
  • urticaria

Idiopathic cold urticaria (ICU) is characterized by the rapid onset of pruritus, erythema, and swelling after a cold stimulus in the absence of any abnormal circulating protein ( 1 ). Pathogenesis is still unclear.

ICU can be passively transferred to normal individuals (2), and cold-dependent histamine release can be obtained from skin biopsies (3). Serum from patients with ICU may cause a wheal-and-flare reaction on intradermal injection and may contain anti-IgE autoantibodies (4). Altogether, several immunological features of ICU resemble those of chronic idiopathic urticaria (5). We studied five patients (4 men and 1 woman, aged 13–57 years (mean 32 years)) seen with ICU in 1997–1999. At the baseline visit, intradermal tests with fresh autologous serum (ASST) were carried out (6) and blood samples were taken for in-vitro basophil histamine release assays (HRA) (6). Three patients accepted a follow-up visit in June 2001, when an ice-cube test, ASST, and HRA were carried out. On HRA a 5% release cutoff value was used. Sera were tested with basophils from six normal donors. As a control, basophils were stimulated with an optimal dose (10 µg/ml) of goat polyclonal antihuman IgE. Serum from one patient that showed significant histamine releasing activity was filtered through an Amicon anisotropic, hydrophilic YM membrane with a 10 kDa cutoff. Both fractions > and < 100 kDa were tested on HRA.

At the baseline visit, all five patients scored strongly positive on ASST. Sera from five, one, none, and five patients induced histamine release from basophils of donor numbers 1, 2, 3, and 4, respectively (Table 1). The responses of basophils to anti-IgE and to patients' sera did not show any correlation (Table 1). At the follow-up visit patients 1 and 3 had recovered from their disease and were negative on the ice-cube test and on ASST. By contrast, patient 2 still had active disease and was positive on both tests. On HRA, serum from patient 3 (in clinical remission) still induced histamine release, whereas sera from patients 1 (in remission) and 2 (clinically active) were negative (Table 1). Only the fraction > 100 kDa of serum from patient 3 induced histamine release from basophils.

At the baseline evaluation, all five patients were positive on ASST, and their sera (variably) induced histamine release from basophils of two out of four donors. Notably, the releasing activity of sera in no way paralleled that of anti-IgE, suggesting that a mechanism other than anti-IgE was responsible for basophil activation.

Altogether these findings show the presence of circulating histamine releasing factors that are already active at body temperature in these patients. Occasionally cold urticaria resolves spontaneously (1), as in two out of three of our participants. We could, therefore, evaluate the histamine releasing activity of sera from two ICU patients during two distinct clinical phases both in vivo and in vitro. Both the ice-cube test and ASST were found to parallel disease activity, which was not the case for HRA (negative in a patient with an ongoing disease but still positive in a patient in clinical remission). As previously observed (6), in-vitro histamine releasing activity of serum was associated with the > 100  kDa fraction containing immunoglobulins. Our findings suggest that the presence of functionally active autoantibodies, directed against FcɛRI or against IgE, is not necessarily associated with disease activity in ICU, and that histamine release from basophils (in vitro) and mast cells (ASST) might not be mediated by the same factor.

In effect, IgG-depleted sera from patients with chronic idiopathic urticaria maintain their ability to induce histamine release on ASST (7). The reasons why patients with ICU experience their clinical symptoms only after a cold stimulus remain unclear. Notably, symptoms are often at a maximum after the area exposed to cold is warmed (1), suggesting that reactive vasodilation may facilitate the activity of circulating histamine releasing factors on mast cells, maybe causing an increase in the concentration of these factors in the skin.

Accepted for publication 21 June 2002 Allergy 2002: 57:1211-1212 Copyright © Blackwell Munksgaard 2002 ISSN 0105-4538


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  2. References
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  • 2
    Wanderer AA, Maselli R, Ellis R, Ishizaka K. Immunologic characterization of serum factors responsible for cold urticaria. J Allergy Clin Immunol 1971;48: 1322.
  • 3
    Kaplan AP, Garofalo J, Sigler R, Hauber T. Idiopathic cold urticaria: in vitro demonstration of histamine release upon challenge of skin biopsies. N Eng J Med 1981;305:10741077.
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    Gruber BL, Baeza ML, Marchese MJ, Agnello V, Kaplan AP. Prevalence and functional role of anti-IgE autoiantibodies in urticarial syndromes. J Invest Dermatol 1988;90:213217.
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