TUMOR-NECROSIS-FACTOR-ALPHA RELEASE DURING SYSTEMIC REACTION IN COLD URTICARIA

Primary cold urticaria (PCU) characterized by the association of urticaria, angioedema, and sometimes a shock-like reaction after cold exposure, is usually considered to be linked with histamine and prostaglandin D-2 release by mast cells. To determine the involvement of cytokines, we studied the release of armor necrosis factor-alpha (TNF-alpha) in the blood of the efferent vein after immersion of the hand in chilled water. Five patients with PCU were compared with a control population (three patients with nonphysical urticaria and three healthy subjects). Among patients with PCU who underwent the cold immersion test, two exhibited a shock-like reaction with a large urticarial plaque (patients 1 and 2), one had only a mild cutaneous reaction, and two had no reaction. Patient 1 was reevaluated after 6 months of treatment with H-1 and H-2 antihistamines: he did not respond to this challenge. All controls were strictly negative. Histamine was released within the first minute after the challenge in the three patients with PCU but at a higher level for the two patients who had a systemic reaction. TNF-alpha was undetectable in the blood of the patient with only a mild cutaneous reaction, whereas TNF-alpha release was observed for the two patients with a systemic reaction, 2 and 6 minutes after the end of the cold immersion test. The two other patients and the control subjects released neither histamine nor TNF-alpha. In parallel, pathologic and immunohistochemical (with a rabbit anti-TNF-alpha antibody) studies were performed on skin biopsy specimens collected 10 minutes after ice-cube test. Four patients with PCU who had positive ice-cube test results were studied, as well as patient 1 after treatment, who did not respond to the ice-cube rest. The pathologic study revealed that mast cells were the only cells infiltrating the dermis in PCU and that most of mast cells were degranulated but only in the four patients with positive ice-cube test results. Immunohistochemical study revealed that only mast cells were stained by anti-TNF antibody (90% +/- 2.5%). In conclusion, besides histamine release, cold exposure in PCU induces a concomittent TNF-alpha release by mast cells. Its detection in blood suggests that in addition to histamine, TNF-alpha may be implicated in the shock-like reaction in cold urticaria.