Detection of Low-Molecular-Weight Mast Cell–Activating Factors in Serum From Patients With Chronic Spontaneous Urticaria

Abstract

Background: Functionally active autoantibodies to IgE and to the high-affinity IgE receptor (FcεRI) can be detected in serum in about 40% of patients with chronic spontaneous urticaria (CSU). Recent studies showed that serum from patients with CSU can induce activation of mast cells, irrespective of whether they carry high-affinity IgE receptors. Objective: To evaluate mast cell activation induced by factors in the serum of CSU patients with a molecular weight lower than that of autoantibodies. Methods: Eight CSU patients and 5 healthy controls were evaluated. Whole serum and serum fractionated at 100, 50, and 30 kDa were used to stimulate in vitro LAD2 mast cells. The enzymatic activity of β-hexosaminidase was evaluated in supernatants and cell pellets as a measure of mast cell degranulation. Results: Mean (SEM) release of mast cell β-hexosaminidase induced by whole serum from CSU patients was higher than that induced by serum from the healthy controls (14.4 [2.7%] vs 5.1 [2.4%]; P=.027). In addition, serum fractions below 100 kDa and below 50 kDa from CSU patients induced mast cell degranulation that was significantly higher than that induced by the corresponding fractions in sera from healthy controls (10.2% [ Conclusions: This study shows that sera from CSU patients may contain low-molecular-weight mast cell-activating factors other than autoantibodies. These factors could be an additional mechanism contributing to the pathogenesis of CSU.

Chronic urticaria: a focus on pathogenesis

“…This fact suggests a pathomechanism that bypasses the IgE receptor mechanism. In subsequent studies, we showed that low-molecular-weight circulating factors (molecular weight about 30 kDa) may be involved in the activation of mast cells in chronic urticaria patients 41 , thus confirming very old data by Grattan and co-workers 42 .…”

A single reaction-diffusion equation for the multifarious eruptions of urticaria

“…This brings various histamine releasing factors to the blood, such as activated coagulation factors to activate protease activating receptor (PAR) on mast cells, autoantibodies against IgE or the high affinity IgE receptor (FcεRI) and autoantigens for IgE to the tissue. These factors should induce further release of histamine from mast cells in the vicinity, as well as neuropeptides released from free nerve endings in the skin by histamine [20,[30][31][32][33][34][35]. On the other hand, the expression of tissue factor on endothelial cells and histamine release from mast cells are consequentially suppressed by adenosine derived from ATP which is released from mast cells together with histamine [25,26].…”

Increase of tissue factor expression on the surface of peripheral monocytes of patients with chronic spontaneous urticaria

“…Because of the increase of the intrinsic coagulation potential in CSU,3 the activation of factor X and II in the common pathway of coagulation, and the induction of vascular endothelial cell gap formation by these factors may be further enhanced in CSU.Autoantibodies against IgE or its receptor (FcɛRI) on mast cellsare known to be involved in the pathogenesis of CSU. Moreover, the presence of histamine-releasing factors has also been reported in the plasma of patients with CSU 7,8. We presume that plasma leakage caused by the activation of the coagulation cascade triggered by TF expressed on either endothelial cells or monocytes allows these factors to move out to the extravascular space and encounter dermal mast cells, which then degranulate and cause massive vascular hyperpermeability and wheal formation.…”