Chronic spontaneous urticaria (CSU) is a mast cell-driven skin disease characterized by the recurrence of transient wheals, angioedema, or both for more than 6 weeks. Autoimmunity is thought to be one of the most frequent causes of CSU. Type I and II autoimmunity (ie, IgE to autoallergens and IgG autoantibodies to IgE or its receptor, respectively) have been implicated in the etiology and pathogenesis of CSU. We analyzed the relevant literature and assessed the existing evidence in support of a role for type I and II autoimmunity in CSU with the help of Hill's criteria of causality. For each of these criteria (ie, strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy), we categorized the strength of evidence as "insufficient," "low," "moderate," or "high" and then assigned levels of causality for type I and II autoimmunity in patients with CSU from level 1 (causal relationship) to level 5 (causality not likely). Based on the evidence in support of Hill's criteria, type I autoimmunity in patients with CSU has level 3 causality (causal relationship suggested), and type II autoimmunity has level 2 causality (causal relationship likely). There are still many aspects of the pathologic mechanisms of CSU that need to be resolved, but it is becoming clear that there are at least 2 distinct pathways, type I and type II autoimmunity, that contribute to the pathogenesis of this complex disease.

This review presents evidence that the skin mast cell, in particular the MC subtype, is the primary effector cell in urticaria. Mast cells are located in the upper dermis, the ideal situation for wheal formation and sensory nerve stimulation. Increased numbers of mast cells are found in both lesional and non-lesional skin in CSU and inducible urticaria. Mast cell degranulation in the area of wheals has been demonstrated repeatedly by light and electron microscopy. Histamine, PGD and tryptase are found in the venous blood draining wheal formation. The last 2 are specific for mast cells rather than basophils. Mast cell reactivity is increased in active urticaria by local inflammatory cytokines and neuropeptides. Mast cell cytokines and neuropeptides, particularly nerve growth factor, induce a Th2 type inflammation that is particularly obvious at the sites of whealing. In conclusion, autoimmunity, either of Type 1 viz. IgE antibodies to local autoallergens, or Type 2b, viz. IgG autoantibodies to IgE or its receptor, are considered to be the most frequent causes of CSU. In both cases, the mast cell is likely to be the axial cell in producing the wheals.

This update on chronic urticaria (CU) focuses on the prevalence and pathogenesis of chronic spontaneous urticaria (