Chronic urticaria: a focus on pathogenesis

Autoreactivity/autoimmunity

More than 30 years ago, Grattan and co-workers demonstrated that the intradermal injection of autologous serum induces a wheal-and-flare reaction in a large proportion of patients with chronic urticaria²; this led them to conclude that chronic urticaria is characterized by circulating histamine-releasing factors. Since then, a positive autologous serum skin test (ASST) has been considered as a marker of “autoreactivity”. This in vivo test is quite easy to perform and seems sufficiently specific for chronic urticaria, as normal subjects do not show any skin reactivity³, although it may score positive in inducible urticarias such as cold urticaria⁴ as well as in some other “allied” conditions, such as the multiple drug allergy syndrome and multiple hypersensitivity to non-steroidal anti-inflammatory drugs^5,6. However, the ASST scores positive in only about one half of chronic urticaria patients^7,8, leaving a large proportion of patients who do not show any autoreactivity despite their maybe severe and ongoing disease.

Following the first observation on skin reactivity to autologous serum that remains a cornerstone in urticaria research, the second important step in the definition of the pathogenic mechanism was the demonstration of histamine-releasing autoantibodies about 20 years ago, suggesting an autoimmune origin. This was based on the detection of circulating and functionally active IgG autoantibodies directed against either the high-affinity IgE receptor (FcεRI) present on both mast cells and basophils (in most cases) or membrane-bound IgE (in a minority of patients)^9–12.

Although this was a fascinating explanation for the ongoing histamine release, several subsequent studies found that this mechanism is in fact viable in only a minority of patients^8,13. Furthermore, both types of autoantibodies have been detected with similar frequency in chronic urticaria patients and controls without chronic urticaria¹³. Nonetheless, in more recent times, the autoimmune pathogenesis hypothesis has received new, indirect but strong support from the detection of circulating autoreactive CD4⁺ T cells that proliferate in response to FcεRI in >50% of patients with chronic urticaria examined¹⁴.

Basophils: their pathogenic role and use in chronic urticaria diagnosis

Although there is little doubt that the mast cell is the main final effector cell in chronic urticaria, basophils and their role in the disease have received much attention during the last decade. It is well known that active chronic urticaria is characterized by basopenia due to the elective recruitment of circulating basophils into the skin lesions¹⁵ and that basopenia is directly related to disease severity. Recent studies found that chronic urticaria blood basophils show a reduced surface expression of CRTH2 (the chemoattractant receptor–homologous molecule expressed on TH2 cells), the receptor for prostaglandin D2 (PGD2). It is therefore possible that decreased CRTH2 levels on basophils in patients with chronic urticaria are due to in vivo PGD2-mediated activation, suggesting the engagement of CRTH2 in patients with chronic urticaria¹⁶. Furthermore, basophils from chronic urticaria patients show different phenotypes (either responder or non-responder, based on the degranulation response to polyclonal goat anti-human IgE) that seem independent of the presence of IgG autoantibodies to IgE or FcεRI and seem stable during active disease^13,17, and their IgE receptor-mediated degranulation is enhanced during disease remission^13,17.

The finding that at least a proportion of chronic urticaria patients show autoimmune phenomena targeting mast cells and basophils has led to the investigation of the diagnostic accuracy of basophil-based in vitro tests aiming to diagnose autoimmunity. The first test used was the time-consuming and cumbersome basophil histamine release assay (BHRA), first introduced in the 1960s and subsequently marketed as a more convenient testing kit¹⁸; on the other hand, the observation that chronic urticaria sera were able to induce the surface expression of basophil activation markers such as CD63¹⁹ led to the investigation of the diagnostic usefulness of the basophil activation test (BAT) measuring CD63 and CD203c surface expression by flow cytometry^20,21. However, in view of the fact that no more that 50% of chronic urticaria patients have an autoimmune disease and of the intrinsic variability of basophil releasability, the clinical usefulness of these tests has been questioned²² and they have not reached the status of routine investigation for this disease.

Auto-allergy

Another important step was the discovery of specific IgE for thyroid peroxidase (TPO) for dsDNA and ssDNA, which has recently provided a different mechanism potentially able to promote the survival, proliferation, and activation of mast cells²³. This pathogenic mechanism could be classified as “auto-allergic” and autoimmune at the same time. However, the proportion of patients in whom such IgE autoantibodies can be detected is limited, and TPO-specific IgE autoantibodies are generally associated with the more common TPO IgG autoantibodies that characterize patients with Hashimoto’s thyroiditis which are found in a minority of patients. However, research in this field is very active, and it cannot be excluded that other “auto-allergens” will be detected in larger proportions of patients with chronic urticaria in the near future²⁴.

Inflammation

It is increasingly clear that chronic urticaria is characterized by a systemic pro-inflammatory state. The studies showing increased levels of different single markers of inflammation (e.g. matrix metalloproteinase and others) that have appeared in the medical literature over the years will not be reviewed in detail here. Recent studies showed the co-existence of chronic urticaria and metabolic syndrome (MS) in a Korean population²⁵; patients with both chronic urticaria and MS were older, had a more severe disease, had higher levels of inflammation markers (i.e. eosinophil cationic protein [ECP], tumor necrosis factor [TNF]-alpha, and complement), and, interestingly, more frequently scored negative on the ASST than those without MS. In another Asian-based population study, chronic urticaria was more frequent among subjects with a prior diagnosis of hyperlipidemia²⁶. Recently, chronic urticaria patients were found to show increased levels of a series of adipokines (lipocalin-2, TNF-alpha, IL-6, and IL-10) but lower levels of adiponectin²⁷. The findings with IL-6 are in keeping with a previous study²⁸ showing an association between IL-6 and disease severity.

Coagulation

The observation that the autologous plasma skin test (APST) may score positive in some ASST-negative patients²⁹ has prompted investigation of the coagulation system in patients with chronic urticaria. Specific studies have shown that the coagulation cascade is activated in chronic urticaria and involves the extrinsic pathway first and the intrinsic pathway second^29–32. The process seems to be triggered by the hyper-expression of tissue factor by activated eosinophils³³ and parallels disease activity. IgG autoantibodies to the low-affinity IgE receptor FcεRII, which is present on the membrane of eosinophils, have been detected in quite a large proportion of patients (about 65%) with chronic urticaria³⁴ and might be involved in the activation of such cells with subsequent release of major basic protein and other mediators causing mast cell degranulation. The activation of the coagulation cascade might potentially play a relevant pathogenic role if one considers that thrombin can markedly increase the vascular permeability and is a potent inducer of mast cell degranulation in experimental models. The activation of the coagulation cascade occurs in other skin disorders characterized by an increase of vascular permeability, such as angioedema due to C1-inhibitor deficiency and bullous pemphigoid^35,36, but also in a wide spectrum of systemic diseases, such as disseminated intravascular coagulation³⁷, deep venous thrombosis³⁸, and endotoxemia³⁹, all prothrombotic conditions that are not characterized by urticaria or edema. However, the activation of coagulation should not necessarily be considered a non-specific phenomenon but rather a common intermediate step occurring in the pathophysiology of different diseases. Thus, the involvement of coagulation is another piece of truth unable to explain the whole story.

Other mechanisms

Quite recently, we were able to show that sera from patients with chronic urticaria induce significant activation of mast cells lacking the high-affinity IgE receptor, irrespective of the autoreactivity status or of the presence/absence of circulating autoantibodies⁴⁰. 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 patients⁴¹, thus confirming very old data by Grattan and co-workers⁴².