Chronic spontaneous urticaria: immune system, blood coagulation, and more

KEY WORDS:

• Chronic urticaria
• pathogenesis
• histamine releasing factors
• mast cells

Despite the great research effort produced over the last 20 years, the etiology and pathogenesis of chronic spontaneous urticaria (CSU) remain largely unclear. A common trait of all the recent findings is that several mechanisms theoretically able to lead to the degranulation of mast cells (the final event of urticaria) have been found. However, the proposed pathomechanisms are individually unable to explain all the cases of CSU and, hence, remain unsatisfactory. While it is conceivable that phenotypically different types of chronic urticaria (e.g., spontaneous, cold-induced or delayed pressure urticaria) may be characterized by different pathogenic mechanisms leading to the clinical expression of the respective diseases, we believe that this heterogeneity is much less likely for a single entity like CSU. Nevertheless, different biologic systems like immunity, inflammation and coagulation may converge in a common mechanism leading to wheal generation. Thus, future research should point to the detection of a common pathogenic mechanism operating in all CSU patients. In this editorial, we will briefly review our knowledge about the pathogenesis of CSU.

Functionally active autoantibodies to the high affinity IgE receptor (FcεRI) present on both mast cells and basophils and to IgE have been detected and described some 20 years ago. This was a perfect explanation for the ongoing histamine release; however, following the initial enthusiasm about this discovery, it became soon clear that such functionally active autoantibodies can be detected only in a minority of patients by the basophil histamine-release assay (about one fourth in our case series).[1] Moreover, immune-enzymatic methods aiming to detect the presence of anti-FcεRI and anti-IgE antibodies in patients’ sera have not reached the status of a routine test. Besides IgG autoantibodies to IgE and FcεRI, other autoantibodies of the IgE class such as autoantibodies to thyroid peroxidase or other thyroid antigens, and IgE autoantibodies to dsDNA and ssDNA can all bind to mast cells, promoting their survival, proliferation and activation.[2] The central role of the IgE/FcεRI system in CSU may explain the therapeutic efficacy of omalizumab by virtue of its ability to deplete IgE.

The autologous serum skin test (ASST) identifies a state of ‘autoreactivity’ of chronic urticaria patients in a quite specific way.[3] In other words, it seems to identify the presence of circulating histamine-releasing factors. ASST-positive patients include all the patients with circulating histamine-releasing autoantibodies and some patients without such autoantibodies. However, again, there is a general agreement that the skin test is positive in about one half of the patients [1,3] and, hence, we are left with a large proportion of patients who do not show any autoreactivity despite their ongoing CSU. Further, another oddity is that heparin turns an ASST from positive to negative,[1,4] a fact that is hardly compatible with an autoantibody nature of histamine-releasing factors detected by the skin test.

The autologous plasma skin test (APST) is positive in a larger number of CSU patients than the ASST,[5] although this observation has not been fully confirmed by all research centers. In our hands, APST-positive patients included most (if not all) ASST-positive ones [5] but, again, there is a proportion of patients with CSU being negative. Nonetheless, this observation represented the trigger to investigate the coagulation system in patients with CSU.

The studies on coagulation in CSU have produced surprising results. The coagulation cascade is activated in CSU, and involves the extrinsic pathway first and the intrinsic pathway secondarily.[5–8] The process seems initiated by the hyper-expression of tissue factor by activated eosinophils (notably, a cell line that is not increased in the blood of CSU patients, to the point that it was considered as a simple bystander of the disease),[9] and parallels the severity of the disease. What primarily activates eosinophils is still unclear although some researchers were able to detect autoantibodies to the low-affinity IgE receptor, FcεRII in a large number of patients (about 65%) with CSU.[10] These autoantibodies were shown to activate eosinophils which in turn released the major basic protein and could cause mast cell degranulation. The observations on coagulation are particularly interesting if one considers that thrombin can increase vascular permeability and is a potent inducer of mast cell degranulation, at least in experimental models. The coagulation cascade is activated in both autoreactive and non-autoreactive patients and elevated D-dimer plasma levels identify patients with severe disease [7,11] who are resistant to H1-antihistamine treatment as well as to ciclosporin therapy.[12,13] The only problem with the coagulation system in CSU is that its activation is not specific, as it occurs in other skin diseases, like bullous pemphigoid and angioedema due to C1-inhibitor deficiency.[14,15] Thus, again, we are left with a piece of truth that is not able to explain the whole story.

A number of cytokines/chemokines and serum factors somehow involved in the immune response and inflammation have been individually investigated in patients with CSU. The most important include among others, the vascular-endothelial growth factor,[16] matrix-metalloproteinase-9 [17] and IL-6.[18] The blood levels of many of these substances have been found to be elevated in CSU, although they appear part of the general inflammatory milieu that characterizes the disease.

More recent research found that sera from patients with CSU are able to induce significant histamine release from mast cells lacking the high affinity IgE receptor, irrespective of the autoreactivity status or of the presence/absence of circulating autoantibodies.[19] Preliminary data from our laboratory indicate that in patients with CSU there are histamine-releasing factors with a molecular weight lower than 30 kDa (unpublished data). These observations are in line with previous data by Grattan and co-workers [20] who were able to detect a low-molecular-weight serum factor causing a wheal-and-flare skin reaction upon intradermal injection in CSU patients, thus suggesting the presence of histamine-releasing factors other than anti-IgE and anti-FcεRI autoantibodies. These findings potentially add another tile in the mosaic of CSU, although much more work on larger number of patients is needed before we can state that this is what happens in most, if not all, CSU patients.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.