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Concise update on the pathogenesis of chronic spontaneous urticaria (CSU)

2022; Elsevier BV; Volume: 150; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2022.08.022

1097-6825

Michihiro Hide, Allen P. Kaplan,

Dermatology and Skin Diseases

It is widely accepted that mast cell activation is the initiating step of wheal formation not only in the reactions of type I allergy but also in chronic types of urticaria, including chronic spontaneous urticaria (CSU). The wheals of CSU have an endogenous origin (hence "spontaneous"), and they can be considered an example of an "internal" inflammatory skin disease.1Hide M. Francis D. Grattan C. Hakimi J. Kochan J. Greaves M. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria.N Engl J Med. 1993; 328: 1599-1604Crossref PubMed Scopus (842) Google Scholar,2Kaplan A.P. Gimenez-Arnau A.M. Saini S.S. Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria.Allergy. 2016; 72: 519-533Crossref Scopus (187) Google Scholar Two autoimmune possibilities for initiation have been considered. The first is mast cell activation by IgG anti-IgE or IgG anti-FcεRI. Both IgG antibodies result in cross-linking FcεRI to initiate cell activation (type IIb autoimmunity). The classical complement pathway can be activated, primarily by IgG1 and IgG3 subclasses, to produce C5a, which further augments mast cell activation.2Kaplan A.P. Gimenez-Arnau A.M. Saini S.S. Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria.Allergy. 2016; 72: 519-533Crossref Scopus (187) Google Scholar,3Giménez-Arnau A. DeMontojoye L. Asero R. Cugno M. Kulthanan K. Yanase Y. et al.The pathogenesis of chronic spontaneous urticaria: the role of infiltrating cells.J Allergy Clin Immunol. 2021; 9: 2195-2208Abstract Full Text Full Text PDF Scopus (54) Google Scholar Thus, histamine release is reduced by elimination of complement in sera or by blocking the C5a receptor.4Kikuchi Y. Kaplan A. A role for C5a in augmenting IgG-dependent histamine release from basophils in chronic urticaria.J Allergy Clin Immunol. 2002; 109: 114-118Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar The second initiating mechanism is autoimmunity dependent on IgE itself, with the assumption that patient IgE reacts with an autoallergen in the skin (type I autoallergy). The presence of IgM and IgA anti-FcεRI has been reported by ELISA methodology. These immunoglobulin classes have not yet been isolated from patients' serum and shown to activate basophils or mast cells as the isolated IgG does. Vasoactive substances released from mast cells, such as histamine, leukotriene, and cytokines, activate endothelial cells. The cytokines and chemokines (chemotactic cytokines) derived from mast cells and endothelial cells lead to perivenular infiltration of inflammatory cells in the superficial dermis of the skin, including T lymphocytes (primarily TH2), monocytes, eosinophils, basophils, and neutrophils.3Giménez-Arnau A. DeMontojoye L. Asero R. Cugno M. Kulthanan K. Yanase Y. et al.The pathogenesis of chronic spontaneous urticaria: the role of infiltrating cells.J Allergy Clin Immunol. 2021; 9: 2195-2208Abstract Full Text Full Text PDF Scopus (54) Google Scholar These cells are activated and may, in turn, further activate mast cells. Of particular note, basophils are also activated by IgG anti-IgE/FcεRI and C5a, as well as by chemokines released from T cells such as MCP-1, which is one of the so-called histamine-releasing factors. The importance of the cellular infiltrate is highlighted by the response to acute administration of corticosteroid, which has little or no effect on cutaneous mast cell degranulation. A role for basophils is exemplified by basopenia in at least 50% of patients, which reverses with therapy or spontaneous remission and hyporesponsiveness to stimuli acting through FcεRI. The latter is due to increased levels of cellular phosphatases that dephosphorylate enzymes involved in cell activation.5Vonakis B. Vasagar K. Gibbons S.J. Gober L. Sterba P. Chang H. et al.Basophil FcepsilonRI histamine release parallels expression of Src-homology 2-containing inositol phosphatases in chronic idiopathic urticaria.J Allergy Clin Immunol. 2007; 119: 441-448Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar In type I autoallergy, the key autoallergens, assuming that there are any, have not been identified, but patients' IgE levels are commonly reactive (about 70% positivity) with thyroperoxidase or IL-24. The antithyroperoxidase may be cross-reactive with eosinophil perioxidase, which is more prominent in skin. The efficacy of omalizumab as therapy speaks to the importance of IgE, either as being an antibody in type I autoallergy6Schmetzer O. Lakin E. Topal F. Preusse P. Freier D. Church M. et al.IL-24 is a common and specific autoantigen of IgE in patients with chronic spontaneous urticaria.J Allergy Clin Immunol. 2018; 142: 876-882Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar or as having an indirect role in that IgE receptor downregulation due to lowering of circulating IgE, thus removing a cellular autoantigen for IgG antireceptor antibody.4Kikuchi Y. Kaplan A. A role for C5a in augmenting IgG-dependent histamine release from basophils in chronic urticaria.J Allergy Clin Immunol. 2002; 109: 114-118Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Thus, either type I or type IIb autoallergy may well explain the activation of mast cells without exposure to exogenous antigens. The various shapes of wheals and their unpredictable timing suggest heterogeneous activation of mast cells in the skin. A number of observations have revealed activation of the coagulation cascade and fibrinolysis in CSU, despite the absence of clinical manifestation of thrombosis or bleeding.7Yanase Y. Takakagi S. Ozawa K. Hide M. The role of coagulation and complement factors for mast cell activation in the pathogenesis of chronic spontaneous urticaria.Cell. 2021; 10: 1759Crossref PubMed Scopus (23) Google Scholar This is exemplified by elevated levels of D-dimer, fibrinogen degradation products, and prothrombin 1 + 2. Despite a low level of sensitivity, these markers are correlated with the severity of CSU. Prominent elevation of D-dimer and fibrinogen degradation product levels reflects both fibrin formation and fibrin digestion by plasmin. Activated coagulation and fibrinolytic factors, such as factor VIIa, factor Xa, and plasmin, may directly cleave C5 into C5a anaphylatoxin, which then activate skin mast cells and basophils via the C5a receptor.8Yanase Y. Matsuo Y. Takahagi S. Kawaguchi T. Uchida K. Ishii K. et al.Coagulation factors induce human skin mast cell and basophil degranulation via activation of complement 5 and the C5a receptor.J Allergy Clin Immunol. 2021; 147: 1101-1104Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Thus, anaphylatoxins may be produced by classical pathway activation through C1 or direct cleavage of individual components by enzymes of blood coagulation. The efficacy of warfarin, antifibrinolytic medications, and protease inhibitors in some cases of CSU (although not recommended in the guidelines) support a pathogenetic role for the coagulation/fibrinolysis pathways.7Yanase Y. Takakagi S. Ozawa K. Hide M. The role of coagulation and complement factors for mast cell activation in the pathogenesis of chronic spontaneous urticaria.Cell. 2021; 10: 1759Crossref PubMed Scopus (23) Google Scholar Patients with CSU express high levels of tissue factor, which may initiate the extrinsic coagulation pathway via eosinophils within urticarial lesions and monocytes in the blood. Monocyte tissue factor expression can be induced by stimulation of Toll-like receptor (TLR)-2, TLR-4, and TLR-5 in vitro. Moreover, vascular endothelial cells, primed by several cytokines or TLR agonists, also express tissue factor in response to histamine or vascular endothelial cell growth factor (VEGF).7Yanase Y. Takakagi S. Ozawa K. Hide M. The role of coagulation and complement factors for mast cell activation in the pathogenesis of chronic spontaneous urticaria.Cell. 2021; 10: 1759Crossref PubMed Scopus (23) Google Scholar The activation of the extrinsic coagulation pathway results in intercellular gap formation via thrombin and factor Xa interaction with protease activating receptor-1 expressed on endothelial cells.8Yanase Y. Matsuo Y. Takahagi S. Kawaguchi T. Uchida K. Ishii K. et al.Coagulation factors induce human skin mast cell and basophil degranulation via activation of complement 5 and the C5a receptor.J Allergy Clin Immunol. 2021; 147: 1101-1104Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Proteins and cells can then leak out from plasma into the skin. Diurnal changes in the symptoms and geometric features of wheals are a unique characteristic of CSU. A mathematical model assuming the presence of feedback mechanisms that are both negative and positive reproduced the varying shapes of wheal formation observed in CSU.8Yanase Y. Matsuo Y. Takahagi S. Kawaguchi T. Uchida K. Ishii K. et al.Coagulation factors induce human skin mast cell and basophil degranulation via activation of complement 5 and the C5a receptor.J Allergy Clin Immunol. 2021; 147: 1101-1104Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar ATP, a nucleotide released from mast cells, is metabolized to adenosine and can suppress secretion from mast cells and endothelial cells,9Seirin Lee S. Yanase Y. Takahagi S. Hide M. A single reaction-diffusion equation for the multifarious eruptions of urticaria.PLoS Comput Biol. 2020; 16e1007590Crossref PubMed Scopus (9) Google Scholar which is an example of such a negative feedback. Other inhibitor molecules expressed on mast cells, as well as eosinophils such as Siglec-8, remain to be investigated in CSU, but they may be a promising target for the development of new medications.10Altricher S. Stauback P. Pasha M. Singh B. Cheng A.T. Bernstein J.A. et al.An open-label proof-of-concept study of lirentelimab for antihistamine-resistant chronic spontaneous and inducible urticaria.J Allergy Clin Immunol. 2022; 149 (e7): 1683-1690Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar The prompt effect of omalizumab, sometimes within a week from its initial administration,3Giménez-Arnau A. DeMontojoye L. Asero R. Cugno M. Kulthanan K. Yanase Y. et al.The pathogenesis of chronic spontaneous urticaria: the role of infiltrating cells.J Allergy Clin Immunol. 2021; 9: 2195-2208Abstract Full Text Full Text PDF Scopus (54) Google Scholar suggests a role of IgE itself beyond downregulation of FcεRI, which takes several weeks to 2 or 3 months.2Kaplan A.P. Gimenez-Arnau A.M. Saini S.S. Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria.Allergy. 2016; 72: 519-533Crossref Scopus (187) Google Scholar In summary, the neutralization of circulating IgE by omalizumab should reduce histamine release from mast cells and basophils by both type I autoallergy and type IIb autoimmunity. The coagulation and fibrinolytic pathways initiated by tissue factor expression on eosinophils, monocytes, and/or endothelial cells act via protease activating receptor-1 to increase vascular permeability, and they specifically activate C5, liberating C5a (Fig 1). Moreover, neuropeptides such as substance P, which is responsible for the flare in "wheal and flare" reactions (ie, urticaria), can also activate mast cells selectively in the skin via MRGPRX2, a G protein–coupled receptor, the level of which is increased in mast cells of the skin of patients with CSU. Finally, the clinical effects of various new medications that target other specific molecules and are currently under development are expected to reveal additional features of hive formation in CSU.