Autoimmune chronic spontaneous urticaria

Kolkhir et al1Kolkhir P. Church M.K. Weller K. Metz M. Schmetzer O. Maurer M. Autoimmune chronic spontaneous urticaria: what we know and what we do not know.J Allergy Clin Immunol. 2017; 139: 1772-1781Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar provide a welcome and comprehensive review of the literature on IgE and IgG autoantibodies in patients with chronic spontaneous urticaria (CSU) and the evidence for their relevance to disease pathogenesis. I would like to clarify 3 points arising in their article. First, they propose a model of urticaria pathogenesis based on Gell and Coombs types I (anaphylactic) and type II (cytotoxic/cytolytic) hypersensitivity.2Gell P.G.H. Coombs R.R.A. The classification of allergic reactions underlying disease.in: Coombs R.R.A. Gell P.G.H. Clinical aspects of immunology. Blackwell, London1963: 317-337Google Scholar Through this model, they propose that specific IgE to soluble autoantigens, including thyroid peroxidase, can initiate mast cell degranulation, resulting in release of histamine and other proinflammatory mediators in patients with CSU (a type I response). They also examine the evidence for IgG autoantibodies causing degranulation by binding IgE or the high-affinity IgE receptor FcεRI on mast cells and basophils and refer to this as type II hypersensitivity. However, Gell and Coombs defined a type II reaction as being initiated by antibody reacting to either an antigenic component of the tissue cell or an antigen that has become intimately associated with tissue cells in which complement is usually, but not always, necessary to effect cellular damage rather than stimulation. Kay3Kay A.B. Allergy and hypersensitivity: history and concepts.in: Kay A.B. Kaplan A.P. Bousquet J. Holt P. Allergy and allergic diseases. 2nd ed. Wiley-Blackwell, Oxford (United Kingdom)2008: 19Crossref Scopus (3) Google Scholar proposed a modification of the Gell and Coombs classification in 2008 to distinguish receptor-mediated stimulation of mast cells and basophils by anti-FcεRIα autoantibodies (type 2b), as seen in patients with chronic urticaria, Graves disease, and myasthenia gravis from cytotoxic/cytolytic hypersensitivity (type 2a) involving complement-induced lysis, seen in some drug and transfusion reactions. The term type V hypersensitivity reaction has also been proposed to account for stimulation of a target cell population by autoantibodies, notably Graves disease, in which antibodies bind to and stimulate the thyroid-stimulating hormone receptor, but Weetman4Weetman A.P. Hypersensitivity: stimulatory (type V). Encyclopedia of Life Sciences, Wiley (NY)2001Google Scholar also cites chronic urticaria as an example. Second, the authors observe that antibodies involved in type II reactions are usually IgG or IgM but do not find direct evidence for IgM autoantibodies in patients with CSU, even though there is indirect evidence that they might be relevant. Gruber et al5Gruber B.L. Baeza M.L. Marchese M.J. Agnello V. Kaplan A.P. Prevalence and functional role of anti-IgE autoantibodies in urticarial syndromes.J Invest Dermatol. 1988; 90: 213-217Abstract Full Text PDF PubMed Scopus (281) Google Scholar described IgM anti-IgE autoantibodies using an enzyme immunoassay in sera of 2 patients with cold urticaria, one of which released histamine, but not from patients with chronic (spontaneous) urticaria or urticarial vasculitis. Immunoadsorption of IgM from the serum fractions of 3 patients with CSU from which IgG had been removed already almost abolished residual histamine release from healthy donor basophils, although the eluted IgM fraction had minimal functional activity.6Grattan C.E.H. Francis D.M. Hide M. Greaves M.W. Detection of circulating histamine releasing autoantibodies with functional properties of anti-IgE in chronic urticaria.Clin Exp Allergy. 1991; 91: 695-704Crossref Scopus (310) Google Scholar Therefore it is possible that IgM autoantibodies to IgE or FcεRIα can occur in patients with CSU, and more research is needed. Third, Kolkhir et al1Kolkhir P. Church M.K. Weller K. Metz M. Schmetzer O. Maurer M. Autoimmune chronic spontaneous urticaria: what we know and what we do not know.J Allergy Clin Immunol. 2017; 139: 1772-1781Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar describe testing IgG autoantibodies in patients with CSU for functional activity through use of a basophil activation test but do not distinguish between the basophil histamine release assay (BHRA) and detection of basophil membrane activation marker expression by using flow cytometry (basophil activation test [BAT]). These tests have different methodologies with different outcomes and might carry different interpretations. In the BHRA serum from the patient is incubated with basophils from a healthy donor. Any resulting histamine release is expressed as a percentage of total histamine. By contrast, the BAT is most commonly used in the context of food allergy when autologous IgE-primed basophils are activated by allergens; it has been used as a test for activation marker upregulation in heterologous basophils after incubation with sera from patients with chronic urticaria. Because the principle of using an indirect measure of basophil activation (histamine) in the BHRA is different from looking for direct evidence of activation marker upregulation in the BAT, it is preferable to keep these terms distinct. The correlation coefficient between CD63 expression on healthy donor basophils induced by serum from patients with chronic urticaria and the BHRA result in one study was low, but concordance between the 2 tests was higher; the BHRA showed higher sensitivity for a positive autologous serum skin test result.7Altrich M.L. Helsey J.F. Altman L.C. Comparison of the in vivo autologous skin test with in vitro diagnostic tests for diagnosis of chronic autoimmune urticaria.Allergy Asthma Proc. 2009; 30: 28-34Crossref PubMed Scopus (39) Google Scholar Autoimmune chronic spontaneous urticaria: What we know and what we do not knowJournal of Allergy and Clinical ImmunologyVol. 139Issue 6PreviewChronic 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. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 141Issue 3PreviewWe thank Dr Grattan1 for commenting on our recent article2 and for proposing that the subtype of chronic spontaneous urticaria (CSU) we call type II autoimmune CSU might better be called type IIb or type V autoimmune CSU. Type IIb and type V are not part of the original classification by Gell and Coombs,3 which we used to distinguish the 2 types of autoimmunity currently thought to be involved in the pathogenesis of CSU (ie, type I and type II). Modifications of this original classification, such as the introduction of type IIb and type V, reflect the fact that not all type II reactions (ie, reactions caused by autoantibodies that bind to a target cell antigen or one that has become closely associated with it) are cytotoxic. Full-Text PDF