Clinical Immunology and Allergy Chronic Urticaria: New Immunologic Aspects
Piersandro Riboldi1 MD1, Riccardo Asero MD2, Alberto Tedeschi MD3, Maria Gerosa MD1 and Pier L. Meroni MD 1Allergy
and Clinical Immunology Unit, IRCCS Istituto Auxologico, Department of Internal Medicine, University of Milan, 2Allergy Unit, Caduti Bollatesi Hospital, and 3Allergy and Immunopharmacology Unit, First Division of Internal Medicine, IRCCS Maggiore Policlinico Hospital, Milan, Italy
Key words:
urticaria, mast cells, autoimmune urticaria, anti-FRI IMAJ 2002;4(Suppl):872±873
Chronic urticaria is defined by the occurrence of cutaneous wheals with or without angioedema lasting more than 6 weeks. Angioedema accompanies urticaria in about 40% of patients and about 20% have angioedema without urticaria, while the remaining 40% have urticaria without angioedema. Physically induced urticarias (e.g., cold, cholinergic, solar, and pressure urticaria) represent a small proportion of CU cases. Recurrent urticaria may occur in patients with systemic autoimmune disorders, such as systemic lupus erythematosus and SjoÈgren's syndrome, but in these cases histologic findings reveal a leukocytoclastic vasculitis rather than the non-necrotizing vasculopathy that is usually seen in CU patients. Chronic hives due to cutaneous vasculitis occur in a very small proportion (< 1%) of patients with CU. Although most patients with CU appear to have an idiopathic disorder, in a consistent proportion of cases an autoimmune mechanism has been suggested. Approximately 5±10% of patients with CU have circulating anti-immunoglobulin E antibodies, and an IgG antibody directed against the a subunit of the high affinity IgE receptor (FceRI) can be detected in sera of about one-third of patients [1±4]. These autoantibodies are both able to induce histamine release from mast cells and basophils via a direct cross-linking of adjacent IgE or of adjacent IgE receptors. Unfortunately, no convenient or reliable immunoassay able to detect such autoantibodies is yet available; thus, basophil histamine release assay still remains the only in vitro diagnostic test. The autologous serum skin test [5] represents a useful screening test for autoimmune urticaria in vivo. Histamine is certainly the main mediator involved in CU but probably not the only one, as cell activation is followed by the release of other inflammatory substances as well. De novo synthesis of leukotriene C4 has been induced in normal basophils in vitro stimulated by sera from CU patients [6]. Notably, on a molecular basis, LTC4 is about 1,000 times more potent than histamine in causing a wheal-and-flare reaction upon intradermal injection; therefore LTC4 can be considered an additional mediator of urticaria [7]. Although platelet-activating factor, cytokines and chemokines can be released by activated mast cells, to date there is little evidence that these substances are involved in the CU = chronic urticaria Ig = immunoglobulin LTC4 = leukotriene C4
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pathogenesis of urticarial lesions. The monovalent combination of FceRI autoantibodies with their ligand causes complement activation and generation of anaphylatoxins. In vitro studies have demonstrated the complement dependence of histamine-releasing activity of CU sera [8], and C5a has been shown to enhance IgGdependent histamine release from basophils in CU [9]. Genetics, familial factors, and clinical associations
Genetic background is thought to be a relevant factor in autoimmune diseases. A recent study in a large population of CU patients showed a marked increase in prevalence of the disease among first-degree relatives [10]. Interestingly, virtually all patients showing a family history of CU were strongly positive on the ASST, which suggests the presence of circulating autoantibodies. A genetic basis of CU has been provided by the high prevalence of human leukocyte antigen-DRB1*04 (DR4) (P = 3.6 x 106) and its associated allele, DQB1*0302 (DQ8) (P = 2 x 104) genotype found in patients with in vivo and in vitro histamine-releasing activity [11]. The association between CU and autoimmune thyroiditis has long been recognized, and anti-thyroglobulin or anti-thyroid peroxidase antibodies can be detected in 25±30% of CU patients [12]. An association with Graves' disease is less common. No obvious explanation for this association has been proposed. The recent observation that the DRB1*04-DQB1*0301 haplotype is significantly increased in Italian patients with Hashimoto's thyroiditis [13] may indicate a common genetic background. Controversial aspects
One of the most puzzling aspects of CU is the discrepancy between in vivo and in vitro findings. In our experience [14], the intradermal injection of 0.05 ml of fresh autologous serum elicits a wheal-andflare reaction in about 60% of patients with CU, a proportion also reported by others. However, IgG antibodies specific for the high affinity IgE receptor or IgE are detected in no more than 30±40% of ASST-positive patients [2,15]. Even the absolute requirement of such autoantibodies has recently been questioned, since CU sera containing anti-FceRI antibodies retain their ability to induce a wheal-and-flare reaction in vivo also after complement inactivation ASST = autologous serum skin test IMA
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and IgG depletion [16]. Since the specificity of ASST has been established in several studies (which means that false positive results are rather unlikely), and in vitro histamine-releasing activity of CU sera is associated with the presence of circulating anti-FceRI (or anti-IgE) autoantibodies, it is conceivable that different histamine-releasing factors may be involved in vivo and that such factors may be clinically relevant (at least in those patients whose sera are not able to induce any histamine release in vitro). Two possible candidate substances are the chemokines RANTES and MIP-1a, both of which are able to induce histamine release from basophils. However, RANTES and MIP-1a do not exert a similar effect on mast cells upon cutaneous challenge; moreover, they induce tissue eosinophilia, which is normally absent in CU [17]. Stem cell factor, produced by endothelial as well as by other stromal cells, plays a central role in the development and maturation of mast cells [18] and is the only cytokine/growth factor known to induce mediator release from human mast cells. We recently investigated the possible role of SCF as a histaminereleasing factor in patients with CU; sera from all CU patients, both positive and negative on ASST as well as positive or negative on in vitro histamine release assay, showed normal circulating SCF levels (unpublished). Another interesting in vitro observation is that sera from some patients are able to induce histamine release from human basophils but do not seem to contain anti-FceRI (or antiIgE) autoantibodies on Western blot [19].
4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Conclusion
An impressive number of studies carried out during the last decade succeeded in shedding some light on the pathogenic mechanisms underlying a relevant proportion of CU cases. The activation of cutaneous mast cells appears to be caused by a combination of direct cross-linking of the high affinity IgE receptor (or IgE) and anaphylatoxin C5a. Nonetheless, several aspects, including the true effect of autoantibodies in vivo, remain controversial and deserve further investigation. The pathogenesis of CU remains elusive in about 40% of patients in whom an autoimmune phenomenon cannot be demonstrated; these cases should be correctly classified as an idiopathic disorder.
14. 15. 16. 17. 18.
References
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Dr. P. Riboldi, Allergy and Clinical Immunology Unit, Istituto Auxologico Italiano, Via Ariosto, 13 - 20145 Milano, Italy. Phone: (39-02) 58211-557 Fax: (39-02) 58211-559 email:
[email protected] Correspondence:
There's no cure for birth or death save to enjoy the interval
George Santayana (1863±1952), American philosopher
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