David M. Francis

Autoantibodies against the High-Affinity IgE Receptor as a Cause of Histamine Release in Chronic Urticaria

BACKGROUND Most urticarias are induced by vasoactive mediators such as histamine released from mast cells. Although mast cells are activated by allergens through cross-linking of cell-surface--bound IgE, this mechanism does not appear to explain most cases of chronic urticaria, which, when allergic, infectious, drug-induced, or physical causes cannot be identified, are classified as idiopathic. METHODS We recruited 26 patients with chronic idiopathic urticaria, in whom intradermal injection of autologous serum caused a wheal-and-flare response. Serum from four patients that induced marked histamine release from basophils from a donor with very low serum IgE levels was studied with respect to the IgE dependence of the histamine release, the activity of the IgG fractions, and the neutralizing effect of a recombinant preparation of the soluble extracellular domain of the alpha subunit of the high-affinity IgE receptor (sFc epsilon RI alpha). RESULTS The histamine-releasing activity of the serum was abolished by passive sensitization of basophils with myeloma IgE, enhanced after dissociation of IgE by treatment with lactic acid, and induced by IgG fractions from the serum of all four patients. Preincubation of the serum and isolated IgG with sFc epsilon RI alpha resulted in almost complete neutralization. CONCLUSIONS Histamine-releasing IgG autoantibodies against the alpha subunit of the high-affinity IgE receptor are present in the circulation of some patients with chronic urticaria. Autoantibody-induced cross-linking of IgE receptors may be an important mechanism in the pathogenesis of chronic urticaria and other diseases mediated by mast cells.

Randomized double-blind study of cyclosporin in chronic 'idiopathic' urticaria

Background Histamine‐releasing activity (HRA) is detectable in up to 50% of patients with chronic ordinary urticaria.  Objectives To determine the effect of cyclosporin on clinical features and HRA in patients with chronic urticaria.  Methods Thirty patients with severe unremitting disease, responding poorly to antihistamines and showing a positive autologous serum skin test (ASST) as a marker of HRA, were randomized to 4 mg kg−1 daily of cyclosporin (Sandimmun®, n = 20) or placebo (n = 10) for 4 weeks. Non‐responders were offered open‐label cyclosporin for 4 weeks. All were followed for up to 20 weeks or until clinical relapse; all took cetirizine 20 mg daily throughout the study. The primary measure of efficacy was a daily urticaria activity score (UAS) of weal numbers and itch (maximum score 42 per week). A positive response was defined as a reduction to < 25% of baseline weekly UAS and relapse as a return to > 75%. The effect of cyclosporin on serum HRA was assessed by in vitro basophil histamine release assays and ASSTs before and after treatment.  Results Twenty‐nine patients (19 active, 10 controls) completed the randomized trial medication. Eight of 19 on active treatment but none on placebo had responded at 4 weeks (P < 0·05). Three others on active drug met the criterion for response at 2 weeks but not at 4 weeks. Mean reduction in UAS between weeks 0 and 4 was 12·7 (95% confidence interval, CI 6·6–18·8) for active and 2·3 (95% CI − 3·3–7·9) for placebo (P = 0·005). Seventeen non‐responders (seven randomized to active and 10 to placebo) chose open‐label cyclosporin and 11 responded after 4 weeks. Six of the eight randomized active drug responders relapsed within 6 weeks. Of the 19 responders to randomized and open‐label cyclosporin, five (26%) had not relapsed by the study end‐point. Mean in vitro serum HRA fell from 36% (95% CI 22–49%) to 5% (95% CI 1–8%) after cyclosporin treatment (n = 11, P < 0·0001). The ASST response to post‐treatment serum was also reduced (P < 0·05).  Conclusions This study shows that cyclosporin is effective for chronic urticaria and provides further evidence for a role of histamine‐releasing autoantibodies in the pathogenesis of this chronic ‘idiopathic’ disease.

Anti-FcϵRI autoantibodies and basophil histamine releasability in chronic idiopathic urticaria☆☆☆★★★♢

Abstract Background: Circulating functional autoantibodies to the high-affinity IgE receptor (FcϵRI) or to IgE have been found in approximately one third of patients with chronic idiopathic urticaria (CIU). Objective: We sought to compare basophil histamine release and basophil numbers in patients with CIU with and without autoantibodies. Methods: Basophil histamine release to the anti-FcϵRI mAb 22E7, anti-IgE, and formyl-methionyl-leucyl-phenylalanine (fMLP); basophil numbers; and total cellular histamine were measured in 26 patients with CIU and 18 healthy control subjects. Twelve patients were classified as having functional anti-FcϵRI and/or anti-IgE autoantibodies on the basis of their serum-evoked histamine release from the basophils of 2 healthy donors. Results: 22E7 and anti-IgE, but not fMLP, released less histamine from basophils of patients with CIU than from those of control subjects. Mean ± SEM maximum histamine release to 22E7 from basophils of control subjects and patients with CIU with and without autoantibodies was 38.5% ± 5.0%, 17.9% ± 6.0% ( P = .01), and 1.0% ± 0.3% ( P P = .04), and 5 ± 1 ( P 6 cells/L, respectively, and similar changes were found in measurements of total cellular histamine. Conclusion: Patients with autoantibodies have both markedly reduced basophil numbers and basophil histamine release to factors acting through FcϵRI, which indicates either a residual pool of functionally distinct basophils or may be a consequence of desensitization of the FcϵRI pathway. (J Allergy Clin Immunol 1998;102:651-8.)

Contact urticaria due to the common stinging nettle (Urtica dioica)--histological, ultrastructural and pharmacological studies.

A frequent cause of contact urticaria is skin exposure to the common stinging nettle (Urtica dioica). The urticaria is accompanied by a stinging sensation lasting longer than 12 h. Little is known of the cellular and molecular mechanism of stinging‐nettle urticaria. After preliminary pharmacological analysis of pro‐inflammatory activity in nettle stings, the cellular response of mononuclear cells, polymorphonuclear cells and mast cells was examined in six people 5 min and 12 h after nettle contact. Only mast cell numbers were significantly increased at 12 h. Ultrastructurally, some mast cells showed evidence of degranulation at 5 min and 12 h. At 12 h mast cells were closely associated with dermal dendritic cells and lymphocytes suggesting a functional unit. The mean histamine and serotonin contents of a nettle hair were found to be 6.1 ng and 33.25 pg, respectively. Nettle‐sting extracts did not demonstrate histamine release from dispersed rat mast cells in vitro. These results suggest that part of the immediate reaction to nettle stings is due to histamine introduced by the nettle. However, the persistence of the stinging sensation might suggest the presence of substances in nettle fluid directly toxic to nerves or capable of secondary release of other mediators.

Basal cell carcinoma is associated with high TNF‐α release but not with TNF‐α polymorphism at position − 308

Abstract:  The mechanisms underlying induction of UVB‐induced immunosuppression are not fully understood, but tumour necrosis factor alpha (TNF‐α) is suggested to play a central role. A single base pair polymorphism at position − 308 in the promoter region of the TNF‐α gene associated with an enhanced secretion of TNF‐α has been identified in humans. We have therefore investigated the association of the − 308 polymorphism with the risk of basal cell carcinoma (BCC) in humans. The frequency of TNF G and TNF A alleles among Caucasian patients with a previous BCC (n= 191) and healthy adults (n= 107) were compared. For the TNF − 308 polymorphism there was no significant association between the genotype or allele frequencies and having a BCC. To determine whether patients with a previous BCC had an increased capacity to secrete TNF‐α, mononuclear cells were stimulated with lipopolysaccharide. Mononuclear cells from patients with a previous BCC (n= 15) demonstrated a significantly increased release of TNF‐α upon stimulation with lipopolysaccharide (P < 0.03) compared with mononuclear cells from age‐matched control subjects (n= 16). Further studies of other polymorphisms of the TNF‐α gene associated with increased TNF‐α production and BCC are necessary.

IgE Receptor Autoantibodies

Publisher Summary This chapter provides an overview of type E immunoglobulin (IgE) receptor autoantibodies. As with other receptors for immunoglobulins, the high affinity IgE receptor (FcɛRI) is activated by crosslinking of multiple receptors, with resultant histamine release and cytokine production by mast cells and basophils. Approximately one-quarter of the patients with chronic idiopathic urticaria have autoantibodies to FcɛRI, a third of which are competitive with IgE for the binding to FcɛRI. The functional significance of anti- FcɛRI autoantibodies is that they activate rather than impair receptor function, leading to mediator release from mast cells. Several immunotherapies developed for autoimmune disorders including plasmapheresis, high-dose immunoglobulin infusion, and administration of low-dose cyclosporin A are effective for some patients with severe, refractory urticaria.

(17) Contact urticaria due to the common stinging nettle (Urtica dioica): histological, ultrastructural and pharmacological studies

Dupuytren, in his original report on palmar fibromatosis, described cases with plantar involvement. Today Dupuytrens contracture is an easily diagnosed condition while its plantar equivalent is poorly recognized and often mis-diagnosed. This poster describes the clinical features of five cases and the characteristic histological findings. The correct diagnosis was not made initially in any of the cases. In three cases hypertrophic scarring or keloid formation was suggested both clinically and histologically. In two patients the extent of involvement led to significant disability and one of them was treated by surgical excision. If surgery is undertaken for this condition it should involve removal of the entire plantar fascia.

A histamine releasing factor in serum of chronic urticaria with anti‐IgE autoantibody‐like properties

45 foot involvement at 4 weeks but not at 8 weeks. There were no differences between topical PUVA and placebo in patients with hand or foot involvement in respect of erythema, scaling and fissuring scores, nor symptom assessments. Topical PUVA has some therapeutic effect in PPP. However, the clinical improvement is small and does not result in significant symptomatic improvement compared with placebo. This study indicates that topical PUVA does not produce clinically worthwhile improvement in PPP. Oral PUVA may be a more effective alternative in patients unresponsive to other measures.