Malcolm W. Greaves

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.

Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions.

Lesions of the common inflammatory skin disease psoriasis are characterized by epidermal hyperproliferation, leucocyte adhesion molecule expression and leucocyte infiltration. The local release of proinflammatory cytokines. such as TNF‐α, may play an important role in the induction of these events. We have, therefore, analysed aqueous extracts of lesional and uninvolved (clinically normal) stratum corneum for the presence of TNF‐α immunoreactivity and biological activity. TNF‐α immunoreactivity and bioactivity were consistently higher in lesional compared with uninvolved samples. By using an anti‐TNF‐α neutralizing antibody it was demonstrated that the biological activity measured was due to the presence of TNF‐α alone. Concentrations of soluble TNF receptors (p55 and p75) were also higher in lesional stratum corneum extracts, with the p55 form predominating. The plasma of psoriatic patients was also found to contain elevated concentrations of soluble p55 compared with normal controls. These results confirm the presence of immunoreactive TNF‐α and, for the first time, conclusively demonstrate TNF‐α biological activity and quantifiable concentrations of soluble TNF receptors (p55 and p75) in lesional psorialic samples. TNF‐α recovery from stratum corneum probably reflects synthesis in deeper, viable layers, where il is likely lo exert its biological effects. Local and systemic release of soluble TNF receplors, in particular p55, may serve to regulate the effects of TNF‐α in psoriasis.

The impact of chronic urticaria on the quality of life

The impact of chronic urticaria (CU) on the quality of life is undocumented. We assessed quality of life in patients with CU, including patients with associated delayed pressure urticaria (DPU). One hundred and forty–two out–patients completed self–administered questionnaires: a disease–specific, purpose designed questionnaire, and the Nottingham health profile (NHP). Many patients reported problems attributable to their skin condition in facets of everyday life including home management, personal care, recreation and social interaction, mobility, emotional factors, sleep, rest and work. The NHP part I scores showed restriction in the areas of mobility, sleep, energy, and demonstrated pain, social isolation and altered emotional reactions. Part II of the NHP showed that patients experienced difficulties in relation to work, looking after the home, social life, home relationships, sex life, hobbies and holidays. The patients with DPU had significantly more problems with mobility, gardening and choice of clothing than the uncomplicated CU patients. They also suffered more pain, had more problems with work and were more restricted in their hobbies.

Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report

To cite this article: Maurer M, Weller K, Bindslev‐Jensen C, Giménez‐Arnau A, Bousquet PJ, Bousquet J, Canonica GW, Church MK, Godse KV, Grattan CEH, Greaves MW, Hide M, Kalogeromitros D, Kaplan AP, Saini SS, Zhu XJ, Zuberbier T. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy 2011; 66: 317–330.

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.

Detection of circulating histamine releasing autoantibodies with functional properties of anti-IgE in chronic urticaria.

Circulating histamine releasing factor(s) have been demonstrated previously in chronic urticaria by an immediate weal‐and‐flare response to intradermal autologous serum injection. We have studied 25 chronic urticaria patients by in vivo skin testing with autologous sera and an in vitro histamine release assay using mixed leukocytes of healthy donors, to define the nature and functional properties of the serum factor(s). Twenty showed a weal response to autologous serum (mean ± s.e.m., 37.3±6.8 mm3). Weal formation was confined to ultrafiltered serum fractions > 100 kD in nine of nine patients. There was no response in 10 healthy controls or five patients with symptomatic dermographism. Fourteen chronic urticaria sera elicited histamine release > 10% (mean ± s.e.m., 44‐3%± 6 7) above basal levels from leukocytes of at least one of seven healthy donors. This in vitro response was also confined to ultrafiltered serum fractions > 100 kD in seven of seven sera and was present in IgG fractions of six of seven chronic urticaria sera that showed histamine releasing activity. Functional studies indicated that this histamine releasing autoantibody had the properties of anti‐IgE: chronic urticaria sera ‘desensitized’ basophil leukocytes to subsequent challenge with other chronic urticaria sera and to goat anti‐human IgE antibody; human myeloma IgE inhibited histamine release from leukocytes in response to chronic urticaria sera; removal of surface‐bound IgE by lactic acid “stripping” reduced histamine release in response to chronic urticaria sera and anti‐IgE and subsequent passive sensitization with IgE myeloma serum partially restored it, Stainable peripheral blood basophils/mm3 in chronic urticaria patients were significantly reduced (mean ± s.e.m., 7.9 ± 2 0) when compared to healthy controls (39.6 ± 44), P < 0.001. These results suggest that histamine releasing autoantibodies are important in the pathogenesis of chronic urticaria by stimulating or facilitating degranulation of basophils and cutaneous mast cells through cross‐linking cell surface IgE receptors.

Recovery of Prostaglandins in Human Cutaneous Inflammation

An in-vivo skin perfusion technique has been used to study the pharmacological activity in inflamed skin of patients with allergic contact eczema. Perfusates from 35 out of 45 patients contained a smooth-muscle-contracting agent with prostaglandin-like properties. Solvent partition followed by thinlayer chromatography revealed this activity to be due to a mixture of prostaglandins E and F. This direct evidence supports the view that prostaglandins mediate inflammation in man.

Plasmapheresis for severe, unremitting, chronic urticaria

Histamine-releasing autoantibodies have been identified in chronic idiopathic urticaria. 8 patients with severe disease and histamine-releasing activity in their sera underwent plasmapheresis. Symptoms were abolished for 2 months in 1 patient and for 3 weeks in another, 2 showed almost complete resolution of symptoms, 2 had temporary relief, and the other 2 showed little change. Further investigation in 4 of the patients showed significantly reduced skin-test responses to fresh post-exchange autologous sera after plasmapheresis compared with stored pre-exchange sera, but the response to intradermal histamine remained unchanged. Blood cellular histamine increased as in-vitro serum histamine-releasing activity fell after plasmapheresis. These results favour a pathogenetic role for histamine-releasing autoantibodies in patients with chronic urticaria.

The extent and nature of disability in different urticarial conditions

Chronic forms of urticaria are common, often adversely impacting on quality of life. No formal studies have assessed the extent and nature of disability in different types of urticaria. The Dermatology Life Quality Index (DLQI) is a simple and validated 10‐item questionnaire designed to measure and compare disability in different skin conditions. In this study, we aimed to assess the disability in different urticarial groups using the DLQI, allowing comparison with previously published DLQI scores in common skin diseases. The DLQI was administered to 170 consecutive patients attending a specialist urticaria clinic over a 4‐month period. Consistent with previous studies using the DLQI, mean scores were not influenced by gender or age. Patients with chronic idiopathic urticaria without a concurrent physical urticaria (n = 47) suffered moderate quality of life impairment (mean ± SD DLQI 25 ± 24%). In comparison, patients with chronic idiopathic urticaria with concurrent delayed pressure urticaria (DPU) (n = 26) suffered significantly higher quality of life impairment (mean ± SD DLQI 43 ± 23%, 95% confidence interval for difference 7–29%). Disability in this group was greatest in the dimensions of work/study, symptoms/feelings and leisure. Subjects with another form of physical urticaria, cholinergic urticaria, also endured high levels of disability (n = 9, mean ± SD DLQI 50 ± 34%). From our urticaria study group, we have shown that subjects with DPU and cholinergic urticaria endure the most quality of life impairment. The mean DLQI scores demonstrated in these groups are comparable with those previously seen in severe atopic dermatitis out‐patients (60%) and higher than those seen in out‐patients with psoriasis (29.7%), acne (24.3%) and vitiligo (16.1%).

Pathophysiology of itching

Itching is the predominant symptom of skin disease but it is ill-understood and a challenge for future research. Even the major nerve pathways for itch, and its relationship to pain are debatable. In inflamed skin, histamine plays a major role and its mode of release from mast cells in, for example, chronic urticaria is now better appreciated. Tachykinins including substance P and cytokines including interleukin-2 are evidently important peripherally. Opioid mu-receptor-dependent processes activate inhibitory circuits in the central nervous system and regulate the extent of intensity and quality of perceived itch. It is proposed that stimulation of large areas of skin such as by scratching, generates inhibitory activity which suppresses itch excitation. Therapeutic intervention based upon understanding these regulatory processes is a real prospect.