Involvement of complement in psoriasis and atopic dermatitis — Measurement of C3a and C5a,C3, C4 and C1 inactivator

Summary Normal complement components and activation products were determined in the peripheral blood of 35 patients with atopic dermatitis (AD) and 24 patients with psoriasis at a mild to intermediate stage. None of the patients had received systemic or local steroid therapy 6 weeks prior to blood collection. Levels of C3, C4 and C1 inactivator (C1 INA) were determined in serum by radial immunodiffusion, whereas C3a and C5a levels were measured by radioimmunoassay. In comparison to healthy non-atopic controls, the levels of C3, C4 and C1 INA were found to be significantly increased in both diseases. No substantial differences were detected between patients with psoriasis vulgaris and psoriasis guttata, which suggests that the dissimilarities found were not due to preceding or concomitant infections. In AD, there was a tendency towards increased C3a levels, whereas in psoriasis, C3a levels were significantly increased. In both diseases, no measurable amounts of C5a could be detected. The results indicate that, in both AD and psoriasis, the complement participates in the inflammatory process. Elevated levels of C3a suggest that there is a continuous activation of the complement system leading to the generation of inflammatory mediators.     

Increased anaphylatoxins (C3a and C4a) in psoriatic sera

We measured C3a and C4a anaphylatoxins in the serum of 56 psoriatic patients and 36 healthy control subjects by radioimmunoassay in order to clarify the mechanism of complement activation occurring in psoriatic lesions. Whereas a small amount of anaphylatoxins were demonstrable even in the sera of healthy adults, the serum concentrations of C3a and C4a anaphylatoxins were significantly higher in psoriatic patients than those in non-psoriatic controls. The increased serum anaphylatoxin levels did not correlate well with either the extent or the activity of the skin lesions, but a comparison of anaphylatoxin levels in 10 patients before and after successful treatment of skin lesions showed that the serum anaphylatoxin levels decreased with improvement of the skin lesions. Our results suggest that complement activation takes place in psoriatic patients chiefly via the classical pathway.     

Human plasmacytoid dendritic cells express receptors for anaphylatoxins C3a and C5a and are chemoattracted to C3a and C5a

The presence of plasmacytoid dendritic cells (pDC) was recently demonstrated in lesions of inflammatory skin diseases. Since anaphylatoxins or their precursors were also found in such lesions, we investigated a possible interaction between pDC and anaphylatoxins C3a and C5a. pDC precursors isolated from peripheral blood did not express the receptors for C3a and C5a, complement C3a receptor (C3aR) and complement C3a receptor (C5aR). If these pDC precursors were cultured with IL-3, the resultant immature pDC expressed both receptors. Expression of C3aR and C5aR could also be demonstrated on pDC in lesions of cutaneous lupus erythematosus and allergic contact dermatitis. Such pDC were immature since they lacked the expression of the maturation marker CD83. Blood-derived pDC matured with CpG oligonucleotides downregulated the receptors. Immature pDC responded to C3a and C5a (but not C3adesArg) stimulation with increased F-actin polymerization and chemotactic migration. In contrast, interferon alpha production, surface molecule expression, and T-cell stimulatory capacity were not significantly modulated by C3a or C5a. Thus, immature pDC represent another type of antigen-presenting cell that express C3aR and C5aR, and respond to anaphylatoxins with chemotaxis. This might be relevant in the direction of pDC to cutaneous lesions of inflammation, for example, in lupus erythematosus or contact dermatitis.     

Atopic dermatitis. IV. The role of proteinase inhibitors in the pathogenesis, assessment of the severity and the prognosis of the disease

Examinations of 59 patients with atopic dermatitis have revealed increased content of the major inhibitors of proteinases, a relationship between the patients' age and alpha 2-macroglobulin level in both the patients and the reference group normal subjects. Detection of correlations between alpha 1-proteinase inhibitor and serum IgE as well as between C1 inactivator and C3c have lead to a supposition on the contribution of proteinase inhibitors in the modulation of immune reactions. Clinical features of atopic dermatitis in alpha 1-proteinase inhibitor deficiency and in various blood serum IgE levels are discussed.     

Atopic dermatitis. III. The role of immune complexes in the pathogenesis, assessment of the severity and the prognosis of the disease

Examinations of 78 patients with atopic dermatitis have confirmed the important role played by the immune complexes in the immunopathological and inflammatory processes. In atopic dermatitis elevated concentrations of immune complexes could be detected only in the patients with a severe diffuse process. The findings evidence that the most informative parameters of circulating immune complexes are their size and composition, that are of diagnostic and prognostic value in this condition. Studies of the relationships between the characteristics of immune complexes and the parameters of the immune status of patients have revealed correlations between serum IgE levels and immune complexes IgM, as well as between C4 concentration and size of the immune complexes.     

Atopic dermatitis and the indoor climate. The effect from preventive measures

Nine patients with atopic dermatitis (AD) were clinically evaluated before and after moving to new houses with improved air exchange, low relative humidity and optimal temperature control. During a 2-year period three clinical and subjective assessments were performed each month of disease activity, and compared with changes in suspended and respirable dust particles, room temperature, air exchange rate, concentration of house-dust mites in bedrooms, and the concentration of organic solvents in the indoor air. Ten matched patients with AD, who did not move, served as a control group. The skin condition of patients moved improved significantly after moving. The indoor climate was improved on: 1) air exchange rate, 2) relative humidity, and 3) room temperature, but the amounts of house dust mites, respirable air particles and organic solvents were unchanged. The clinical and subjective improvement in AD could not be correlated to any single indoor environmental factor. The present investigation supports the current concept, that AD may be a multifactorial disease, and that the indoor climate may be a contributing factor affecting the eczema.     

IgA and C3 complement in the uninvolved skin in dermatitis herpetiformis after gluten withdrawal

IgA deposits in the skin in 53 patients with dermatitis herpetiformis (DH) have been studied in relation to treatment. In 19 patients the disorder was controlled by a gluten-free diet (GFD) alone, in 13 patients by dapsone and GFD and in 18 by dapsone alone. In 3 patients the skin disorder became insignificant and required no treatment. Of the patients taking a GFD alone, six had been clear of skin lesions for 7 years, 5 for 3–5 years, and 8 for periods of 6 months-3 years. IgA deposits were found in all patients in an initial biopsy and in a second biopsy after treatment for periods varying from I to 7 years. There was no difference in the quantity of IgA, as assessed by the amount of fluorescence, whether patients were controlled with a GFD alone, GFD and dapsone, dapsone alone, or in those in clinical remission. The C₃ component of complement was present in the skin in 3 of the 19 patients (16%) controlled by a GFD alone, 6 of the 13 patients (46%) of those controlled by a GFD and dapsone, and in 12 of 18 (66%) of the patients taking dapsone alone, and in one of the patients in clinical remission.     

Participation of complement 3a receptor (C3aR) in the sensitization phase of Th2 mediated allergic contact dermatitis

The complement system has emerged as a bridge between innate and adaptive immune responses. An involvement of C3aR has been described during skin inflammation. The aim of the study was to investigate the role of C3a in a mouse model of allergic skin inflammation, such as allergic contact dermatitis (ACD) which is a clinical manifestation of contact sensitivity (CS). The sensitization phase was studied using the local lymph node test: Mice were sensitized on three consecutive days by application of non-irritant concentrations of toluene-2,4-diisocyanate (TDI; 0.5%) onto the ear skin. On day 5, auricular draining lymph nodes were obtained. The elicitation phase was investigated by sensitization with TDI on the depilated and tape-stripped abdominal skin and challenge with TDI on the ear skin and measuring of ear swelling in vivo and cytokine secretion in activated splenocytes in vitro respectively. Complement 3a receptor deficient (C3aRKO) mice showed increased cytokine responses (interleukin[IL]-5, IL-6, IL-17, granulocyte macrophage-colony stimulating factor [GM-CSF]) in the sensitization phase of ACD to TDI. However, no differences in CS responses to TDI were observed in C3aR KO mice compared with WT controls in the elicitation phase of ACD as assessed by measuring of ear swelling in vivo and cytokines in skin and in activated splenocytes in vitro, namely IL-1α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, interferon-γ (IFN-γ), GM-CSF and tumor necrosis factor (TNF)-α. These findings provide a new insight into the participation of C3a in the sensitization phase of CS immune responses.     

The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis II. Observer variation of clinical diagnosis and signs of atopic dermatitis

The level of agreement between 14 physicians as to what constitutes a case of atopic dermatitis was tested on 15 selected patients with a range of diagnoses. Between-observer agreement was good, with a mean pair agreement index (P₀) of 0.94, and a chance corrected index (κ) of 0.78. Between- observer agreement in the recording of 18 separate physical signs of atopic dermatitis was then tested by asking the 14 physicians to note the presence or absence of each sign in a different group of patients to those seen in the first part of the exercise. Substantial between-observer agreement (κ>0.61) was only present for truncal dermatitis. Most signs showed only fair to moderate agreement (κ0.21–0.60), and some signs, such as keratosis pilaris, xerosis, orbital pigmentation, fine hair, and extensor dermatitis, showed poor agreement (κ0.01–0.20). The findings were similar when the responses of two independent observers from the national study outlined in Paper I were compared for each sign. Within-observer variation for the recording of physical signs was substantially better than between-observer variation. Physicians interested in atopic dermatitis agree reasonably well on what constitutes a typical case of atopic dermatitis. Between-observer variation with regard to some physical signs of atopic dermatitis is of a magnitude which argues against their continued use in clinical and epidemiological studies.     

Pustular irritant dermatitis due to croton oil. Evaluation of the role played by leukocytes and complement

To elucidate the pathomechanisms of irritant pustular dermatitis and to evaluate the role of leukocytes in pustulation induced by croton oil, we compared the skin responses in leukopenic-and decomplemented guinea pigs with those in control saline-injected animals, to 1% croton oil application. Both decomplemented and control animals responded similarly to croton oil, showing erythema and pustulation at 24 h after topical application; microscopically numerous mononuclear and polymorphonuclear cells infiltrated the skin. Meanwhile, the clinical and histopathological response of leukopenic animals to croton oil was significantly depressed. Time-course study of inflammatory infiltrate in the dermis of controls revealed that mononuclear cells preceded the infiltration of polymorphonuclears. Although leukocytes constitute an important component in croton oil dermatitis, our results suggest that unclarified chemical mediators, other than complement-derived chemotactic factors, play a crucial role as a primary chemoattractant in the production of pustulation at the croton oil-applied site.     

Atopic dermatitis. I. Characteristics of the clinical course and state of the immune status in relation to the initial level of serum IgE

Altogether 97 patients with atopic dermatitis have been examined to follow this relationship, 72 patients presented with disseminated efflorescence, 25 patients with local rash. Measurements of immunoglobulins A, M, G, and D, of the C3c complement components, of the total and allergen-specific IgE C4, inactivators have been carried out, as well as of the total lymphocyte, B lymphocyte, and CD3+, CD4+, and CD8+ lymphocyte subpopulations; the lymphocyte response to ConA mitogenic stimulation has been also under study. The patients with normal and elevated levels of IgE differed by the clinical picture of the disease and by case histories, as well as by the immunity parameters and by the results of zaditen therapy. Cases with very low IgE levels may be indicative of alternative pathogenetic mechanisms.     

Prevalence of atopic dermatitis, asthma, allergic rhinitis, and hand and contact dermatitis in adolescents. The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis

BACKGROUND: Atopic diseases are common in children and adolescents. However, epidemiological knowledge is sparse for hand eczema and allergic contact dermatitis in this age group. Furthermore, no population-based studies have evaluated the prevalence of atopic diseases and hand and contact dermatitis in the same group of adolescents. OBJECTIVES: To assess prevalence measures of atopic dermatitis (AD), asthma, allergic rhinitis and hand and contact dermatitis in adolescents in Odense municipality, Denmark. METHODS: The study was carried out as a cross-sectional study among 1501 eighth grade school children (age 12-16 years) and included questionnaire, interview, clinical examination and patch testing. RESULTS: The lifetime prevalence of AD was 21.3% (girls 25.7% vs. boys 17.0%, P < 0.001) using predefined questionnaire criteria. The 1-year period prevalence of AD was 6.7% and the point prevalence 3.6% (Hanifin and Rajka criteria). In the interview the lifetime prevalence of inhalant allergy was estimated as 17.7% (6.9% allergic asthma, 15.7% allergic rhinitis). The lifetime prevalence of hand eczema based on the questionnaire was 9.2%, the 1-year period prevalence was 7.3% and the point prevalence 3.2%, with a significant predominance in girls. A significant association was found both between AD and inhalant allergy, and between AD and hand eczema using lifetime prevalence measures. The point prevalence of contact allergy was 15.2% (girls 19.4% vs. boys 10.3%, P < 0.001), and present or past allergic contact dermatitis was found in 7.2% (girls 11.3% vs. boys 2.5%). Contact allergy was most common to nickel (8.6%) and fragrance mix (1.8%). CONCLUSIONS: High prevalence figures were found for atopic diseases, hand eczema and allergic contact dermatitis, and the diseases were closely associated. A considerable number of adolescents still suffers from AD, and a considerable sex difference was noted for hand eczema and allergic contact dermatitis. Nickel allergy and perfume allergy were the major contact allergies. In the future this cohort of eighth grade school children will be followed up with regard to the course and development of atopic diseases, hand eczema and contact dermatitis.     

慢性荨麻疹患者红细胞补体受体1分子表达及外周血IgE和补体C3、 C4水平的相关性研究

目的 探讨红细胞补体受体1(CR1)在慢性荨麻疹发病机制中的作用及意义.方法 慢性荨麻疹患者59例,其中含人工划痕症14例,慢性特发性荨麻疹45例,采用流式细胞仪检测外周血红细胞CR1的表达,并采用双抗体夹心酶联免疫吸附法(ELISA)检测外周血补体C3、C4、CH50及IgE水平.29例健康人作为对照组.利用ONE-WAY ANOVA进行三组样本间均数比较,两组均数的比较采用独立样本t检验,相关分析采用Pearson相关分析法.结果 外周血红细胞CR1的表达水平人工划痕症组为35.06±2.06(10 000个红细胞表面的荧光强度)、慢性特发性荨麻疹组为29.17±1.53,均高于健康对照组(20.46±2.57),t值分别为4.20、3.33,P值均＜0.05,人工划痕症组与慢性特发性荨麻疹组间差异无统计学意义(P＞0.05).外周血IgE水平人工划痕症组为(769.89±123.06) μg/L,慢性特发性荨麻疹组为(340.09±29.74) μg/L,均高于健康对照组(107.63±88.79μg/L),t值分别为5.58、5.85,P值均＜0.05,人工划痕症组高于慢性特发性荨麻疹组(t=3.49,P＜ 0.05).慢性荨麻疹患者中IgE为0～240 μg/L的22例患者CR1水平(24.45±10.83)与IgE为500 μg/L以上的17例患者CR1水平(33.09±11.86)差异有统计学意义(t=3.33,P＜0.05).血清总IgE与CR1水平呈显著正相关(r=0.27,P＜ 0.05),与C3(r=0.16,P＞ 0.05)、C4(r=-0.08,P＞ 0.05)均无相关性.C3与C4具有正相关(r=0.54,P＜ 0.01).3组C3、C4和CH50水平经ONE-WAY ANOVA检验,差异均无统计学意义(P＞0.05).结论 红细胞CR1在慢性荨麻疹患者中的表达存在异常.