Does allergy impair innate immunity? Leads and lessons from atopic dermatitis.

Host defence responses against invading pathogens are well-balanced, inflammatory processes of the innate and adaptive immune system. Impaired development or abnormal function of either system can result in failure to control pathogens and to clear infections. Infections have been claimed to modulate the onset and course of allergic diseases. This so-called hygiene hypothesis is still an active area of research. In contrast, the effects of allergies on infections and pathogen-directed immune responses are less well understood. Here, we have reviewed the existing evidence that allergies result in impaired innate immunity and we discuss recent observations that may explain why and how innate immunity is dysfunctional in allergic patients. With a focus on atopic dermatitis as a model of allergic disease, we speculate that one of the key features of allergic conditions, namely Th2 polarization, leads to several independent inhibitory effects on host defence and consequently to a higher risk of infections in allergic patients. A better understanding of impaired host defence and its mechanisms in allergic subjects will help to improve the management of these diseases.

Innate immunity in atopic dermatitis.

One of the most important functions of the skin is to provide protection from infectious pathogens. This is achieved by two complex and complementary powerful strategies, namely by preventing pathogen invasion and by raising innate and/or adaptive immune responses following infection. Most pathogens cannot penetrate healthy skin, and the vast majority of skin infections, thus, results from breaches of cutaneous integrity (skin wounds, arthropod bites, barrier function defects). Cutaneous infections, in turn, are controlled primarily by a functioning skin innate immune system and efficient host defence responses. Patients with atopic dermatitis (AD) exhibit both, impaired skin barrier function and defects in skin innate immunity. As a result, AD patients frequently develop skin infections which contribute to the pathogenesis and the course of their chronic inflammatory skin condition. Here, we discuss how skin innate immunity works in healthy individuals and how skin innate immunity is impaired in patients with AD.

Deficiency in immunoglobulin G2 antibodies against staphylococcal enterotoxin C1 defines a subgroup of patients with atopic dermatitis.

BACKGROUND AND AIM: Atopic dermatitis (AD) is a common chronic inflammatory skin disease often accompanied by cutaneous Staphylococcus aureus colonization and, in this regard, especially complicated by the presence of superantigen-producing strains. Because IgG antibodies comprise an important defence mechanism of the adaptive immune system against bacteria, it was investigated whether AD patients have an abnormal pattern or distribution of superantigen-specific IgG subclass antibodies in association with disease severity and activity. METHODS: Staphylococcal enterotoxin B (SEB) and staphylococcal enterotoxin C1 (SEC1) specific IgG antibody subclasses were assessed in n=89 adult AD patients with mild to severe disease activity as determined by the SCORAD score and in n=28 healthy age-matched controls. Results were correlated with the current status of bacterial skin colonization and severity score. RESULTS: Thirty-eight per cent of the AD patients showed a selective deficiency in IgG2 antibodies against SEC1 compared with only 14% in the control group. The absence of these antibodies was found in both currently colonized and non-colonized AD patients and was associated with a severe phenotype (SCORAD more than 40 points in two-thirds of the deficient patients). However, these patients had normal production levels of IgG2 antibodies against pneumococcal capsular polysaccharide (PCP) and SEB, but higher IgG1 and IgG4 titres against SEC1. Except for elevated total IgG1, total IgG subclass levels were normal in this AD subgroup. Yet, peripheral blood mononuclear cells (PBMCs) derived from these patients clearly produced IL-4 and IL-5 upon SEC1 re-stimulation whereas PBMCs from those providing SEC1-specific IgG2 antibodies failed in the production of these cytokines. CONCLUSION: A subgroup of AD patients suffers from a selective deficiency to produce anti-SEC1 IgG2 antibodies. This patient group is characterized by a severe AD phenotype.

Alpha-toxin is produced by skin colonizing Staphylococcus aureus and induces a T helper type 1 response in atopic dermatitis.

BACKGROUND: Staphylococcus aureus is a well known trigger factor of atopic dermatitis (AD). Besides the superantigens, further exotoxins are produced by S. aureus and may have an influence on the eczema. OBJECTIVE: To explore the impact of staphylococcal alpha-toxin on human T cells, as those represent the majority of skin infiltrating cells in AD. METHODS: Adult patients with AD were screened for cutaneous colonization with alpha-toxin producing S. aureus. As alpha-toxin may induce necrosis, CD4(+) T cells were incubated with sublytic alpha-toxin concentrations. Proliferation and up-regulation of IFN-gamma on the mRNA and the protein level were assessed. The induction of t-bet translocation in CD4(+) T cells was detected with the Electrophoretic Mobility Shift Assay. RESULTS: Thirty-four percent of the patients were colonized with alpha-toxin producing S. aureus and alpha-toxin was detected in lesional skin of these patients by immunohistochemistry. Sublytic alpha-toxin concentrations induced a marked proliferation of isolated CD4(+) T cells. Microarray analysis indicated that alpha-toxin induced particularly high amounts of IFN-gamma transcripts. Up-regulation of IFN-gamma was confirmed both on the mRNA and the protein level. Stimulation of CD4(+) T cells with alpha-toxin resulted in DNA binding of t-bet, known as a key transcription factor involved into primary T helper type 1 (Th1) commitment. CONCLUSION: alpha-toxin is produced by S. aureus isolated from patients with AD. We show here for the first time that sublytic alpha-toxin concentrations activate T cells in the absence of antigen-presenting cells. Our results indicate that alpha-toxin is relevant for the induction of a Th1 like cytokine response. In AD, this facilitates the development of Th1 cell dominated chronic eczema.