Alexandra Gruber-Wackernagel

Involvement of IL-9 in Th17-Associated Inflammation and Angiogenesis of Psoriasis

It is thought that a Th1/Th17-weighted immune response plays a predominant role in the pathogenesis of psoriasis. Our findings now indicate a link between IL-9, a Th2 and Th9 cytokine, and Th17 pathway in psoriasis. In K5.hTGF-β1 transgenic mice, exhibiting a psoriasis-like phenotype, we found increased IL-9R and IL-9 expression in the skin and intradermal IL-9 injection induced Th17-related inflammation. IL-9 also promoted angiogenesis and VEGF and CD31 overexpression in mice in vivo and increased tube formation of human endothelial cells in vitro. Injecting anti-IL-9 antibody into K5.hTGF-β1 transgenic mice not only diminished inflammation (including skin infiltration by T cells, monocytes/macrophages, and mast cells) and angiogenesis but also delayed the psoriasis-like skin phenotype. Notably, injection of anti-psoriatic acting anti-IL-17 antibody reduced skin IL-9 mRNA and serum IL-9 protein levels in K5.hTGF-β1 transgenic mice and prevented IL-9-induced epidermal hyperplasia and inflammation of the skin of wild type mice. In addition, we observed that IL-9R expression in lesional skin from psoriasis patients was markedly higher than in healthy skin from control subjects. Moreover, IL-9 significantly enhanced IL-17A production by cultured human peripheral blood mononuclear cells or CD4+ T cells, especially in psoriasis patients. Thus, IL-9 may play a role in the development of psoriatic lesions through Th17-associated inflammation and angiogenesis.

Efficacy of psoralen plus ultraviolet A therapy vs. biologics in moderate to severe chronic plaque psoriasis: retrospective data analysis of a patient registry.

Background  Few studies have directly compared the clinical efficacy of psoralen plus ultraviolet A (PUVA) vs. biologics in the treatment of psoriasis.

Treatment with 311-nm ultraviolet B enhanced response of psoriatic lesions in ustekinumab-treated patients: a randomized intraindividual trial

Background  Treatment with the interleukin‐12/23 antibody ustekinumab produces a satisfactory response [i.e. 75% reduction in Psoriasis Area and Severity Index (PASI) compared with baseline (PASI 75)] in the majority of patients with moderate to severe chronic plaque‐type psoriasis.

Randomized double-blinded placebo-controlled intra-individual trial on topical treatment with a 1,25-dihydroxyvitamin D3 analogue in polymorphic light eruption

Background  Polymorphic light eruption (PLE) is a very frequent photodermatosis whose pathogenesis may involve resistance to ultraviolet (UV)‐induced immune suppression. Similar to UV radiation, calcitriol (1,25‐dihydroxyvitamin D3) and its analogues such as calcipotriol have been shown to exhibit immunosuppressive properties.

New insights into the mechanisms of polymorphic light eruption : resistance to ultraviolet radiation-induced immune suppression as an aetiological factor

Abstract:  An abnormal immune response has long been thought responsible for the patho‐aetiology of polymorphic light eruption, the most common photodermatosis. Recent evidence indicates that polymorphic light eruption patients are resistant to the immune suppressive effects of sunlight, a phenomenon that leads to the formation of skin lesions upon seasonal sun exposure. This immunological abnormality in polymorphic light eruption supports the concept of the biological significance and evolutionary logic of sunlight‐induced immune suppression, i.e. the prevention of immune responses to photo‐induced neo‐antigens in the skin, thereby preventing autoimmunity and skin rashes. This article focuses on the immunological alterations in polymorphic light eruption and the pathogenic significance to the disease state and skin carcinogenesis.

311 nm ultraviolet B-accelerated response of psoriatic lesions in adalimumab-treated patients.

Background: Treatment with the tumor necrosis factor‐alpha antibody adalimumab for 12–16 weeks produces a satisfactory response [i.e., 75% reduction in psoriasis area and severity index (PASI)] in a majority (70–80%) of patients with psoriasis. We asked whether 311 nm ultraviolet B (UVB) can improve therapeutic response of psoriatic lesions to adalimumab.

Polymorphous light eruption: clinic aspects and pathogenesis.

Polymorphous light eruption is an immunologically mediated photodermatosis with high prevalence, particularly among young women in temperate climates, characterized by pruritic skin lesions of variable morphology, occurring in spring or early summer on sun-exposed body sites. A resistance to ultraviolet radiation (UVR)-induced immunosuppression and a subsequent delayed-type hypersensitivity response to a photoantigen have been suggested as key factors in the disease. Molecular and immunologic disturbances associated with disease pathogenesis include a failure of skin infiltration by neutrophils and other regulatory immune cells on UVR exposure linked to a disturbed cytokine microenvironment. Standard management is based on prevention.

Levels and function of regulatory T cells in patients with polymorphic light eruption: relation to photohardening

We hypothesized that regulatory T cells (Tregs) are involved in the immunological abnormalities seen in patients with polymorphic light eruption (PLE).

Patients with polymorphic light eruption have decreased serum levels of 25-hydroxyvitamin-D3 that increase upon 311 nm UVB photohardening

BACKGROUND Polymorphic light eruption (PLE) is a very common condition whose pathogenesis may involve immunological abnormalities. Vitamin D sufficiency is thought to be important for normal immune function. OBJECTIVE To determine whether PLE patients are vitamin D deficient and to study how photohardening with 311 nm UVB affects the vitamin D status of PLE patients. METHODS The vitamin D status of 23 PLE patients (21 females and 2 males; age range, 18-55 years) was analysed at four different time points (early spring, late spring, summer, and winter) by measuring 25-hydroxyvitamin-D(3) (25(OH)D) serum levels through a standardised immunoassay. Fifteen of those patients received 311 nm UVB in early spring for prevention of PLE symptoms. 25(OH)D levels of the PLE patients were compared to that of 23 sex-, age-, and body-mass-index post hoc-matched control subjects. RESULTS PLE patients had low levels of 25(OH)D throughout the year compared to that of the control subjects. At baseline in early spring, the mean ± SD 25(OH)D level was 14.9 ± 3.0 ng ml(-1) in the PLE patients that would later receive 311 nm UVB and 14.4 ± 2.4 ng ml(-1) in the patients not receiving 311 nm UVB. Successful prophylactic treatment with 311 nm UVB significantly increased 25(OH)D levels to a mean of 21.0 ± 3.4 ng ml(-1) (p < 0.001; ANOVA, Tukeys test). Heading into summer, the 25(OH)D levels in treated patients decreased again, reaching their lowest levels in winter. In contrast, the 25(OH)D levels of untreated PLE patients stayed in the low range in early and late spring but increased by trend towards summer, reaching similar levels to that of the PLE patients who had received 311 nm UVB (17.1 ± 2.3 vs. 17.3 ± 6.0 ng ml(-1)). Like the treated PLE patients, 25(OH)D levels of untreated patients significantly decreased in winter to comparable levels (12.2 ± 1.9 vs. 13.8 ± 1.8 ng ml(-1)). Taken together, the 25(OH)D levels of PLE patients were significantly lower at all time points than that observed in the matched control population (34.4 ± 12.5 ng ml(-1)) (p < 0.000003). CONCLUSIONS PLE patients have low 25(OH)D serum levels. 311 nm UVB phototherapy that prevented PLE symptoms increased those levels. Thus, we speculate that boosting levels of vitamin D may be important in ameliorating PLE.

Photohardening of polymorphic light eruption patients decreases baseline epidermal Langerhans cell density while increasing mast cell numbers in the papillary dermis

The pathogenesis of polymorphic light eruption (PLE) has been linked to a lack of UV‐induced immune suppression. To determine the role of Langerhans cells (LC), mast cells and regulatory T cells, biopsies from PLE patients were taken from exposed sites in spring before and after photohardening with 311 nm or PUVA as well as again in summer. Skin sections were assessed for the presence of Langerin/CD1a+ LC and CD3+, CD4+, CD25+ or FoxP3+ T cells and mast cells. Photohardening transiently decreased the density of epidermal LC and significantly increased a low baseline mast cell density in the papillary dermis of PLE patients. Baseline T cell numbers in the skin were low, and there was no difference in PLE patients among any time point. This suggests that LC suppression together with recruitment of mast cells into photohardened skin may be a key cellular event underlying the mechanism by which phototherapy protects from PLE.