Psoriasis is an inflammatory disease with dynamic interactions between the immune system and the skin. Recent studies have demonstrated that the interleukin (IL)‐23//T‐helper (Th)17 cell axis plays ...an important role in the pathogenesis of psoriasis. Here, the biology and function of Th17 cells as well as the crucial role of IL‐23 in the context of the Th17 cell‐dependent chronic inflammation in psoriatic skins are reviewed. Recent study about the role of the IL‐23//Th17 axis in the pathogenesis of psoriasis‐like lesions in K5.Stat3C transgenic mice is also discussed. This model mouse for psoriasis not only verifies the therapeutic efficacies of biologics that specifically target the IL‐23//Th17 axis, but also clarifies the pathogenesis of psoriasis.
Psoriasis is an inflammatory skin disorder that includes dynamic interactions between the immune system and skin and is clinically characterized by keratinocyte proliferation and distinct ...inflammatory cell infiltrates. Cross-talk between keratinocytes and immunocytes is essential for the development of psoriasis given that it mediates the production of cytokines, chemokines and growth factors. To resolve the pathogenesis of psoriasis, numerous experimental animal models have been generated. In this review, we discuss recent findings from mouse models, their relevancy to psoriasis and use, including the discovery of new therapies.
Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and systemic flushing accompanied by extensive sterile pustules. The committee of the guidelines was founded as ...a collaborative project between the Japanese Dermatological Association and the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labour, and Welfare Research Project on Overcoming Intractable Diseases. The aim of the guidelines was to provide current information to aid in the treatment of patients with GPP in Japan. Its contents include the diagnostic and severity classification criteria for GPP, its pathogenesis, and recommendations for the treatment of GPP. Since there are few clinical trial data with high levels of evidence for this rare disease, recommendations by the committee are described in the present guidelines.
Objective
To examine whether topical treatment of wild‐type mice with Toll‐like receptor 7 (TLR‐7) agonists leads to lupus‐like autoimmunity.
Methods
Wild‐type FVB/N, BALB/c, and C57BL/6 mice were ...treated with the topical TLR‐7 agonist imiquimod or R848 administered to the ear 3 times weekly. During treatment, the mice were monitored for serum autoantibody and creatinine levels as well as histopathology of the kidneys, spleens, livers, hearts, and skin. Immunologic abnormalities were analyzed by immunohistochemistry, quantitative reverse transcription–polymerase chain reaction, and fluorescence‐activated cell sorting. The role of plasmacytoid dendritic cells (PDCs) in the development of autoimmune disease was validated by in vivo treatment with an anti‐PDC antibody. Diseased mice underwent ultraviolet B irradiation, to evaluate skin photosensitivity. The disease‐causing effect of topical application of imiquimod was compared with that of systemic (intraperitoneal) administration. TLR‐7– and TLR‐9–deficient mice were used to validate the role of TLR‐7.
Results
Wild‐type mice of different genetic backgrounds developed systemic autoimmune disease following 4 weeks of topical treatment with imiquimod or R848, with elevated levels of autoantibodies to double‐stranded DNA and multiple organ involvement, including glomerulonephritis, hepatitis, carditis, and photosensitivity. Expression of Ifna and Mx1, the interferon‐α–stimulated gene, was up‐regulated in the organs of imiquimod‐treated mice. However, disease caused by intraperitoneal injection of imiquimod was less severe than that induced by topical application. In vivo depletion of PDCs by a specific antibody protected mice against the autoimmunity induced by topical administration of imiquimod, suggesting a role of PDCs. Furthermore, TLR‐7–deficient mice, but not TLR‐9–deficient mice, were protected against autoimmunity.
Conclusion
This protocol provides a novel model of inducible systemic lupus erythematosus in wild‐type mice and underscores the skin as the primary organ that allows TLR‐7 agonists to induce SLE.
Psoriasis is an inflammatory disease associated with aberrant crosstalk between the epidermis and immune system. However, the role of Langerhans cells (LCs) in psoriasis remains controversial.
To ...elucidate whether LCs are functionally involved in the development of psoriasis using a mouse model.
Two lines of transgenic mice were used and crossed. They included K5.Stat3C, the psoriasis-model mouse and langerin DTR knock-in (KI) mouse. We performed immunofluorescence staining for LCs in psoriatic lesion of human and model mice. Flow cytometric analyses were performed to compare between dendritic cells (DCs) and LCs in the epidermis and skin-draining lymph nodes (sDLNs). To assess cytokine/chemokine expression in the skin lesion or primary cultured keratinocytes, we performed RT-PCR, microarray analysis or intracellular staining on the flow cytometer.
LCs were activated in psoriatic lesion of patients with psoriasis and K5.Stat3C mice. Compared with non-transgenic mice, K5.Stat3C mice constitutively showed an increased number of LCs in the sDLNs before psoriasis-like lesion developed. Stat3C transgenic keratinocytes expressed an elevated level of IL-1α. Psoriasis-like lesion in K5.Stat3C mice were attenuated in the absence of LCs, indicating that LCs were essential to the development of psoriasis-like lesion. Furthermore, we also recognized that epidermal LCs in psoriatic lesion of not only K5.Stat3C mice but also psoriasis patients produced IL-23.
Our study suggests that Stat3 activation in keratinocytes may impact on LC activation in situ via IL-1α stimulation, at least in part, and that their presence may be essential for the pathogenesis of psoriasis through producing IL-23.
Dermatitis herpetiformis is an autoimmune bullous disease that is associated with gluten sensitivity which typically presents as celiac disease. As both conditions are multifactorial disorders, it is ...not clear how specific pathogenetic mechanisms may lead to the dysregulation of immune responses in the skin and small bowel, respectively. Recent studies have demonstrated that IgA and antibodies against epidermal transglutaminase 3 play an important role in the pathogenesis of dermatitis herpetiformis. Here, we review recent immunopathological progress in understanding the pathogenesis of dermatitis herpetiformis.
Generalized pustular psoriasis (GPP) is a rare inflammatory skin disease that can be life-threatening. Recently, it has been reported that familial GPP is caused by homozygous or compound ...heterozygous mutations of IL36RN. However, the majority of GPP cases are sporadic and it is controversial whether IL36RN mutations are a causative/predisposing factor for sporadic GPP. We searched for IL36RN mutations in two groups of GPP patients in the Japanese population in this study: GPP without psoriasis vulgaris (PV), and GPP with PV. Eleven cases of GPP without PV (GPP alone) and 20 cases of GPP accompanied by PV (GPP with PV) were analyzed. Surprisingly, 9 out of 11 cases of GPP alone had homozygous or compound heterozygous mutations in IL36RN. In contrast, only 2 of 20 cases of GPP with PV had compound heterozygous mutations in IL36RN. The two cases of GPP with PV who had compound heterozygous mutations in IL36RN are siblings, and both cases had PV-susceptible HLA-A*0206. We determined that GPP alone is a distinct subtype of GPP and is etiologically distinguished from GPP with PV, and that the majority of GPP alone is caused by deficiency of the interleukin-36 receptor antagonist due to IL36RN mutations.
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