Detection of N-glycolyl-neuraminic acid-containing glycolipids in human skin.

Humans lack the enzyme that produces the sialic acid N-glycolyl neuraminic acid (Neu5Gc), but several lines of evidence have shown that Neu5Gc can be taken up by mammalian food sources and replace the common human sialic acid N-acetyl neuraminic acid (Neu5Ac) in glycans. Cancer tissue has been shown to have increased the presence of Neu5Gc and Neu5Gc-containing glycolipids such as the ganglioside GM3, which have been proposed as tumor-specific antigens for antibody treatment. Here, we show that a previously described antibody against Neu5Gc-GM3 is binding to Neu5GC-containing gangliosides and is strongly staining different cancer tissues. However, we also found a strong intracellular staining of keratinocytes of healthy skin. We confirmed this staining on freshly isolated keratinocytes by flow cytometry and detected Neu5Gc by mass spectrometry. This finding implicates that non-human Neu5Gc can be incorporated into gangliosides in human skin, and this should be taken into consideration when targeting Neu5Gc-containing gangliosides for cancer immunotherapy.

Interleukin-13 Receptor α1-Mediated Signaling Regulates Age-Associated/Autoimmune B Cell Expansion and Lupus Pathogenesis.

OBJECTIVE: Age-associated/autoimmune B cells (ABCs) are an emerging B cell subset with aberrant expansion in systemic lupus erythematosus. ABC generation and differentiation exhibit marked sexual dimorphism, and Toll-like receptor 7 (TLR-7) engagement is a key contributor to these sex differences. ABC generation is also controlled by interleukin-21 (IL-21) and its interplay with interferon-γ and IL-4. This study was undertaken to investigate whether IL-13 receptor α1 (IL-13Rα1), an X-linked receptor that transmits IL-4/IL-13 signals, regulates ABCs and lupus pathogenesis. METHODS: Mice lacking DEF-6 and switch-associated protein 70 (double-knockout [DKO]), which preferentially develop lupus in females, were crossed with IL-13Rα1-knockout mice. IL-13Rα1-knockout male mice were also crossed with Y chromosome autoimmune accelerator (Yaa) DKO mice, which overexpress TLR-7 and develop severe disease. ABCs were assessed using flow cytometry and RNA-Seq. Lupus pathogenesis was evaluated using serologic and histologic analyses. RESULTS: ABCs expressed higher levels of IL-13Rα1 than follicular B cells. The absence of IL-13Rα1 in either DKO female mice or Yaa DKO male mice decreased the accumulation of ABCs, the differentiation of ABCs into plasmablasts, and autoantibody production. Lack of IL-13Rα1 also prolonged survival and delayed the development of tissue inflammation. IL-13Rα1 deficiency diminished in vitro generation of ABCs, an effect that, surprisingly, could be observed in response to IL-21 alone. RNA-Seq revealed that ABCs lacking IL-13Rα1 down-regulated some histologic characteristics of B cells but up-regulated myeloid markers and proinflammatory mediators. CONCLUSION: Our findings indicate a novel role for IL-13Rα1 in controlling ABC generation and differentiation, suggesting that IL-13Rα1 contributes to these effects by regulating a subset of IL-21-mediated signaling events. These results also suggest that X-linked genes besides TLR7 participate in the regulation of ABCs in lupus.

Siglec Receptors Modulate Dendritic Cell Activation and Antigen Presentation to T Cells in Cancer.

Interactions between sialylated glycans and sialic acid-binding immunoglobulin-like lectin (Siglec) receptors have been recently described as potential new immune checkpoint that can be targeted to improve anticancer immunity. Myeloid cells have been reported to express a wide range of different Siglecs; however, their expression and functions on cancer-associated dendritic cells (DCs) were not fully characterized. We found that classical conventional DCs (cDCs) from cancer patient samples have a high expression of several inhibitory Siglecs including Siglec-7, Siglec-9, and Siglec-10. In subcutaneous murine tumor models, we also found an upregulation of the inhibitory Siglec-E receptor on cancer-associated cDCs. DC lines and bone marrow-derived DCs (BMDCs) with expression of these inhibitory Siglecs showed impaired maturation states on transcriptome and protein level. Furthermore, ablation of these inhibitory Siglecs from DCs enhanced their capability to prime antigen-specific T cells and induce proliferation. Our work provides a deeper understanding of the influence of inhibitory Siglecs on DCs and reveals a potential new target to improve cancer immunotherapy.

Altered function and differentiation of age-associated B cells contribute to the female bias in lupus mice.

Differences in immune responses to viruses and autoimmune diseases such as systemic lupus erythematosus (SLE) can show sexual dimorphism. Age-associated B cells (ABC) are a population of CD11c+T-bet+ B cells critical for antiviral responses and autoimmune disorders. Absence of DEF6 and SWAP-70, two homologous guanine exchange factors, in double-knock-out (DKO) mice leads to a lupus-like syndrome in females marked by accumulation of ABCs. Here we demonstrate that DKO ABCs show sex-specific differences in cell number, upregulation of an ISG signature, and further differentiation. DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c- effector B cell populations with pathogenic and pro-inflammatory function as demonstrated by BCR sequencing and fate-mapping experiments. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs, resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function and differentiation of ABCs that accompanies TLR7-driven immunopathogenesis.

Targeting glyco-immune checkpoints for cancer therapy.

Introduction: Targeting immune checkpoints with antibodies has significantly improved the outcome of cancer patients, but only few patients have long-term benefits from currently used PD-1/PD-L1 and CTLA-4 inhibitors. New approaches are needed to increase the number of patients going into long-term remission after cancer immunotherapy. Glyco-immune checkpoints are new targets for cancer immunotherapy. They are defined as immune-modulatory pathways including interactions of glycans with glycan-binding proteins or lectins. The most prominent pathway is the sialoglycan-Siglec axis and inhibitors of this axis are already successfully tested in early clinical trials.Area covered: Here, we summarize the current knowledge on glyco-immune checkpoints with a focus on the sialoglycan-Siglec axis. We also provide an overview on current approaches to clinically target glyco-immune checkpoints and give an outlook for the further clinical development of glyco-immune checkpoint targeting agents.Expert opinion: Glyco-immune checkpoints are interesting new targets to improve cancer immunotherapy. Antibodies targeting the sialoglycan-Siglec axis are already in clinical development. Other approaches with higher risk of toxicity including tumor-targeted sialidases are in late stage pre-clinical development. Despite the challenges, targeting of glyco-immune checkpoints could lead to the development of a new class of drugs providing improved anti-cancer immunity and eventually benefit cancer patients.

Selective dysregulation of ROCK2 activity promotes aberrant transcriptional networks in ABC diffuse large B-cell lymphoma.

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive subtype of lymphoma usually associated with inferior outcomes. ABC-DLBCL exhibits plasmablastic features and is characterized by aberrancies in the molecular networks controlled by IRF4. The signaling pathways that are dysregulated in ABC-DLBCL are, however, not fully understood. ROCK2 is a serine-threonine kinase whose role in lymphomagenesis is unknown. Here we show that ROCK2 activity is constitutively dysregulated in ABC-DLBCL but not in GCB-DLBCL and BL. We furthermore show that ROCK2 phosphorylates IRF4 and that the ROCK2-mediated phosphorylation of IRF4 modulates its ability to regulate a subset of target genes. In addition to its effects on IRF4, ROCK2 also controls the expression of MYC in ABC-DLBCL by regulating MYC protein levels. ROCK inhibition furthermore selectively decreases the proliferation and survival of ABC-DLBCL in vitro and inhibits ABC-DLBCL growth in xenograft models. Thus, dysregulated ROCK2 activity contributes to the aberrant molecular program of ABC-DLBCL via its dual ability to modulate both IRF4- and MYC-controlled gene networks and ROCK inhibition could represent an attractive therapeutic target for the treatment of ABC-DLBCL.

Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis.

Germinal center (GC) responses require B cells to respond to a dynamic set of intercellular and microenvironmental signals that instruct B cell positioning, differentiation, and metabolic reprogramming. RHO-associated coiled-coil-containing protein kinase 2 (ROCK2), a serine-threonine kinase that can be therapeutically targeted by ROCK inhibitors or statins, is a key downstream effector of RHOA GTPases. Although RHOA-mediated pathways are emerging as critical regulators of GC responses, the role of ROCK2 in B cells is unknown. Here, we found that ROCK2 was activated in response to key T cell signals like CD40 and IL-21 and that it regulated GC formation and maintenance. RNA-Seq analyses revealed that ROCK2 controlled a unique transcriptional program in GC B cells that promoted optimal GC polarization and cholesterol biosynthesis. ROCK2 regulated this program by restraining AKT activation and subsequently enhancing FOXO1 activity. ATAC-Seq (assay for transposase-accessible chromatin with high-throughput sequencing) and biochemical analyses revealed that the effects of ROCK2 on cholesterol biosynthesis were instead mediated via a novel mechanism. ROCK2 directly phosphorylated interferon regulatory factor 8 (IRF8), a crucial mediator of GC responses, and promoted its interaction with sterol regulatory element-binding transcription factor 2 (SREBP2) at key regulatory regions controlling the expression of cholesterol biosynthetic enzymes, resulting in optimal recruitment of SREBP2 at these sites. These findings thus uncover ROCK2 as a multifaceted and therapeutically targetable regulator of GC responses.

Regulation of age-associated B cells by IRF5 in systemic autoimmunity.

Age-associated B cells (ABCs) are a subset of B cells dependent on the transcription factor T-bet that accumulate prematurely in autoimmune settings. The pathways that regulate ABCs in autoimmunity are largely unknown. SWAP-70 and DEF6 (also known as IBP or SLAT) are the only two members of the SWEF family, a unique family of Rho GTPase-regulatory proteins that control both cytoskeletal dynamics and the activity of the transcription factor IRF4. Notably, DEF6 is a newly identified human risk variant for systemic lupus erythematosus. Here we found that the lupus syndrome that developed in SWEF-deficient mice was accompanied by the accumulation of ABCs that produced autoantibodies after stimulation. ABCs from SWEF-deficient mice exhibited a distinctive transcriptome and a unique chromatin landscape characterized by enrichment for motifs bound by transcription factors of the IRF and AP-1 families and the transcription factor T-bet. Enhanced ABC formation in SWEF-deficient mice was controlled by the cytokine IL-21 and IRF5, whose variants are strongly associated with lupus. The lack of SWEF proteins led to dysregulated activity of IRF5 in response to stimulation with IL-21. These studies thus elucidate a previously unknown signaling pathway that controls ABCs in autoimmunity.

Regulation of systemic autoimmunity and CD11c+ Tbet+ B cells by SWEF proteins.

Recent studies have revealed the existence of a T-bet dependent subset of B cells, which expresses unique phenotypic and functional characteristics including high levels of CD11c and CD11b. In the murine system this B cell subset has been termed Age/autoimmune-associated B cells (ABCs) since it expands with age in non-autoimmune mice and it prematurely accumulates in autoimmune-prone strains. The molecular mechanisms that promote the expansion and function of ABCs are largely unknown. This review will focus on the SWEF proteins, a small family of Rho GEFs comprised of SWAP-70 and its homolog DEF6, a newly identified risk variant for human SLE. We will first provide an overview of the SWEF proteins and then discuss the complex array of biological processes that they control and the autoimmune phenotypes that spontaneously develop in their absence, highlighting the emerging involvement of these proteins in regulating ABCs. A better understanding of the pathways controlled by the SWEF proteins could help provide new insights into the mechanisms responsible for the expansion of ABCs in autoimmunity and potentially guide the design of novel therapeutic approaches.

The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity.

Post-transcriptional modifications can control protein abundance, but the extent to which these alterations contribute to the expression of T helper (TH) lineage-defining factors is unknown. Tight regulation of Bcl6 expression, an essential transcription factor for T follicular helper (TFH) cells, is critical as aberrant TFH cell expansion is associated with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here we show that lack of the SLE risk variant Def6 results in deregulation of Bcl6 protein synthesis in T cells as a result of enhanced activation of the mTORC1-4E-BP-eIF4E axis, secondary to aberrant assembly of a raptor-p62-TRAF6 complex. Proteomic analysis reveals that this pathway selectively controls the abundance of a subset of proteins. Rapamycin or raptor deletion ameliorates the aberrant TFH cell expansion in mice lacking Def6. Thus deregulation of mTORC1-dependent pathways controlling protein synthesis can result in T-cell dysfunction, indicating a mechanism by which mTORC1 can promote autoimmunity.Excessive expansion of the T follicular helper (TFH) cell pool is associated with autoimmune disease and Def6 has been identified as an SLE risk variant. Here the authors show that Def6 limits proliferation of TFH cells in mice via alteration of mTORC1 signaling and inhibition of Bcl6 expression.

Calcitonin Gene-Related Peptide-Exposed Endothelial Cells Bias Antigen Presentation to CD4+ T Cells toward a Th17 Response.

Calcitonin gene-related peptide (CGRP) is a neuropeptide with well-established immunomodulatory functions. CGRP-containing nerves innervate dermal blood vessels and lymph nodes. We examined whether CGRP regulates the outcome of Ag presentation by Langerhans cells (LCs) to T cells through actions on microvascular endothelial cells (ECs). Exposure of primary murine dermal microvascular ECs (pDMECs) to CGRP followed by coculture with LCs, responsive CD4(+) T cells and Ag resulted in increased production of IL-6 and IL-17A accompanied by inhibition of IFN-γ, IL-4, and IL-22 compared with wells containing pDMECs treated with medium alone. Physical contact between ECs and LCs or T cells was not required for this effect and, except for IL-4, we demonstrated that IL-6 production by CGRP-treated pDMECs was involved in these effects. CD4(+) cells expressing cytoplasmic IL-17A were increased, whereas cells expressing cytoplasmic IFN-γ or IL-4 were decreased by the presence of CGRP-treated pDMECs. In addition, the level of retinoic acid receptor-related orphan receptor γt mRNA was significantly increased, whereas T-bet and GATA3 expression was inhibited. Immunization at the site of intradermally administered CGRP led to a similar bias in CD4(+) T cells from draining lymph node cells toward IL-17A and away from IFN-γ. Actions of nerve-derived CGRP on ECs may have important regulatory effects on the outcome of Ag presentation with consequences for the expression of inflammatory skin disorders involving Th17 cells.

IRF4-Dependent and IRF4-Independent Pathways Contribute to DC Dysfunction in Lupus.

Interferon Regulatory Factors (IRFs) play fundamental roles in dendritic cell (DC) differentiation and function. In particular, IRFs are critical transducers of TLR signaling and dysregulation in this family of factors is associated with the development of autoimmune disorders such as Systemic Lupus Erythematosus (SLE). While several IRFs are expressed in DCs their relative contribution to the aberrant phenotypic and functional characteristics that DCs acquire in autoimmune disease has not been fully delineated. Mice deficient in both DEF6 and SWAP-70 (= Double-knock-out or DKO mice), two members of a unique family of molecules that restrain IRF4 function, spontaneously develop a lupus-like disease. Although autoimmunity in DKO mice is accompanied by dysregulated IRF4 activity in both T and B cells, SWAP-70 is also known to regulate multiple aspects of DC biology leading us to directly evaluate DC development and function in these mice. By monitoring Blimp1 expression and IL-10 competency in DKO mice we demonstrate that DCs in these mice exhibit dysregulated IL-10 production, which is accompanied by aberrant Blimp1 expression in the spleen but not in the peripheral lymph nodes. We furthermore show that DCs from these mice are hyper-responsive to multiple TLR ligands and that IRF4 plays a differential role in in these responses by being required for the TLR4-mediated but not the TLR9-mediated upregulation of IL-10 expression. Thus, DC dysfunction in lupus-prone mice relies on both IRF4-dependent and IRF4-independent pathways.

Epigenetics and the IRFs: a complex interplay in the control of immunity and autoimmunity.

Effective immune responses require the coordinated activation and differentiation of several cell types, including T-cells, B-cells and myeloid cells. Abnormalities in the appropriate regulation of these processes underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE). Recent studies have revealed that, in addition to sequence-specific DNA-binding factors, the chromatin landscape of a cell can play a pivotal role in controlling these processes and in regulating the onset of autoimmunity. Interferon regulatory factors (IRFs) are emerging as critical regulators of the activation and differentiation of immune cells and deregulation in the expression and/or function of members of the IRF family has increasingly been linked to the pathogenesis of lupus. In this review, we will provide a brief overview of the role of different IRFs in immune responses and SLE development and discuss studies, which highlight the intricate relationship of this family of transcription factors with the epigenetic machinery.

Norepinephrine and adenosine-5'-triphosphate synergize in inducing IL-6 production by human dermal microvascular endothelial cells.

Endothelial cells (ECs) play important roles in cutaneous inflammation, in part, by release of inflammatory chemokines/cytokines. Because dermal blood vessels are innervated by sympathetic nerves, the sympathetic neurotransmitter norepinephrine (NE) and the co-transmitter adenosine-5'-triphosphate (ATP) may regulate expression of EC inflammatory factors. We focused on IL-6 regulation because it has many inflammatory and immune functions, including participation in Th17 cell differentiation. Strikingly, NE and ATP synergistically induced release of IL-6 by a human dermal microvascular endothelial cell line (HMEC-1). Adrenergic antagonist and agonist studies indicated that the effect of NE on induced IL-6 release is primarily mediated by ß2-adrenergic receptors (ARs). By real-time PCR IL-6 mRNA was also synergistically induced in HMEC-1 cells. This synergistic effect of NE and ATP was reproduced in primary human dermal endothelial cells (pHDMECs) and is also primarily mediated by ß2-ARs. Under conditions of stress, activation of the symphathetic nervous system may lead to release of ATP and NE by sympathetic nerves surrounding dermal blood vessels with induction of IL-6 production by ECs. IL-6 may then participate in immune and inflammatory processes including generation of Th17 cells. Production of IL-6 in this manner might explain stress-induced exacerbation of psoriasis, and perhaps, other skin disorders involving Th17-type immunity.

Pituitary adenylate cyclase-activating peptide and vasoactive intestinal polypeptide bias Langerhans cell Ag presentation toward Th17 cells.

Epidermal Langerhans cells (LCs) are dendritic APCs that play an important role in cutaneous immune responses. LCs are associated with epidermal nerves and the neuropeptides vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) inhibit LC Ag presentation for Th1-type immune responses. Here, we examined whether PACAP or VIP modulates LC Ag presentation for induction of IL-17A-producing CD4(+) T cells. Treatment with VIP or PACAP prior to in vitro LC Ag presentation to CD4(+) T cells enhanced IL-17A, IL-6, and IL-4 production, decreased interferon (IFN)-γ and interleukin (IL)-22 release, and increased RORγt and Gata3 mRNA expression while decreasing T-bet expression. The CD4(+) T-cell population was increased in IL-17A- and IL-4-expressing cells and decreased in IFN-γ-expressing cells. Addition of anti-IL-6 mAb blocked the enhanced IL-17A production seen with LC preexposure to VIP or PACAP. Intradermal administration of VIP or PACAP prior to application of a contact sensitizer at the injection site, followed by harvesting of draining lymph node CD4(+) T cells and stimulation with anti-CD3/anti-CD28 mAbs, enhanced IL-17A and IL-4 production but reduced production of IL-22 and IFN-γ. PACAP and VIP are endogenous mediators that likely regulate immunity and immune-mediated diseases within the skin.

ß2-Adrenergic agonists bias TLR-2 and NOD2 activated dendritic cells towards inducing an IL-17 immune response.

This study tested the hypothesis that activation of ß2-adrenoceptors on DCs influences NOD2 signaling along with its cross-talk with Toll-like receptor-2 resulting in altered Th cell priming ability. Th17 cells are a newly discovered lineage of CD4(+) T cells involved in defense against extracellular bacteria and also implicated in autoimmune disorders. Initiation and polarization of the adaptive immune response is controlled by innate immune recognition mediated by DCs. Previous studies demonstrated that adrenergic receptors modulate cytokine production by DCs and affect their Th cell priming ability. We show that the ß2-adrenoceptor agonist salbutamol enhanced IL-6 production in murine bone marrow-derived DCs stimulated with the nucleotide-binding oligomerization domain 2 ligand muramyl dipeptide. However, when the Toll-like receptor-2 ligand Pam3CysSK4 was added, salbutamol inhibited IL-12 but did not alter IL-6 and IL-23 expression. Gene expression analysis showed that salbutamol inhibited the p40 subunit as well as IL-12p35, while IL-23p19 and IL-6 were stimulated. Therefore, ß2-adrenoceptors modulated cytokine production resulting in a Th17 cell priming cytokine pattern. Indeed, when antigen-pulsed DCs stimulated by muramyl dipeptide or Pam3CysSK4+muramyl dipeptide in the presence of salbutamol were used for in vivo immunization, the resulting Th17/Th1 cell ratio was increased as evaluated by IL-17 and IFN-γ production. In addition, intradermal injection of norepinephrine along with Pam3CysSK4+muramyl dipeptide increased the Th17 response to an immunogenic protein and this effect was reversed by a ß2-adrenoceptor antagonist. Thus, ß2-adrenoceptors may be involved in the regulation of defense against extracellular bacteria and the pathogenesis of inflammatory diseases.

Muramyl dipeptide induces Th17 polarization through activation of endothelial cells.

Endothelial cells (ECs) express the nucleotide-binding oligomerization domain (Nod) receptor 2, which recognizes the bacterial derivate muramyl dipeptide (MDP). MDP stimulation of these cells enhances their IL-6 production and may thus contribute to the immune and inflammatory activities in the skin. However, whether ECs are capable of influencing the development of T cell priming and its polarization remains unknown. We report that in vitro the murine bEnd.3 EC line induces, following MDP stimulation, a Th17 polarization at the expense of Th1 and Th2 polarization in the setting of Langerhans cell (LC) Ag presentation to responsive T cells as assessed by IL-17, IL-6, IFN-γ, and IL-4 production. Interestingly, IL-22 production, which has been associated with Th17 priming, was not influenced by MDP-treated bEnd.3 cells, illustrating differential regulation of this cytokine from IL-17. Additional analysis confirmed a significantly increased percentage of IL-17(+)CD4(+) T cells by flow cytometry and an increased mRNA level of the specific Th17 transcription factor retinoic acid-related orphan receptor γt in cocultures of LCs and responsive T cells in the presence of activated bEnd.3 cells. Experiments using the RNA interference technique to knockdown IL-6 in bEnd.3 cells confirmed that IL-6 produced by bEnd.3 cells stimulated by MDP is at least partially involved in Th17 polarization. Our data suggest that activated ECs are capable of influencing LC Ag processing and presentation to T cells and induce a Th17 polarization. These results are important for the understanding of Th17-related disorders of the skin such as psoriasis.

Sympathetic nervous modulation of the skin innate and adaptive immune response to peptidoglycan but not lipopolysaccharide: involvement of beta-adrenoceptors and relevance in inflammatory diseases.

Disorders of the skin immune activity are implicated in the pathogenesis of acquired inflammatory skin disorders. Inflammatory diseases including psoriasis, atopic dermatitis, lichen planus and vitiligo have also been associated with local alterations of adrenergic mechanisms and emotional stress. Here we show that the beta-adrenergic receptors antagonist propranolol along with peptidoglycan, but not LPS, combined with intradermal injection of a soluble protein, shifted the recall memory response to the Th1 type. The specific beta2-AR antagonist ICI 118,551 did not reproduce this effect suggesting that inhibition of both beta1- and beta2-AR caused the Th1 polarization. The underlying mechanism included enhanced local expression of IFN-gamma, IL-12 and IL-23 as well as of IFN-beta and CXCR3 ligands during the innate phase of the response which resulted in an increase of antigen-positive plasmacytoid dendritic cells (pDCs) in the draining lymph node. In particular, modulation of inflammatory cytokines, and IFN-beta inducible genes expression appeared to involve also the beta1-AR. Plasmacytoid dendritic cells and IL-23 were recently reported to play a central role in the pathogenesis of Th1-sustained inflammatory skin diseases such as psoriasis. Thus, primary beta-adrenoceptors signaling defects or altered sympathetic nervous activity together with selected pattern recognition receptors activation might serve as initiation and/or persistence factors for numerous Th1-sustained inflammatory skin diseases.