Does MBL2 codon 54 polymorphism play a role in the pathogenesis of psoriasis?

Background Psoriasis is a T cell‐mediated immune disease in which various cytokines, primarily tumor necrosis factor‐α (TNF‐α), are complexly involved. Mannose‐binding lectin (MBL) gene polymorphisms decrease MBL serum levels, thereby increasing the synthesis of proinflammatory cytokines such as TNF‐α. Objectives This trial was designed to evaluate the role of the MBL2 codon 54 polymorphism in the pathogenesis of psoriasis. Methods Fifty patients diagnosed with psoriasis vulgaris and 53 healthy subjects were included in the trial. The polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP) method was applied to determine the MBL2 codon 54 polymorphism. Genotypes were determined according to the bands formed in agarose electrophoresis gels. For the statistical analysis, the level of significance was set at P < 0.05. Results A total of 33 (66.0%) of the 50 psoriasis patients were detected to have A/A genotype and 17 (34.0%) had B/B genotype. Of the control subjects, 44 (83.0%) had A/A genotype and nine (17.0%) had B/B genotype. There was a statistically significant difference between the groups (P = 0.047). The analysis of allele frequencies revealed A allele prevalences to be 79 (79.0%) and 95 (89.6%), and B allele prevalences to be 21 (21.0%) and 11 (10.4%), in the patient and control groups, respectively. A statistically significant difference between allele frequencies was detected (P = 0.031). Conclusions This study suggests that the MBL2 codon 54 polymorphism may have an association with psoriasis in the Turkish population.     

Does collapse of immune privilege in the hair‐follicle bulge play a role in the pathogenesis of primary cicatricial alopecia?

Background. The hair‐follicle bulge has recently been added to a growing list of human tissue compartments that exhibit a complex combination of immunosuppressive mechanisms, termed immune privilege (IP), which seem to restrict immune‐mediated injury in specific locations. As epithelial hair‐follicle stem cells (eHFSC) reside in the hair‐follicle bulge region, it is conceivable that these IP mechanisms protect this vital compartment from immune‐mediated damage, thereby ensuring the ongoing growth and cyclic regeneration of the hair follicle. Primary cicatricial alopecias (PCA) are a group of inflammatory hair disorders that result in hair‐follicle destruction and permanent alopecia. Growing evidence suggests that eHFSC destruction is a key factor in the permanent follicle loss seen in these conditions. Aim. To explore the possible role of bulge IP collapse in PCA pathogenesis. Methods. We report three clinically distinct cases of PCA. Immunohistochemical analyses of paired biopsies from lesional and uninvolved scalp skin were compared using recognized markers of IP. Results. Immunohistochemical investigation found increased expression of major histocompatibility complex (MHC) classes I and II and of β2‐microglobulin in the bulge region of lesional follicles compared with uninvolved follicles in each case. Further, expression of the bulge marker keratin 15 was reduced in lesional skin in two of the cases. Conclusions. This small series represents our first preliminary attempts to ascertain whether bulge IP collapse may play a role in PCA pathogenesis. We present standard parameters relating to hair‐follicle IP in the bulge region of three patients with distinct PCA variants, and show the presence of features consistent with bulge IP collapse in each case.     

The role of stem cell factor and c‐KIT in keloid pathogenesis: do tyrosine kinase inhibitors have a potential therapeutic role?

Background Keloids are fibroproliferative disorders characterized by increased deposition of extracellular matrix components. Stem cell factor (SCF) and its receptor c‐KIT are expressed in a wide variety of cells and have also been demonstrated to be important modulators of the wound healing process. Objectives To examine the role of the SCF/c‐KIT system in keloid pathogenesis. Methods Immunohistochemical staining and Western blot analyses were used to examine localization and expression of SCF and c‐KIT in keloid and normal skin tissue. This was followed by the detection of SCF and c‐KIT expression in fibroblasts cultured in vitro and fibroblasts exposed to serum. To investigate the effect of epithelial–mesenchymal interactions, a two‐chamber system was employed in which keratinocytes on membrane inserts were cocultured with the fibroblasts. SCF and c‐KIT expression levels in all cell extracts and conditioned media were assayed by Western blotting. In another set of experiments, the effect of imatinib (Glivec^®, Gleevec^®; Novartis Pharma AG, Basel, Switzerland) on keloid fibroblasts was examined. Results SCF and c‐KIT were upregulated in keloid scar tissue and in cultured fibroblasts stimulated with serum, highlighting their importance in the initial phase of wound healing. We further demonstrated that epithelial–mesenchymal interactions, mimicked by coculture of keratinocytes and fibroblasts in vitro, not only stimulated secretion of the soluble form of SCF in keloid cocultures but also brought about shedding of the extracellular domain of c‐KIT perhaps by upregulation of tumour necrosis factor‐α converting enzyme which was also upregulated in keloid scars in vivo and keloid cocultures in vitro. In addition keloid cocultures expressed increased levels of phosphorylated c‐KIT highlighting an activation of the SCF/c‐KIT system. Finally, we demonstrated that imatinib, a tyrosine kinase inhibitor, may be a possible therapeutic agent for keloids. Conclusion These data indicate that the SCF/c‐KIT system plays an important role in scar pathogenesis, and underscore the role of imatinib as a key therapeutic agent in keloid scars.     

The role of streptococcal hypersensitivity in the pathogenesis of Behçet's Disease

Beh?et's disease (BD) is still considered as a mysterious multisystemic disorder characterized by recurrent involvement of muco-cutaneous, ocular, intestinal, vascular and/or nervous system organs. In this review, we would like to highlight and discuss several important advances in our understanding of the pathogenesis of BD based on the intrinsic genetic factors including HLA-B51 and MICA expression and extrinsic triggering factors. As one of the extrinsic triggering factors, we focused on the hypersensitivity against oral streptococci which might be acquired through the innate immune mechanism. It was found that HLA-B51 restricted CD8 T cell response was clearly correlated with the target tissues expressing MICA*009 by stress in active BD patients with HLA-B51 as the intrinsic factors. Bes-1 gene and HSP-65 derived from oral S. sanguinis, which is the uncommon serotype (KTH-1, strain BD113-20), are supposed to play important roles as an extrinsic factor in BD pathogenesis. The peptides of the Bes-1 gene are highly homologous with the retinal protein Brn3b and moreover, the Bes-1 peptides were homologous with HSP-65 derived from microorganisms in association with the counterpart human HSP-60, which appeared reactively in the patients. HSP-65/60 also has high homologies with the respective T cell epitope of BD patients. Although HSP-65/60 and the peptides of Bes-1 gene were found to stimulate PBMCs from BD patients in the production of pro-inflammatory Th1 type cytokines, some homologous peptides of HSP-65 with T cell epitopes were found to reduce IL-8, IL-12 and TNF-alpha produced from PBMCs of active BD patients. The findings might be correlated with the clinically therapeutic effects for BD patients with severe uveitis, who were led to immunotolerance by the peptide of human HSP-60 (336-351), as previously reported. Then, the pathogenesis of BD was discussed referring to intrinsic genetic factors and extrinsic triggering factors in aspects of streptococcal hypersensitivity, which might be acquired through the innate immune mechanisms. The BD symptoms were thought to be due to vascular reactions as immune responses in correlation with monocyte expressed streptococcal agents.     

Human herpesvirus 7 in dermatology: what role does it play?

Human herpesvirus 7 (HHV-7) was discovered in 1989 as a new member of the beta-herpesvirus subfamily. Primary infection occurs early in life and manifests as exanthema subitum, or other febrile illnesses mimicking measles and rubella. Thus, HHV-7 has to be considered as a causative agent in a variety of macular-papular rashes in children. In addition, HHV-7 was found in some cases of other inflammatory skin disorders, such as psoriasis. There are controversial data on the detection of HHV-7 in pityriasis rosea, but so far there is not enough evidence for a pathogenetic association of HHV-7 with this exanthematic skin disease. Although HHV-7 can be found in some cases of Hodgkin's disease, there are no data supporting a direct causative role in this lymphoma type nor in other nodal or primary cutaneous lymphomas. In various epidemiologic forms of Kaposi's sarcoma, infection of monocytic cells with HHV-7 was demonstrated, which may indirectly influence tumor biology. In the context of immunosuppression, HHV-7 has recently been identified as an emerging pathogen in transplant recipients and may exacerbate graft rejection in renal transplant recipients. The ability of HHV-7 to induce cytokine production in infected cells could make HHV-7 an important pathogenetic co-factor in inflammatory and neoplastic disorders. Moreover, the restricted cellular tropism of HHV-7 may render this virus an interesting vector for gene therapy. Thirteen years after the discovery of HHV-7, there has been considerable progress in characterizing its genetic structure, virus-induced effects on infected host cells and in the development of diagnostic tools. Nevertheless, the role of HHV-7 in various skin diseases and the clinical manifestations of reactivation of HHV-7 infection have still to be defined.     

Phage typing in dermatitis cruris pustulosa et atrophicans: does staphylococcal carrier status have a role?

Background Dermatitis cruris pustulosa et atrophicans (DCPA) is a form of chronic folliculitis of the legs with a multifactorial etiopathogenesis, seen primarily in tropical countries. Staphylococcus aureus has been isolated from the pustules in earlier studies, although the organisms isolated have not been further characterized. Materials and methods Patients with DCPA, who attended the Dermatology outpatient clinic at JIPMER, Pondicherry, India, during the study period (December 2006–June 2008) were included. Pus from the lesions as well as swabs from carrier sites (nares, axillae, and gluteal fold) were cultured. Staphylococcus aureus isolates were subjected to phage typing at the National Staphylococcal Phage Typing Center, Department of Microbiology, Maulana Azad Medical College, New Delhi, India. Results Thirty‐seven patients were included in the study. Pus from the folliculitic lesions grew S. aureus in 32 (86.49%) patients. Based on the comparison of antibiotic sensitivity patterns, isolates from pus and carrier sites were found to be similar in 15 patients. Phage typing established the organism to be identical in five of these patients. Conclusions Characterization of S. aureus in DCPA shows that there is no specific phage type that is uniformly responsible for the lesions in most patients. However, in view of the unclear etiology of this condition, the pathogenicity of a staphylococcal carrier state in individual patients needs to be addressed.