|Year : 2011 | Volume
| Issue : 3 | Page : 31-33
Session P: Alopecia Areata – Part I and II
|Date of Web Publication||16-Jun-2011|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
. Session P: Alopecia Areata – Part I and II. Int J Trichol 2011;3, Suppl S1:31-3
Alopecia areata: A model for studying autoimmunity
Aviad Keren, Amos Gilhar*
Skin Research Laboratory, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, and Flieman Medical Center, Haifa, Israel.
Alopecia Areata (AA) is thought to be a tissue-specific autoimmune disease, which occurs most probably, following a breakdown of the hair follicles immune privilege. Indeed, this model may serve as a tool for investigating not only AA, but also other crucial organs such as the eye, uterus and fetus in which immune privilege exists. Various components establish the immunosuppressive environment of the hair follicle, such as cytokines, hormones, neuropeptides, enzymes and an absence of cells related to the innate and acquired immunity. The genetic background of the patients takes part in maintaining and breaking immune privilege. Stress might alter neuropeptides production which affects the immune response and indirectly to the production of IFN-γ, which seems to be pivotal in the immunopathology of AA. The most characteristic histological feature of AA is a perifollicular lymphocytic infiltrate comprised primarily of CD4+ cells associated with a CD8+ intrafollicular infiltrate, as well as a T-helper 1 cytokine profile. Evidence of immune activation includes the expression of HLA-DR, HLA-A, B, C and ICAM-1 on the follicular epithelium. The follicular expression of HLA-DR and ICAM-1 is likely induced by IFN-γ produced by T-cells. The literature has focused on the role of CD8+ T cells as effector cells in the pathogenesis of AA and has largely ignored the possible contribution of Natural Killer (NK) or NKT cells in this matter. However, recent studies demonstrated a possible role of these cells in the disease. All these data demonstrate that AA is a powerful model for studying the induction and pathogenesis of tissue directed autoimmune disease.
Genome-wide linkage and association studies in alopecia areata
Jennifer K. Kuhn 1,2,3 , Franz Rüschendorf 4 , Hella Blech 1 , Janine Kurtenbach 1 , Ingelore Bäßmann 1 , Kevin J. McElwee 5 , Rolf Hoffmann 6 , Peter Nürnberg 1,3,7 , Hans C Hennies 1,3,7 *
1 Dermatogenetics, Cologne Center for Genomics, University of Cologne, Germany; 2 Faculty for Mathematics and Natural Sciences, University of Cologne, Germany; 3 Center for Molecular Medicine, University of Cologne, Germany; 4 Max Delbrueck Center for Molecular Medicine, Berlin, Germany; 5 Department of Dermatology, University of British Columbia, Vancouver, Canada; 6 Praxis für Dermatologie, Freiburg, Germany; 7 Cologne Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Germany.
Alopecia areata (AA) (MIM 104000) is a chronic inflammatory disorder of the hair follicles in the actively growing anagen stage. It is characterized by circular regions of hair loss on the head. Isolated hair loss may occur also on other parts of the body. AA would eventually culminate in alopecia totalis and alopecia universalis, respectively. Frequent familial occurrence of the disease demonstrates a strong genetic susceptibility with a multifactorial background in humans. AA has been suggested as a tissue-specific autoimmune disease, considering a potential role for loss of immune privilege, and a recent study pointed to an important involvement of innate and adaptive immunity. Here, we have completed a SNP-based genome-wide association study (GWAS) with 259 families, mostly comprising affected sib pairs and their parents. This family-based approach allows both parametric and non-parametric investigations; moreover, we have used a total of 357 cases and 2,534 controls in a case/control study. A first analysis identified several regions with significant or suggestive association. 19 markers significantly associated (P<5x10 -7 ) with AA reside in the HLA region on chromosome 6p, with the lowest p value of 5x10 -12 at rs9469220. The analysis of families will further elucidate the modes of inheritance in AA and increase the power for identifying susceptiblity loci for AA and assessing the role of candidate genes. The results will thus further our knowledge of the molecular basis of AA and contribute to identifying targets for a pathogenesis-based therapy for this psychologically devastating disease.
Moving from genetics to translational research in alopecia areata
Lynn Petukhova, Angela M. Christiano*
Departments of Dermatology, Genetics and Development, Columbia University, New York, NY, USA
Alopecia areata (AA), an autoimmune disease that targets the hair follicle, is the most prevalent autoimmune disease in the US, affecting approximately 5.3 million people, more than most other autoimmune diseases combined. Despite its prevalence, there is little information on the underlying pathogenesis and there are currently no evidence-based treatments available to treat or cure this disease. Genetics provides us with a valuable tool for gaining insight into disease pathology. We recently completed the first genome-wide association study (GWAS) in AA and successfully identified at least eight regions in the genome with overwhelming evidence for association to AA. Importantly, this work identifies a discrete set of genes, some of which have been well-studied within the context of other autoimmune diseases and already have targeted therapies available or in development, such as CTLA4-Ig. We have further characterized the evidence for shared mechanisms of autoimmunity that operate in AA, by pursuing a number of methods, including screening AA patient sera for circulating antibodies frequently found in other autoimmune diseases (celiac disease, rheumatoid arthritis and type 1 diabetes), by performing high resolution sequencing of classical HLA alleles in our patient cohort, and by performing meta-analyses across AA and related autoimmune diseases. This work has illuminated pathologically important disease processes and argues for unifying/general mechanisms that dysregulate immune tolerance at one of several multiple end organ sites. The insight that we have gained through our GWAS thus sets the stage for the rational development of novel effective therapeutic approaches and heralds in an exciting new era with the commencement of translational research in AA.
Treating people with alopecia areata: What works and what doesn't
University of Melbourne, Australia.
Alopecia Areata is a life altering condition. Under recognized by the community, underestimated by health policy makers and undertreated by medical practitioners, many affected people feel isolated and alienated. The pathogenesis involved a fixed, multi factorial genetic predisposition and a variable, mercurial, multi factorial environmental trigger. The risk of new lesions is increased in the presence of active disease. This implies that active lesions should be treated to reduce risk of secondary lesions, however evidence for this proposition is not available. Of the myriad of treatments tried in this condition, corticosteroids are the most reliable. No other immunomodulatory agents has consistent efficacy. This raises the issue of how these agents that are also know to induce hypertrichosis actually work. The rate of appearance of lesions, growth dynamics and the rapidity of response to corticosteroid treatment challenge the traditional model for pathogenesis. In the absence of any significant therapeutic breakthrough in recent times, I propose for a new approach to this condition and a new treatment paradigm.
Differential expression of toll-like receptors may contribute to severity of alopecia areata
Hoon Kang*, Kwan Ho Jung, Young Min Park, Jung Eun Kim, Hyung Ok Kim
Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Toll-like receptors (TLRs) play an essential role in innate immune response to microbial pathogens in mammalian species. The TLRs activated by microbial ligands result in cytokine production as well as other host defense mechanisms. Increased expressions of CD4+ and CD8+ T cells and hair follicle reactive antibodies has been reported in AA patients. These immunologic alterations could be evoked by some microbials. This investigation was carried out to explore the potential contribution of innate immunity in the development of alopecia areata (AA) through the TLRs. Thirty-five AA patients were enrolled. Scalp skin biopsies at the lesional margin and blood samplings were done. Microdissection was employed to obtain the follicular bulb. Immunohistochemistry and quantitative real-time PCR analysis was conducted to determine the TLRs expressions. Some peculiar findings of IHC and gene expression were found in scalp skin of AA patients. TLR3, 7, and 9 were strongly expressed follicular epitheliums and upregulated in lesional margin. TLR7 and 9 genes showed increase fold changes in peripheral blood mononuclear cells which have not been reported previously. When the tissue group was subdivided, upregulated TLR7 gene expression was prominent in patient with severe conditions. These results reveal some TLRs may involve the pathogenesis of AA pathogenesis directly or indirectly and support.
Alopecia areata lesion demonstrates decreased filaggrin expression unrelated to atopic status
Sillani Caulloo, Ying Zhao, Ze-ming Cai, Bin Zhang, Jian Yang, Xing-qi Zhang*
Department of Dermatology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
Alopecia areata (AA) and atopic diseases (AD) has been often found to be of concomitance. Recently, AD has closely been associated with filaggrin gene mutations. We here aim to investigate filaggrin expression in AA lesions. Clinical data of 80 AA and 80 AA in concomitance with AD patients as well as laboratory data of 55 patients from each group were analyzed. 37 AA patients' lesional skin biopsies underwent IHC staining for filaggrin and were compared to 10 normal controls based on the number of positively stained granular layer. Quantitative RT-PCR analysis of filaggrin expression level was done in 16 AA and 10 normal controls. Comparative clinical analysis of AA and AA with AD patients' groups did not reveal any statistically significant difference in respect to age of onset, duration of disease, area of hair loss, family history of AA as well as nail aberrations (P>0.05). Among laboratory values, increased serum IgE and eosinophils was noted in AA with AD group compared to AA without AD group (P<0.05). A remarkable decrease of epidermal filaggrin staining area and decreased filaggrin expression at mRNA level in AA patients as compared to controls (P<0.05). Besides, the decrease was more appreciated in patients with hair loss area of >30% and with nail aberrations. Interestingly, decrease in filaggrin staining in AA and AA with AD groups were both comparable. We therefore conclude that decreased filaggrin expression in AA patients suggests its possible role in the pathogenesis of AA and atopic status does not affect AA course.
An extraordinary colocalization of alopecia areata and vitiligo
Yuval Ramot 1 *, Elena Thomaidou 2 , Alexander Mali 3 , Abraham Zlotogorski 1
Departments of 1 Dermatology and 3 Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 2 Trinity College-University of Dublin, Dublin, Ireland.
Although the association of alopecia areata (AA) and vitiligo occurring in the same patient has been frequently reported in the literature, the colocalization of AA and vitiligo is very rare, and has been reported only four times in the medical literature, and only in children and adolescents. We report for the first time a 60-year-old female patient with anatomic concurrence of AA and vitiligo on the scalp. In recent years, the theory that autoimmunity stands at the basis of AA has gained much support, and is now considered the prevailing theory, based on both direct and indirect evidence. Further support to this theory comes from its reported association with other autoimmune diseases, and particularly with vitiligo. However, even though both AA and vitiligo are thought to have the same underlying pathophysiologic mechanisms, the striking rarity of their colocalization challenges this postulated common pathogenesis, and raises the question if autoimmunity is responsible for only a fraction of AA or vitiligo.
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