The Evolving Pathogenesis of Alopecia Areata: Major Open Questions.

Concordance rate of alopecia areata in identical twins supports both genetic and environmental factors

Alopecia areata (AA) is a common autoimmune disorder that targets anagen hair follicles. The most widely accepted hypothesis in its pathogenesis is that it is a T-cell-mediated autoimmune condition in genetically predisposed individuals. MicroRNAs (miRNAs) are implicated in disease etiology and treatment. Interestingly, miRNAs 31, 155 and 29c have shown an important role in alopecia areata. Since miRNA can be used as serum biomarker in other autoimmune diseases. This study aimed to assess and compare serum levels of miRNAs 31, 155 and 29c in 50 AA patients with their levels in 50 healthy subjects & correlate their levels to severity of AA. Serum levels of miRNAs 31, 155 and 29c were estimated by qRT-PCR technique and miRNAs 31 and 29c were found to be significantly higher in AA patients compared to controls. MicroRNA 155 however, showed no significant difference between serum levels of AA patients compared to controls. These findings suggest the important role of miRNAs 31, 29c and 155 in the pathogenesis of AA.

Alopecia areata (AA) is a common chronic tissue-specific autoimmune disease, resulting in hair loss, that affects up to 2% of the general population. The exact pathobiology of AA has still remained elusive, while the common theory is the collapse of the immune privilege of the hair follicle caused by immunological mechanism. Multiple genetic and environment factors contribute to the pathogenesis of AA. There are several clinical treatments for AA, varying from one or multiple well-defined patches to more diffuse or total hair loss of the scalp (alopecia totalis) or hair loss of the entire body (alopecia universalis). The available treatments for AA, such as corticosteroids and other immunomodulators, minoxidil, and contact immunotherapy, are of limited efficacy with a high risk of adverse effects and high recurrence rates, especially for patients with severe AA. Recent insights into the pathogenesis of AA have led to the development of new treatment strategies, such as Janus kinase (JAK) inhibitors, biologics, and several small molecular agents. In addition, modern therapies for AA, including antihistamines, platelet-rich plasma (PRP) injection, and other novel therapies have been well explored. In this review, we discussed the recent advances in the pathogenesis, diagnosis, and treatment of AA.

Alteration in T-lymphocyte function and cytokines secreted by T-cell subsets has been proposed in the immunopathogenesis of alopecia areata (AA). The role of T-helper and regulatory T-cell cytokines in the pathogenesis of active AA has not been established. To assess the role of hallmark cytokines of T-helper cells (Th1, Th2 and Th17) and regulatory T cells (Tregs) in the pathogenesis of AA, and its clinical correlation. Fifty-one patients with AA and 45 age- and sex-matched healthy control subjects were included in the study. Serum interleukin (IL)-2, interferon (IFN)-γ, IL-10, IL-13, IL-17A and transforming growth factor (TGF)-β1 were measured by enzyme-linked immunosorbent assay in both groups. Correlation of serum cytokine levels with age, sex, disease subtype and duration, number of patches on the scalp, associated autoimmune disorders and atopy was studied. The serum cytokine levels of IL-2, IFN-γ, IL-13 and IL-17A were significantly increased, and serum TGF-β1 levels were significantly decreased (P < 0·05) in patients with AA compared with controls. Serum IL-2 levels were significantly different among AA subgroups (P < 0·05). IL-2 levels were positively correlated with the total disease duration and the number of patches on the scalp. The increased levels of serum IL-2, IFN-γ, IL-13 and IL-17A suggested altered T-helper cell function, and reduced serum TGF-β1 levels suggested a defect in Treg function. Therefore, enhanced T-cell-mediated immunity and breakdown of immune tolerance due to deficiency in Tregs may facilitate the occurrence of AA.

Protein biochips have a great potential in future parallel processing of complex samples as a research tool and in diagnostics. For the generation of protein biochips, highly automated technologies have been developed for cDNA expression library production, high throughput protein expression, large scale analysis of proteins, and protein microarray generation. Using this technology, we present here a strategy to identify potential autoantigens involved in the pathogenesis of alopecia areata, an often chronic disease leading to the rapid loss of scalp hair. Only little is known about the putative autoantigen(s) involved in this process. By combining protein microarray technology with the use of large cDNA expression libraries, we profiled the autoantibody repertoire of sera from alopecia areata patients against a human protein array consisting of 37,200 redundant, recombinant human proteins. The data sets obtained from incubations with patient sera were compared with control sera from clinically healthy persons and to background incubations with anti-human IgG antibodies. From these results, a smaller protein subset was generated and subjected to qualitative and quantitative validation on highly sensitive protein microarrays to identify novel alopecia areata-associated autoantigens. Eight autoantigens were identified by protein chip technology and were successfully confirmed by Western blot analysis. These autoantigens were arrayed on protein microarrays to generate a disease-associated protein chip. To confirm the specificity of the results obtained, sera from patients with psoriasis or hand and foot eczema as well as skin allergy were additionally examined on the disease-associated protein chip. By using alopecia areata as a model for an autoimmune disease, our investigations show that the protein microarray technology has potential for the identification and evaluation of autoantigens as well as in diagnosis such as to differentiate alopecia areata from other skin diseases.

Alopecia areata (AA) is a disease that manifests as patchy hair loss on the scalp and other parts of the body; severe disease may result in disfigurement, functional impairment, and significant psychological distress. This condition is understood to be caused by autoimmunity to the hair follicle and subsequent arrest of hair growth. New medications, baricitinib and ritlecitinib, belong to the Janus kinase (JAK) inhibitor family and are among the first FDA-approved treatments for severe AA. In this manuscript, we aim to answer the question: What treatment options exist for AA in the military health care system (MHS)? In doing so, we review the pathogenesis, physical and psychosocial impact of AA, conventional treatment of AA, and the efficacy and safety of baricitinib and ritlecitinib. A literature search was performed using PubMed, Embase, and Ovid for the history and pathogenesis of AA, psychosocial impact of disease, functional impairments, and current treatments. Keywords "alopecia areata," "current therapy for alopecia areata," "pathogenesis alopecia areata," "baricitinib," "ritlecitinib," "JAK inhibitor alopecia," "JAK inhibitor safety," "baricitinib efficacy," "alopecia eyelash," "alopecia nails," and "psychosocial impact of alopecia" were used for the search. The TRICARE manual was searched for guidelines applicable to the treatment of AA, DoD Instruction 6130.03 Volume 2 for medical standards for military service, and the U.S. Central Command Modification 15 for fitness of deployment to Central Command area of operations. Traditional treatments such as intralesional steroids may be effective for some patients, but difficulty lies in controlling extensive or refractory disease. Janus kinase inhibitors, baricitinib and ritlecitinib, are found effective at improving severe refractory disease; baricitinib induced hair regrowth in 32.6% more patients than placebo, and ritlecitinib was found to be superior to placebo by at least 24%. Currently, there is no coverage for therapeutic treatment of hair growth in the MHS. Additionally, military members are disqualified for continued service if they require immunomodulator medications such as baricitinib and ritlecitinib. Those on immunomodulators are unable to deploy worldwide. Baricitinib and ritlecitinib are effective treatments for widespread, progressive, and refractory AA. Although JAK inhibitors demonstrate improved effectiveness compared to non-immunomodulator treatments, their use in the MHS for this purpose is limited.

Innate lymphoid cells type 1 suffice to induce hallmarks of alopecia areata phenotype in organ-cultured human scalp hair follicles ex vivo and in human scalp skin xenotransplants in vivo, suggesting that these cells play a role in early AA pathogenesis.

Innate lymphoid cells type 1 suffice to induce hallmarks of alopecia areata phenotype in organ-cultured human scalp hair follicles ex vivo and in human scalp skin xenotransplants in vivo, suggesting that these cells play a role in early AA pathogenesis.

Pro-inflammatory Vδ1+T-cells infiltrates are present in and around the hair bulbs of non-lesional and lesional alopecia areata hair follicles

Alopecia areata is considered to be a cell-mediated autoimmune disease, in which autoreactive cytotoxic T cells recognize melanocyte-associated proteins such as tyrosinase. This review discusses recent advances in the understanding of the pathogenesis of alopecia areata, focusing on immunobiology and hormonal aspects of hair follicles (HFs). The HF is a unique “miniorgan” with its own immune and hormonal microenvironment. The immunosuppressive milieu of the anagen hair bulb modulated by immunosuppressive factors is known as “hair follicle immune privilege.” The collapse of the hair follicle immune privilege leads to autoimmune reactions against hair follicle autoantigens. Alopecia areata is sometimes triggered by viral infections such as influenza that causes excess production of interferons (IFN). IFN-γ is one of the key factors that lead to the collapse of immune privilege. This paper reviews the interactions between the endocrine and immune systems and hair follicles in the pathogenesis of alopecia areata.

Forty-one patients with severe alopecia areata (AA) were studied. They were classified into four types according to clinical manifestations (type 1: fixed alopecia universalis or multiple AA, type 2: active alopecia totalis, type 3: active multiple AA and type 4: active multiple AA with anti-thyroid antibodies). T cell, activated T cell and NK cell subsets in the peripheral blood lymphocytes were investigated using a fluorescence activated cell sorter. (1) The percentage of Leu4 + cells in total lymphocytes showed a significant decrease in AA with types 1, 3 and 4 when compared to those of the normal controls. (2) The percentages of Leu3a+-DR+ cells in Leu3a+ cells and of Leu2a +-DR + cells in Leu2a + cells were significantly higher in AA with types 1, 3 and 4 than those of the normal controls. (3) The percentages of Leu11 + cells and Leu7 + Leu11+ cells in total lymphocytes were significantly high in AA with type 3. Leu7 − Leu11 + cells were elevated in AA with types 1 and 3. (4) The percentage increase of Leu7 − Leul l + cells was proportional to the disease activity in AA with type 3. The increase of activated T cell in peripheral blood lymphocytes from AA suggests that immune mechanisms are involved in the pathogenesis of AA. In type 3 AA, NK cell may play an important role in the pathogenesis of AA.

Clinical significance of serum high-mobility group box 1 level in alopecia areata

An implication for post-transcriptional control: Reciprocal changes of melanocortin receptor type 2 mRNA and protein expression in alopecia areata

Alopecia areata (AA) is a chronic inflammatory disease characterised by patchy hair loss with T cell infiltration of hair follicles. AA occurs in approximately 0.1% of the general population, but this is increased to 9% in Down syndrome (DS). DS is associated with an additional copy (full or partial) of chromosome 21, and the DS region may potentially include genes involved in the pathogenesis of AA. MX1 is the gene encoding the interferon-induced p78 protein (MxA). MxA protein confers resistance to influenza viruses, and we have previously shown that MxA protein is strongly expressed in lesional anagen hair bulbs from patients with AA but not in normal follicles. We therefore studied the possible involvement of MX1 in the pathogenesis of AA. To establish markers in the MX1 region which could be screened by PCR-based methods, we defined the human MX1 exon/intron organisation and screened the exons and the introns by conformation-sensitive gel electrophoresis. We found that the MX1 gene contains 17 exons extending over 33 kb. The size and sequence of the region from exon 6 to exon 16 are highly conserved between human and mouse. Screening of 4747 bp within the MX1 gene revealed four single nucleotide polymorphisms in intron 6. These polymorphisms are concentrated within 147 bp and show strong linkage disequilibrium. In a case-control association study for the MX1 (+9959) polymorphism in 165 AA patients and 510 controls we found a significant association of this marker with AA (odds ratio 1.79, 95% CI 1.21-2.66, chi2 = 8.464, P = 0.0036). The risk of disease was greater for patchy AA (mild disease) and with early age at onset (odds ratio 2.34, 95% CI 1.24-4.43, P = 0.0072), providing new evidence of genetic heterogeneity in AA. Our demonstration of genetic association between the MX1 gene and disease supports the hypothesis that this is a new candidate gene in AA.

Factors that influence the growth of the anagen hair follicle or initiate the switch to a catagen growth pattern have so far not been definitely determined, but there is increasing evidence that cytokines and growth factors play an important role during these processes. Recently we detected an aberrant in situ expression pattern of cytokines of the Th1 type (IFN gamma, IL-2) plus IL-1 beta expression in untreated alopecia areata (AA), and a switch to high levels of IL-10 TGF-beta 1 expression after successful treatment with the contact allergen diphenylcyclopropenone (DCP). Hence the question arose as to whether cytokines are able to arrest hair growth and whether IL-10 or TGF beta 1 have the capacity to antagonize this process. Using whole-organ cultures of microdissected human hair follicles we studied the effect of a panel of cytokines and growth factors on hair growth and on the gross morphology of the hair follicles in vitro. IL-2, IL-10 and IFN-gamma had no effect in this regard, whereas TGF beta 1 partially inhibited hair growth and EGF, TNF alpha and IL-1 beta completely abrogated it. EGF and TNF alpha induced the formation of a club-like hair follicle, similar to catagen morphology of the hair bulb, whereas hair follicles grown in the presence of IL-1 beta or TGF beta 1 showed no particular morphological changes. We conclude that cytokines and growth factors are pivotal regulators of hair growth at least in vitro. IL-1 is suggested as playing an important role during the pathogenesis of AA. Possible mediators of therapeutic contact dermatitis (IL-10, TGF beta 1, TNF alpha, PGE2) are, at least in vitro, not able to antagonize the IL-1 beta-triggered hair growth inhibition. Therefore, we infer that these mediators rather "modulate' the immune response in AA.