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A mouse model of clonal CD8+ T lymphocyte-mediated alopecia areata progressing to alopecia universalis.

ABSTRACT: Alopecia areata is among the most prevalent autoimmune diseases, yet compared with other autoimmune conditions, it is not well studied. This in part results from limitations in the C3H/HeJ mouse and DEBR rat model systems most commonly used to study the disease, which display a low frequency and late onset. We describe a novel high-incidence model for spontaneous alopecia areata. The 1MOG244 T cell expresses dual TCRA chains, one of which, when combined with the single TCRB present, promotes the development of CD8(+) T cells with specificity for hair follicles. Retroviral transgenic mice expressing this TCR develop spontaneous alopecia areata at nearly 100% incidence. Disease initially follows a reticular pattern, with regionally cyclic episodes of hair loss and regrowth, and ultimately progresses to alopecia universalis. Alopecia development is associated with CD8(+) T cell activation, migration into the intrafollicular region, and hair follicle destruction. The disease may be adoptively transferred with T lymphocytes and is class I and not class II MHC-dependent. Pathologic T cells primarily express IFNG and IL-17 early in disease, with dramatic increases in cytokine production and recruitment of IL-4 and IL-10 production with disease progression. Inhibition of individual cytokines did not significantly alter disease incidence, potentially indicating redundancy in cytokine responses. These results therefore characterize a new high-incidence model for alopecia areata in C57BL/6J mice, the first to our knowledge to apply a monoclonal TCR, and indicate that class I MHC-restricted CD8(+) T lymphocytes can independently mediate the pathologic response.

SUBMITTER: Alli R

PROVIDER: S-EPMC3244525 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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A mouse model of clonal CD8+ T lymphocyte-mediated alopecia areata progressing to alopecia universalis.

Alli Rajshekhar R Nguyen Phuong P Boyd Kelli K Sundberg John P JP Geiger Terrence L TL

Journal of immunology (Baltimore, Md. : 1950) 20111123 1

Alopecia areata is among the most prevalent autoimmune diseases, yet compared with other autoimmune conditions, it is not well studied. This in part results from limitations in the C3H/HeJ mouse and DEBR rat model systems most commonly used to study the disease, which display a low frequency and late onset. We describe a novel high-incidence model for spontaneous alopecia areata. The 1MOG244 T cell expresses dual TCRA chains, one of which, when combined with the single TCRB present, promotes the ...[more]

PMID: 22116824

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Project description:ImportanceAlopecia areata (AA) is characterized by nonscarring hair loss of the scalp, face, and/or body. Alopecia totalis (AT) and alopecia universalis (AU) involve complete loss of the scalp and body hair, respectively. The epidemiology of AA in the US remains unclear, having previously been extrapolated from older studies that were limited to specific geographic areas or clinical settings, or from self-reported data.ObjectiveTo estimate the annual prevalence and incidence of AA and AT and/or AU (AT/AU) in the US.Design, setting, and participantsThis retrospective, population-based cohort study was conducted from January 2016 to December 2019 and included enrollees in the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental databases and their dependents, with plan enrollment during each study calendar year and the year prior.ExposuresPrevalent cases were identified by 1 or more claims for AA or AT/AU (International Statistical Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] codes L63.x, L63.0, L63.1) during each year of interest or the year prior. Incident cases were identified by 1 or more claims for AA or AT/AU during a specific year and no diagnosis the year prior.Main outcomes and measuresAnnual incidence and prevalence rates were calculated and stratified by age, sex, and region. National employer-sponsored insurance population estimates were obtained using population-based weights.ResultsAmong eligible patients (2016: n = 18 368 [mean (SD) age, 40.6 (17.9) years; 12 295 women (66.9%)]; 2017: n = 14 372 [mean (SD) age, 39.6 (17.7) years; 9195 women (64.0%)]; 2018: n = 14 231 [mean (SD) age, 38.9 (17.3) years; 8998 women (63.2%)]; 2019: n = 13 455 [mean (SD) age, 39.1 (17.4) years; 8322 women (61.9%)]), AA prevalence increased from 0.199% (95% CI, 0.198%-0.200%) in 2016 to 0.222% (95% CI, 0.221%-0.223%) in 2019. Roughly 5% to 10% of prevalent and incident cases of AA were AT/AU. The prevalence of AT/AU increased from 0.012% (95% CI, 0.012%-0.013%) to 0.019% (95% CI, 0.018%-0.019%) from 2016 to 2019. Incidence of AA per 100 000 person-years ranged from 87.39 (95% CI, 86.84-87.96) in 2017 to 92.90 (95% CI, 92.35-93.45) in 2019. Incidence of AT/AU ranged from 7.09 (95% CI, 6.94-7.25) in 2017 to 8.92 (95% CI, 8.75-9.09) in 2016. Prevalence and incidence of AA and AT/AU were higher among female vs male individuals, adults vs children and adolescents, and in the Northeast vs other regions.Conclusions and relevanceThe results of this cohort study suggest that these recent AA prevalence and incidence estimates could help improve current understanding of the disease burden. Further research is warranted to elucidate subpopulation differences and trends in AA in the broader US population.

Project description:The treatment of autoimmune diseases still poses a major challenge, frequently relying on non-specific immunosuppressive drugs. Current efforts aim at reestablishing self tolerance using immune cells with suppressive activity like the regulatory T cells (Treg) or the myeloid-derived suppressor cells (MDSC). We have demonstrated therapeutic efficacy of MDSC in mouse Alopecia Areata (AA). In the same AA model, we now asked whether MDSC exosomes (MDSC-Exo) can replace MDSC. MDSC-Exo from bone marrow cells (BMC) cultures of healthy donors could substantially facilitate treatment. With knowledge on MDSC-Exo being limited, their suitability needs to be verified in advance. Protein marker profiles suggest comparability of BMC- to ex vivo collected inflammatory MDSC/MDSC-Exo in mice with a chronic contact dermatitis, which is a therapeutic option in AA. Proteome analyses substantiated a large overlap of function-relevant molecules in MDSC and MDSC-Exo. Furthermore, MDSC-Exo are taken up by T cells, macrophages, NK, and most avidly by Treg and MDSC-Exo uptake exceeds binding of MDSC themselves. In AA mice, MDSC-Exo preferentially target skin-draining lymph nodes and cells in the vicinity of remnant hair follicles. MDSC-Exo uptake is accompanied by a strong increase in Treg, reduced T helper proliferation, mitigated cytotoxic activity, and a slight increase in lymphocyte apoptosis. Repeated MDSC-Exo application in florid AA prevented progression and sufficed for partial hair regrowth. Deep sequencing of lymphocyte mRNA from these mice revealed a significant increase in immunoregulatory mRNA, including FoxP3 and arginase 1. Downregulated mRNA was preferentially engaged in prohibiting T cell hyperreactivity. Taken together, proteome analysis provided important insights into potential MDSC-Exo activities, these Exo preferentially homing into AA-affected organs. Most importantly, changes in leukocyte mRNA seen after treatment of AA mice with MDSC-Exo sustainably supports the strong impact on the adaptive and the non-adaptive immune system, with Treg expansion being a dominant feature. Thus, MDSC-Exo could potentially serve as therapeutic agents in treating AA and other autoimmune diseases.

Project description:Alopecia areata (AA) has been associated with multiple comorbidities, yet information regarding the timing of comorbidity development after AA diagnosis is limited. To evaluate the prevalence and new-onset incidence of psychiatric and autoimmune comorbidities in patients with AA in the US. This retrospective cohort analysis used data collected from January 1, 2007, to April 30, 2023, from the Merative MarketScan Research Databases, which contains medical and drug claims data from more than 46 million patients in the US. Data from adolescent and adult patients (aged 12-64 years) diagnosed with AA and patients without AA (ie, controls) were evaluated. For some analyses, patients with AA were matched (1:4) to controls based on sex, age, and geographic region. Prevalence (at the time of AA diagnosis) and incidence (new onset after AA diagnosis) of psychiatric and autoimmune diseases were reported as percentage of patients. Risk of developing a new-onset psychiatric or autoimmune disease after AA diagnosis was calculated as adjusted hazard ratios (AHRs) with 95% CIs. At baseline, 63 384 patients with AA and 3 309 107 without AA were identified. After matching, there were 16 512 and 66 048 patients in the AA and control groups, respectively, with a mean (SD) age of 36.9 (13.4) years and 50.6% of whom were female. Compared with the unmatched controls, patients with AA had higher prevalence of psychiatric (30.9% vs 26.8%; P < .001) and autoimmune (16.1% vs 8.9%; P < .0001) comorbidities at AA diagnosis; incidence was also higher in patients with AA (without history of these comorbidities) vs the matched control group. Patients with AA vs controls had a significantly higher risk of developing a psychiatric (AHR, 1.3; 95% CI, 1.3-1.4) or autoimmune (AHR, 2.7; 95% CI, 2.5-2.8) comorbidity. In this cohort study, patients with AA had a higher prevalence of autoimmune and psychiatric comorbidities at AA diagnosis and demonstrated an elevated risk of new-onset autoimmune and psychiatric comorbidities after their diagnosis. These data highlight the most common comorbidities among patients with AA and may help physicians counsel and monitor patients newly diagnosed with AA.

Project description:IntroductionIndividuals with alopecia areata (AA) may experience significant impacts on their health-related quality of life. The novel Alopecia Areata Patient Priority Outcomes (AAPPO) questionnaire has been developed to assess hair loss signs, emotional symptoms, and activity limitations associated with AA. The objective of this study was to evaluate psychometric properties and establish scoring of the AAPPO in adults and adolescents with AA.MethodsScoring and measurement properties of the AAPPO were examined using baseline and 2-week follow-up data from a prospective, noninterventional, web-based study of 121 patients with AA (85 adults aged ≥ 18 years, 36 adolescents aged 12-17 years) with Severity of Alopecia Tool (SALT) ≥ 25% scalp hair loss.ResultsExploratory and confirmatory factor analysis supported four single Hair Loss (HL) items, an Emotional Symptoms domain (ES; 4 items), and an Activity Limitations domain (AL; 3 items). Among all patients, the multi-item ES and AL domains had strong internal consistency (α ≥ 0.87); all HL items and domain scores had strong test-retest reliability (weighted kappa or intraclass correlation coefficients ≥ 0.78). All HL item scores demonstrated strong construct validity (r ≥ 0.52) compared with the patient-reported Alopecia Areata Symptom and Impact Scale (AASIS) hair loss subscale score; ES and AL domain scores exhibited strong construct validity (r ≥ 0.66) compared with the SF-36 Mental Component Summary (MCS) score. Using SALT scores, HL mean item scores were better (lower) in the 25-49% SALT subgroup versus those with highest SALT scores (76-100%); however, ES mean domain scores were better in the SALT 76-100% subgroup in the same comparison (p < 0.0001). Using AASIS and MCS score-created subgroups, ES and AL mean domain scores demonstrated hypothesized differences across subgroups (all p values < 0.0001).ConclusionThe AAPPO questionnaire is a reliable, valid disease-specific measure of hair loss severity and impact in individuals with AA.

Dataset Information

A mouse model of clonal CD8+ T lymphocyte-mediated alopecia areata progressing to alopecia universalis.

Publications

A mouse model of clonal CD8+ T lymphocyte-mediated alopecia areata progressing to alopecia universalis.

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