Extrathymic expression of Aire controls the induction of effective TH17 cell-mediated immune response to Candida albicans.

Patients with loss of function in the gene encoding the master regulator of central tolerance AIRE suffer from a devastating disorder called autoimmune polyendocrine syndrome type 1 (APS-1), characterized by a spectrum of autoimmune diseases and severe mucocutaneous candidiasis. Although the key mechanisms underlying the development of autoimmunity in patients with APS-1 are well established, the underlying cause of the increased susceptibility to Candida albicans infection remains less understood. Here, we show that Aire+MHCII+ type 3 innate lymphoid cells (ILC3s) could sense, internalize and present C. albicans and had a critical role in the induction of Candida-specific T helper 17 (TH17) cell clones. Extrathymic Rorc-Cre-mediated deletion of Aire resulted in impaired generation of Candida-specific TH17 cells and subsequent overgrowth of C. albicans in the mucosal tissues. Collectively, our observations identify a previously unrecognized regulatory mechanism for effective defense responses against fungal infections.

Transcriptional programs that control expression of the autoimmune regulator gene Aire.

Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-acting and trans-acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus.

Thymic mimetic cells function beyond self-tolerance.

Development of immunocompetent T cells in the thymus is required for effective defence against all types of pathogens, including viruses, bacteria and fungi. To this end, T cells undergo a very strict educational program in the thymus, during which both non-functional and self-reactive T cell clones are eliminated by means of positive and negative selection1.Thymic epithelial cells (TECs) have an indispensable role in these processes, and previous studies have shown the notable heterogeneity of these cells2-7. Here, using multiomic analysis, we provide further insights into the functional and developmental diversity of TECs in mice, and reveal a detailed atlas of the TEC compartment according to cell transcriptional states and chromatin landscapes. Our analysis highlights unconventional TEC subsets that are similar to functionally well-defined parenchymal populations, including endocrine cells, microfold cells and myocytes. By focusing on the endocrine and microfold TEC populations, we show that endocrine TECs require Insm1 for their development and are crucial to maintaining thymus cellularity in a ghrelin-dependent manner; by contrast, microfold TECs require Spib for their development and are essential for the generation of thymic IgA+ plasma cells. Collectively, our study reveals that medullary TECs have the potential to differentiate into various types of molecularly distinct and functionally defined cells, which not only contribute to the induction of central tolerance, but also regulate the homeostasis of other thymus-resident populations.

Autoimmune amelogenesis imperfecta in patients with APS-1 and coeliac disease.

Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis1. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta2. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency3,4, and in patients diagnosed with coeliac disease5-7. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.

The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance.

Aire is a transcriptional regulator that induces the promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for the induction of immunological self-tolerance. Studies have offered molecular insights into how Aire operates, but more comprehensive understanding of this process still remains elusive. Here we found abundant expression of the protein deacetylase Sirtuin-1 (Sirt1) in mature Aire(+) mTECs, wherein it was required for the expression of Aire-dependent TRA-encoding genes and the subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and identifies a unique function for Sirt1 in preventing organ-specific autoimmunity.

Perspectives and Experiences of Stakeholders on Self-Disclosure of Peers in Mental Health Services.

With the movement towards recovery-oriented mental health (MH) services, individuals with MH lived-experience are increasingly employed as peer providers (peers). Peers are unique in that they bring knowledge from experience and eye-level connection to service users that enhance the quality of services and humanize MH systems' culture. In Israel, hundreds of peers are employed in various roles and settings across the MH system. However, peer integration into MH services faces challenges. One issue involves the use of self-disclosure (SD) in MH services which varies with explicitness across roles and settings. This study sought to understand perspectives and experiences regarding peers' SD (use & sharing of knowledge from experience) among different stakeholders in MH health services. Six focus groups and 4 semi-structured interviews (N = 42) were conducted as a part of a larger international project (UPSIDES; ERC Horizon 2020, Moran et al., Trials 21:371, 2020). Data was transcribed verbatim and analyzed using thematic analysis. Four categories and 7 themes were identified regarding current perspectives and experiences with peers' SD in MH organizations: (i) Restrained or cautious organizational approach to SD; (ii) Attitudes of peers to SD approach; (iii) The influence of designated peer roles on SD; and (iv) Unwarranted SD of peers working in traditional roles. The findings reveal that peers' SD in MH services is a complex process. Organizational approaches were often controlling of non-designated peers' SD practices; participants had diverse attitudes for and against peers' SD; SD occurred according to personal preferences, specific peer role and the director's approach to peers' SD; Conflictual SD dilemmas emerged in relation to service users and staff. SD sometimes occurs unwarrantely due to ill mental health. The presence of peer-designated roles positively impacts peers' SD. We interpret the current mix of views and general conduct of peer SD practice in statutory MH services as related to three aspects: 1. The presence of a traditional therapeutic SD model vs. a peer SD model - with the former currently being dominant. 2. Insufficient proficiency and skill development in peers' SD. 3. Stigmatic notions about peer SD among service users and staff. Together, these aspects interrelate and sometimes create a negative cycle create tension and confusion.A need to develop professionalism of peer SD in statutory services is highlighted alongside enhancing staff and service user acknowledgement of the value of peer SD. Developing peer-designated roles can positively impacts peer SD in MH statutory services. Training, support, and organizational interventions are required to further support for peer-oriented SD and the enhancement of a person-centered and recovery orientation of MH services.

UPSIDES Mental Health Peer Support in Face of the COVID-19 Pandemic: Actions and Insights.

The outburst of the COVID-19 pandemic challenged vulnerable populations such as individuals with significant mental illness. In this fresh focus, we describe the innovative development of the UPSIDES mental health peer support intervention, in face of the COVID-19 pandemic in Israel. While the research program is still ongoing, in this paper we focus on the processes and lessons learned from dealing with the rapidly changing circumstances of the pandemic. We portray additional activities conducted above and beyond the UPSIDES protocol in order to maintain continuation and prevent dropout. We learned that an essential combination of keeping a close adherence with the core peer principles and UPSIDES' systematic program and the use of flexible telecommunication means, helped to maintain social connection and service users' participation throughout these times. The sudden pandemic challenges appeared to level out power imbalances and accelerated the formation of reciprocal and supportive relational interactions within the intervention. These processes highlight experiential knowledge as a unique asset, and peer support services as useful in supporting individuals with significant mental illness throughout COVID-19.

AIRE: From promiscuous molecular partnerships to promiscuous gene expression.

Autoimmune regulator (AIRE) is a unique transcriptional regulator that induces promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for the induction of immunological self-tolerance. The past 15 years have seen dramatic progress in our understanding of how AIRE induces immunological self-tolerance on a molecular level. This major advancement can be greatly attributed to the identification of a large variety of proteins that physically associate with AIRE, supporting and regulating its transcription-transactivation capacity. These diverse molecular partnerships have been shown to play roles in shuttling AIRE to the nucleus, securing AIRE's interaction with nuclear matrix and chromatin, releasing RNA polymerase-II from its stalled state and potentiating AIRE-mediated gene expression, among others. In this review we discuss the relationship of AIRE with its vast and rather diverse repertoire of partners and highlight how such "promiscuous partnerships" contribute to the phenomenon of "promiscuous gene expression" in the thymus.

Where do autistic people work? The distribution and predictors of occupational sectors of autistic and general population employees.

LAY ABSTRACT: Studies on employment of autistic individuals mainly assessed if they work and what their working conditions are (e.g. weekly hours, salary) while less is known about where they work. We explore this issue in our study, by examining which employment sectors do autistic adults work in, and comparing them to the general workforce in the Netherlands. We also explored the possibility that gender, age, age at diagnosis, level of education, degree of autistic traits and presence of focused interests could lead to a higher likelihood of working in specific sectors. We assessed data from a survey filled in by 1115 employed autistic adults (476 male; 627 female; 12 other; mean age: 40.75). Dutch workforce information was based on data form the Central Bureau of Statistics. Results showed that a higher proportion of autistic employees worked in healthcare & welfare, information technology, and the public-army-charity sectors. These were the three most-common sectors for this group. A lower proportion of autistic employees worked in economics & finances, and industry & construction, compared to the general workforce. Most autistic employees in the healthcare & welfare sector were females while having a higher educational degree and being male increased the chance of working in information technology. In addition to the common impression that most autistic individuals have interests or abilities that align with employment in information technology and technology sectors, we found that autistic employees worked in various sectors. It is important to address individual characteristics and needs of autistic individuals, while encouraging diverse employment opportunities.

Mental health workers' perspectives on the implementation of a peer support intervention in five countries: qualitative findings from the UPSIDES study.

OBJECTIVE: The introduction of peer support in mental health teams creates opportunities and challenges for both peer and non-peer staff. However, the majority of research on mental health workers' (MHWs) experiences with peer support comes from high-income countries. Using Peer Support In Developing Empowering Mental Health Services (UPSIDES) is an international multicentre study, which aims at scaling up peer support for people with severe mental illness in Europe, Asia and Africa. This study investigates MHWs experiences with UPSIDES peer support. DESIGN: Six focus groups with MHWs were conducted approximately 18 months after the implementation of the UPSIDES peer support intervention. Transcripts were analysed with a descriptive approach using thematic content analysis. SETTING: Qualitative data were collected in Ulm and Hamburg (Germany), Butabika (Uganda), Dar es Salaam (Tanzania), Be'er Sheva (Israel) and Pune (India). PARTICIPANTS: 25 MHWs (19 females and 6 males) from UPSIDES study sites in the UPSIDES Trial (ISRCTN26008944) participated. FINDINGS: Five overarching themes were identified in MHWs' discussions: MHWs valued peer support workers (PSWs) for sharing their lived experiences with service users (theme 1), gained trust in peer support over time (theme 2) and provided support to them (theme 3). Participants from lower-resource study sites reported additional benefits, including reduced workload. PSWs extending their roles beyond what MHWs perceived as appropriate was described as a challenge (theme 4). Perceptions about PSWs varied based on previous peer support experience, ranging from considering PSWs as equal team members to viewing them as service users (theme 5). CONCLUSIONS: Considering local context is essential in order to understand MHWs' views on the cooperation with PSWs. Especially in settings with less prior experience of peer support, implementers should make extra effort to promote interaction between MHWs and PSWs. In order to better understand the determinants of successful implementation of peer support in diverse settings, further research should investigate the impact of contextual factors (eg, resource availability and cultural values). TRIAL REGISTRATION NUMBER: ISRCTN26008944.

Segmented filamentous bacteria-induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover.

Intestinal epithelial cells have the capacity to upregulate MHCII molecules in response to certain epithelial-adhesive microbes, such as segmented filamentous bacteria (SFB). However, the mechanism regulating MHCII expression as well as the impact of epithelial MHCII-mediated antigen presentation on T cell responses targeting those microbes remains elusive. Here, we identify the cellular network that regulates MHCII expression on the intestinal epithelium in response to SFB. Since MHCII on the intestinal epithelium is dispensable for SFB-induced Th17 response, we explored other CD4+ T cell-based responses induced by SFB. We found that SFB drive the conversion of cognate CD4+ T cells to granzyme+ CD8α+ intraepithelial lymphocytes. These cells accumulate in small intestinal intraepithelial space in response to SFB. Yet, their accumulation is abrogated by the ablation of MHCII on the intestinal epithelium. Finally, we show that this mechanism is indispensable for the SFB-driven increase in the turnover of epithelial cells in the ileum. This study identifies a previously uncharacterized immune response to SFB, which is dependent on the epithelial MHCII function.

Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response.

The thymus is a primary lymphoid organ that is essential for the establishment of adaptive immunity through generation of immunocompetent T cells. In response to various stress signals, the thymus undergoes acute but reversible involution. However, the mechanisms governing its recovery are incompletely understood. Here, we used a dexamethasone-induced acute thymic involution mouse model to investigate how thymic hematopoietic cells (excluding T cells) contribute to thymic regeneration. scRNA-seq analysis revealed marked transcriptional and cellular changes in various thymic populations and highlighted thymus-resident innate lymphoid cells type 2 (ILC2) as a key cell type involved in the response to damage. We identified that ILC2 are activated by the alarmins IL-25 and IL-33 produced in response to tissue damage by thymic tuft cells and fibroblasts, respectively. Moreover, using mouse models deficient in either tuft cells and/or IL-33, we found that these alarmins are required for effective thymus regeneration after dexamethasone-induced damage. We also demonstrate that upon their damage-dependent activation, thymic ILC2 produce several effector molecules linked to tissue regeneration, such as amphiregulin and IL-13, which in turn promote thymic epithelial cell differentiation. Collectively, our study elucidates a previously undescribed role for thymic tuft cells and fibroblasts in thymus regeneration through activation of the type 2 immune response.

A Self-Determination Theory Approach to Work Motivation of Autistic Adults: A Qualitative Exploratory Study.

The study explores work motivation of autistic adults through the lens of Self-Determination Theory (SDT). Twelve autistic employees (ages 28-47; 3 females) participated in semi-structured qualitative interviews about their work experience. Analysis combined inductive and deductive approaches, identifying motivational themes emerging from the interviews, and analyzing them according to SDT concepts. Two major themes emerged: (1) work motivation factors positioned on the self-determination continuum: income and self-reliance; a daily routine; social/familial internalized norms; meaning and contribution; and job interest; and (2) satisfaction of psychological needs at work, postulated by SDT: competence, social-relatedness, and autonomy and structure. Findings are discussed in relation to current literature, and practical applications are suggested for meeting the motivational needs of autistic employees and promoting employment stability.

A partial form of AIRE deficiency underlies a mild form of autoimmune polyendocrine syndrome type 1.

Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations in the autoimmune regulator (AIRE) gene. Most patients present with severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood, but the clinical picture is highly variable. AIRE is crucial for negative selection of T cells, and scrutiny of different patient mutations has previously highlighted many of its molecular mechanisms. In patients with a milder adult-onset phenotype sharing a mutation in the canonical donor splice site of intron 7 (c.879+1G>A), both the predicted altered splicing pattern with loss of exon 7 (AireEx7-/-) and normal full-length AIRE mRNA were found, indicating leaky rather than abolished mRNA splicing. Analysis of a corresponding mouse model demonstrated that the AireEx7-/- mutant had dramatically impaired transcriptional capacity of tissue-specific antigens in medullary thymic epithelial cells but still retained some ability to induce gene expression compared with the complete loss-of-function AireC313X-/- mutant. Our data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.

Implications of Employment Changes Caused by COVID-19 on Mental Health and Work-Related Psychological Need Satisfaction of Autistic Employees: A Mixed-Methods Longitudinal Study.

This mixed-methods study examined longitudinal data, assessing Israeli autistic adults' employment-related changes, resulting from the COVID-19 pandemic. In the quantitative phase, 23 participants answered a survey before and during COVID-19, assessing work-status, mental health, and work-related psychological need satisfaction. The qualitative phase included interviews with ten employed participants. Results indicate a significant decrease in mental health of participants who lost their jobs during COVID-19, while participants who continued to physically attend work, maintained pre-COVID-19 levels on all assessed variables. Participants who transitioned to remote-work from home, showed a marginally significant deterioration in mental health and a significant decrease in satisfaction of work-related psychological needs for competence and autonomy. Qualitative accounts supplement these findings and portray advantages and disadvantages of remote-work.

Visual Detection and Decoding Skills of Aerial Photography by Adults with Autism Spectrum Disorder (ASD).

Despite challenges in social communication skills people with ASD often display strengths in visual processing. Aerial photography analysis is an occupation reliant on strong visual processing skills that matches this unique profile. We investigated basic-vision and "real-life" visual tasks in 20 cognitively-able young adults with ASD and 20 typically-developed (TD) "gamers". Basic-vision tests included Visual-Search, Embedded-Figures, and Vigilance; "real-life" tests included aerial-photograph detection and identification. Groups performed equally well, and did not differ significantly on any tasks. The study demonstrates strong visual skills in people with ASD in basic and "real-life" settings, and supports the idea that they may be well suited for employment in occupations that demand high visual perception skills such as aerial photography analysis.

The acetyltransferase KAT7 is required for thymic epithelial cell expansion, expression of AIRE target genes, and thymic tolerance.

The autoimmune regulator (AIRE) induces the transcription of thousands of peripheral tissue genes (PTGs) in thymic epithelial cells (TECs) to mediate immunological tolerance. The chromatin state required for optimal AIRE function in TECs and how this state is induced remains unclear. We tested the role of the histone acetyltransferase, KAT7 (also known as HBO1 or MYST2), which is essential for acetylation of histone 3 lysine 14, in TEC differentiation, AIRE-mediated PTG expression, and thymic tolerance. We find that KAT7 is required for optimal expansion of medullary TEC and has a major role in the expression of AIRE-dependent PTGs, associated with enhanced chromatin accessibility at these gene loci in TECs. Mice with TEC-specific Kat7 deletion develop organ-specific autoimmunity with features resembling those observed in Aire-deficient mice. These findings highlight critical roles for KAT7-mediated acetylation in promoting a chromatin state at PTG loci that enables AIRE function and the establishment of immunological tolerance.

Transcriptional regulation of the thymus master regulator Foxn1.

FOXN1 is a transcription factor critical for the development of both thymic epithelial cell (TEC) and hair follicle cell (HFC) compartments. However, mechanisms controlling its expression remain poorly understood. To address this question, we performed thorough analyses of the evolutionary conservation and chromatin status of the Foxn1 locus in different tissues and states and identified several putative cis-regulatory regions unique to TECs versus HFCs. Furthermore, experiments using genetically modified mice with specific deletions in the Foxn1 locus and additional bioinformatic analyses helped us identify key regions and transcription factors involved in either positive or negative regulation of Foxn1 in both TECs and HFCs. Specifically, we identified SIX1 and FOXN1 itself as key factors inducing Foxn1 expression in embryonic and neonatal TECs. Together, our data provide important mechanistic insights into the transcriptional regulation of the Foxn1 gene in TEC versus HFC and highlight the role of FOXN1 in its autoregulation.

Improving postoperative immune status and resistance to cancer metastasis: a combined perioperative approach of immunostimulation and prevention of excessive surgical stress responses.

BACKGROUND: Surgical procedures, including primary tumor resection, have been suggested to suppress immune competence and to promote postoperative infections and cancer metastasis. Catecholamines and prostaglandins were recently implicated in these processes, and in directly promoting tumor angiogenesis and invasion. OBJECTIVE: To examine the integration of 2 complementary approaches to reduce postoperative immunosuppression and metastatic progression: (1) perioperative immunostimulation with CpG-C and (2) pharmacological blockade of the tumor-promoting and immunosuppressing effects of catecholamines and prostaglandins, using propranolol (P) and etodolac (E), respectively. METHODS: F344 rats were treated before surgery with CpG-C, P+E, both interventions, or vehicles, and were intravenously inoculated with syngeneic MADB106 mammary adenocarcinoma cells. Blood was withdrawn, marginating-pulmonary leukocytes were harvested, and NK activity and lung MADB106 tumor retention were assessed. In addition, C57BL/6 mice were implanted with syngeneic B16F10.9 melanoma cells. When tumors reached 100 mm, mice were treated with CpG-C/vehicle, and 24 hours later the tumor was excised along with P+E/vehicle treatment. Recurrence-free survival was monitored thereafter. RESULTS: Each of the regimens alone, CpG-C or P+E, showed improvement in most indices examined, including improved long-term recurrence-free survival rates. Most importantly, the combined treatment yielded additive or synergistic effects, further improving tumor clearance from the lungs and enhancing NK numbers and cytotoxicity via different, but complimentary, mechanisms. CONCLUSIONS: Treatment aimed at perioperative enhancement of CMI and simultaneous inhibition of excessive catecholamine and prostaglandin responses, employing CpG-C, propranolol, and etodolac, could be successful in limiting postoperative immunosuppression and metastatic progression, more so than each treatment alone.