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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE autoregulation.

The autoimmune regulator (AIRE) is essential for the establishment of central tolerance and prevention of autoimmunity. Interestingly, different AIRE mutations cause autoimmunity in either recessive or dominant-negative manners. Using engineered mouse models, we establish that some monoallelic mutants, including C311Y and C446G, cause breakdown of central tolerance. By using RNAseq, ATACseq, ChIPseq, and protein analyses, we dissect the underlying mechanisms for their dominancy. Specifically, we show that recessive mutations result in a lack of AIRE protein expression, while the dominant mutations in both PHD domains augment the expression of dysfunctional AIRE with altered capacity to bind chromatin and induce gene expression. Finally, we demonstrate that enhanced AIRE expression is partially due to increased chromatin accessibility of the AIRE proximal enhancer, which serves as a docking site for AIRE binding. Therefore, our data not only elucidate why some AIRE mutations are recessive while others dominant, but also identify an autoregulatory mechanism by which AIRE negatively modulates its own expression.

Autistic adults' subjective experiences of hoarding and self-injurious behaviors.

LAY ABSTRACT: Hoarding and self-injurious behaviors are relatively common in autism, but knowledge about their expressions in adulthood is scarce. Through interviews collecting subjective experiences of autistic adults, these behaviors were explored, and categorized to their underlying purposes. Findings portray the occurrence of these behaviors in the lives of autistic adults, their self-regulatory purposes, and their relationship to other behaviors in the domain of Restrictive and Repetitive Behaviors and Interests.

IL18 signaling promotes homing of mature Tregs into the thymus.

Foxp3+ regulatory T cells (Tregs) are potent suppressor cells, essential for the maintenance of immune homeostasis. Most Tregs develop in the thymus and are then released into the immune periphery. However, some Tregs populate the thymus and constitute a major subset of yet poorly understood cells. Here we describe a subset of thymus recirculating IL18R+ Tregs with molecular characteristics highly reminiscent of tissue-resident effector Tregs. Moreover, we show that IL18R+ Tregs are endowed with higher capacity to populate the thymus than their IL18R- or IL18R-/- counterparts, highlighting the key role of IL18R in this process. Finally, we demonstrate that IL18 signaling is critical for the induction of the key thymus-homing chemokine receptor - CCR6 on Tregs. Collectively, this study provides a detailed characterization of the mature Treg subsets in the mouse thymus and identifies a key role of IL18 signaling in controlling the CCR6-CCL20-dependent migration of Tregs into the thymus.

Thymic epithelial cell heterogeneity: TEC by TEC.

The generation of a functional T cell repertoire in the thymus is mainly orchestrated by thymic epithelial cells (TECs), which provide developing T cells with cues for their navigation, proliferation, differentiation and survival. The TEC compartment has been segregated historically into two major populations of medullary TECs and cortical TECs, which differ in their anatomical localization, molecular characteristics and functional roles. However, recent studies have shown that TECs are highly heterogeneous and comprise multiple subpopulations with distinct molecular and functional characteristics, including tuft cell-like or corneocyte-like phenotypes. Here, we review the most recent advances in our understanding of TEC heterogeneity from a molecular, functional and developmental perspective. In particular, we highlight the key insights that were recently provided by single-cell genomic technologies and in vivo fate mapping and discuss them in the context of previously published data.

A Conflict of Interests: A Motivational Perspective on Special Interests and Employment Success of Adults with ASD.

A course of action often suggested in an attempt to improve employment outcomes of adults with autism spectrum disorder, is to match between special interests and job opportunities. In this commentary, we propose that the match may be more complicated than it seems, possibly overseeing more pressing employment needs that should be answered such as: the job's characteristics, labor market demands, and stress resulting from job expectations. Self determination theory of motivation is suggested as a lens through which the association between special interests and a paying job can be examined, highlighting important considerations that hold the potential to increase employment success. Recommendations for new research directions and vocational rehabilitation practice are discussed.

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.

HDAC3 Is a Master Regulator of mTEC Development.

The thymus provides a unique microenvironment enabling development and selection of T lymphocytes. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process by facilitating negative selection of self-reactive thymocytes and the generation of Foxp3(+) regulatory T cells. Although studies have highlighted the non-canonical nuclear factor κB (NF-κB) pathway as the key regulator of mTEC development, comprehensive understanding of the molecular pathways regulating this process still remains incomplete. Here, we demonstrate that the development of functionally competent mTECs is regulated by the histone deacetylase 3 (Hdac3). Although histone deacetylases are global transcriptional regulators, this effect is highly specific only to Hdac3, as neither Hdac1 nor Hdac2 inactivation caused mTEC ablation. Interestingly, Hdac3 induces an mTEC-specific transcriptional program independently of the previously recognized RANK-NFκB signaling pathway. Thus, our findings uncover yet another layer of complexity of TEC lineage divergence and highlight Hdac3 as a major and specific molecular switch crucial for mTEC differentiation.