Toward an understanding of occupational burnout among employees with autism - the Job Demands-Resources theory perspective.

This article aims to gain insight into the phenomenon of occupational burnout among employees with autism based on the theoretical framework of the Job Demands-Resources theory and the literature on employees with autism in the workplace. Firstly, we argue that although the resources and demands of the neurotypical and neurodivergent employees might be different, the theoretical mechanism of occupational burnout formation remains similar among the neurotypical and neurodivergent employees, leading to the similar burnout experience. Next, we distinguish key demands that might drain neurodiverse employees' energy, and spark burnout, and propose a set of resources that might foster their achievement of work goals and mitigate demanding working conditions. We emphasise that the nature of job demands/resources that may cause burnout is not universal but might depend on how employees evaluate them, thus neurotypical and neurodiverse workers who evaluate the same work characteristics differently might complement each other, increasing organisational diversity without losing productivity. Our conceptual elaboration contributes to the theory and practice of healthier workplaces by providing tools and inspiration to managers, policymakers, and all stakeholders interested in creating a diverse and productive workplace. Moreover, our work might spark a much needed debate on occupational burnout among employees with autism and encourage conducting further empirical studies.

Autistic Employees' Technology-Based Workplace Accommodation Preferences Survey-Preliminary Findings.

BACKGROUND: There has been an increase in the number of research studies focused on the design of accommodations aimed at improving the well-being and work performance of autistic employees. These accommodations took various forms; some of them were based on modification of management practices, for example, support in the area of effective communication, or involved modifications to the physical working environment aimed at limiting sensory vulnerabilities. Many of these solutions were based on digital technology. METHODS: This quantitative research aimed to learn about the opinions of the autistic respondents as potential end users and their assessment of the proposed solutions within four main challenge areas: (1) effective communication; (2) time management, task prioritizing, and organization of work; (3) stress management and emotion control; and (4) sensory sensitivities. RESULTS: Respondents gave the highest ratings to solutions aimed at limiting overstimulation and a flexible approach toward working time, support of a job coach, remote work, and support by allowing electronic-mediated communication based on non-direct contact. CONCLUSIONS: The results can be the starting point for further research on the highest rated solutions dedicated to improving working conditions and the well-being of autistic employees and can be an inspiration for employers who plan to introduce such solutions.

Remote Work Support Needs of Employees with Autism Spectrum Disorder in Poland: Perspectives of Individuals with Autism and Their Coworkers.

BACKGROUND AND AIMS: With remote work becoming more common across industries, employees with autism may experience different work support needs from neurotypical peers. However, the specific remote work needs of this group of employees are underexplored in the literature. We aim to propose ways to assess workplace digital adaptation needs for individuals with autism and a framework for communicating these needs to employers. METHODS: This qualitative study included interviews with 13 Polish business professionals, including coworkers and/or supervisors of employees with autism (n = 9) and female employees with autism (n = 4), about their remote work support needs. Participants responded to semi-structured interview questions identifying advantages and risk factors associated with remote work for this specific group of employees. RESULTS: Participants reported advantages of remote work, such as limiting sensory overload and intensive interpersonal contacts, indirect interpersonal communications, flexible work hours, and eliminating the need to travel to work. Participants also reported challenges of remote work, such as reducing wanted or helpful social contacts, engaging in direct electronic communications, limiting opportunities to learn from other employees, and managing work-life balance. CONCLUSION: These findings suggest a need for an autism-inclusive digitalized remote work design customized to the unique needs of employees on the autism spectrum. Business managers would be key partners in the design of autism-inclusive digitalized remote work systems. Additional research is needed with larger and more diverse samples of employees with autism.

The sub-fossil diatom distribution in the Beibu Gulf (northwest South China Sea) and related environmental interpretation.

Located in northwestern South China Sea (SCS), the Beibu Gulf constitutes an environmentally sensitive region shaped by land-ocean-atmosphere interactions in Asia between the western Pacific and eastern Indian Oceans. This study aims to provide a comprehensive view of the sub-fossil diatom biogeography, distribution pattern and oceanographic environmental controls with support of multivariate methods based on Beibu Gulf core-top samples. Cluster analysis of diatom assemblages divides the distribution pattern into four subclusters. Sea surface salinity (SSS), temperature (SST), trophic state (chlorophyll a concentration in this study) and water depth constrain the diatom distribution pattern through canonical redundancy analysis although only partly support an interpretation of the relationship between these various variables. Chlorophyll a has a strong correlation to diatom distribution, and responds to Paralia sulcata occurrence, while SSS and SST also have significant influence and indicate warm water invasion from the open SCS. Water depth is a subordinate factor in terms of Beibu Gulf diatom distribution. The ca. 25 m water-depth marks the upper extent of Paralia sulcata dominance in the northern Beibu Gulf. A strong mixing area with a complex diatom distribution exists below this water depth in the middle of Beibu Gulf. Coastal currents from north of SCS invade Beibu Gulf through Qiongzhou Strait and south of Hainan Island, as recorded by higher percentages of Paralia sulcata and Cyclotella striata at these sites. Our results provide a selection of evaluation method for a marine ecological red-line definition for sustainable development. This study highlights the perspective relationships between the spatial distribution of sub-fossil diatom assemblages in surface sediments and oceanographic variables, which could serve as a model for paleoenvironmental and paleoclimatic reconstruction in future marginal sea geoscience research for the Beibu Gulf, northwestern SCS.

Thermoplastic Intumescent Coatings Modified with Pentaerythritol-Occluded Carbon Nanotubes.

A thermoplastic intumescent coating system (IC) based on poly(vinyl acetate) was modified by two forms of multiwalled carbon nanotubes (CNTs), i.e., by a nanofiller powder and its solid dispersions in pentaerythritol (PER-CNTs). It was revealed that only the PER-CNTs modifier allows us to obtain solvent-borne ICs with a relatively high CNTs concentration (1-3 wt. parts of CNTs/100 wt. parts of paint solids) and acceptable application viscosity. Thermal insulation time (TIT) and intumescent factor (IF) of the ICs on a steel substrate (a fire test according to a cellulosic fire curve), as well as morphology, chemical structure (by the FT-IR technique) and mechanical strength of the charred systems, were investigated. It was found that the CNTs powder decreases TIT and IF values while PER-occluded CNTs improve these parameters (e.g., +4.6 min and +102% vs. an unmodified sample, respectively). Compressive strength of the charred ICs was improved by the PER-CNTs modifier as well.

Inclusive Communication Model Supporting the Employment Cycle of Individuals with Autism Spectrum Disorders.

Difficulties with interpersonal communication experienced by individuals with autism spectrum disorders (ASD) significantly contribute to their underrepresentation in the workforce as well as problems experienced while in employment. Consistently, it is vital to understand how communication within the employment cycle of this group can be improved. This study aims to identify and analyze the possibilities of modifying the communication processes around recruitment, selection, onboarding, and job retention to address the specific characteristics and needs of the representatives of this group. This qualitative study is based on 15 in-depth interviews conducted with 21 field experts, i.e.,: therapists, job trainers, and entrepreneurs employing people with ASD. The findings of this research informed the creation of an inclusive communication model supporting the employment cycle of individuals with ASD. The most important recommendations within the model that was created include the modification of job advertisements, use of less structured job interviews, providing opportunities for mentorship, and supportive and non-direct, electronically mediated communication. To apply the above-mentioned solutions and take full advantage of the talents of people with ASD, it is also necessary to provide tailored sensitivity and awareness training programs for their direct addressees as well as their neurotypical colleagues, including managerial staff.

Support for Employees with ASD in the Workplace Using a Bluetooth Skin Resistance Sensor⁻A Preliminary Study.

The application of a Bluetooth skin resistance sensor in assisting people with Autism Spectrum Disorders (ASD), in their day-to-day work, is presented in this paper. The design and construction of the device are discussed. The authors have considered the best placement of the sensor, on the body, to gain the most accurate readings of user stress levels, under various conditions. Trial tests were performed on a group of sixteen people to verify the correct functioning of the device. Resistance levels were compared to those from the reference system. The placement of the sensor has also been determined, based on wearer convenience. With the Bluetooth Low Energy block, users can be notified immediately about their abnormal stress levels via a smartphone application. This can help people with ASD, and those who work with them, to facilitate stress control and make necessary adjustments to their work environment.

Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis.

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide.

Efficacy of Vedolizumab as Induction Therapy in Refractory IBD Patients: A Multicenter Cohort.

BACKGROUND: Vedolizumab (VDZ) demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease in a multicenter cohort of patients. METHODS: Patients at Massachusetts General Hospital and Brigham and Women's Hospital were considered for inclusion. VDZ (300 mg) was administered at weeks 0, 2, 6, and 14. Efficacy was assessed using the Harvey-Bradshaw index for CD, the simple clinical colitis activity index for UC and physician assessment, along with C-reactive protein and decrease of corticosteroid therapy. Clinical response was defined as decrease in Harvey-Bradshaw index ≥3 and simple clinical colitis activity index ≥3 and remission as Harvey-Bradshaw index ≤4, simple clinical colitis activity index ≤2 and physician assessment of response and remission. RESULTS: Our study included 172 patients (107 CD, 59 UC, 6 inflammatory bowel disease-unclassified, men 48.3%, mean age 40 years and disease duration 14 years). Fourteen patients had ostomy and 9 ileoanal pouch, and only 35.5% fulfilled eligibility for the GEMINI trials. Previous treatment failures with ≥ 2 anti-TNFs occurred in 70.9%, one-third were on an immunomodulator and 46% systemic steroids at baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had clinical response and clinical remission at week 14, respectively. Adverse events occurred in 10.5%. CONCLUSIONS: VDZ is safe and well tolerated in refractory inflammatory bowel disease patients in a clinical practice with efficacy in UC and CD with responses similar to what was seen in clinical trials.

Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4.

OBJECTIVE: IBD is a group of complex, systemic disorders associated with intestinal inflammation and extraintestinal manifestations. Recent studies revealed Mendelian forms of IBD, which contributed significantly to our understanding of disease pathogenesis and the heritability of IBD. DESIGN: We performed exome sequencing in a family with Crohn's disease (CD) and severe autoimmunity, analysed immune cell phenotype and function in affected and non-affected individuals, and performed in silico and in vitro analyses of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) structure and function. RESULTS: A novel missense variant was identified in CTLA4 encoding CTLA-4, a coinhibitory protein expressed by T cells and required for regulation of T cell activation. The residue affected by the mutation, CTLA-4 Tyr60, is evolutionarily highly conserved, and the identified Y60C variant is predicted to affect protein folding and structural stability and demonstrated to cause impaired CTLA-4 dimerisation and CD80 binding. Intestinal inflammation and autoimmunity in carriers of CTLA-4 Y60C exhibit incomplete penetrance with a spectrum of clinical presentations ranging from asymptomatic carrier status to fatal autoimmunity and intestinal inflammation. In a clinically affected CTLA-4 Y60C carrier, T cell proliferation was increased in vitro and associated with an increased ratio of memory to naive T cells in vivo, consistent with impaired regulation of T cell activation. CONCLUSIONS: Our results support the concept that variants in CTLA4 provide the basis for a novel Mendelian form of early-onset CD associated with systemic autoimmunity. Incomplete penetrance of autoimmunity further indicates the presence of other genetic and/or environmental modifiers.

Paneth cells as a site of origin for intestinal inflammation.

The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn's disease. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction. As Atg16l1(HM) mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium, and several genetic risk factors of Crohn's disease affect Paneth cells. Here we show that impairment in either UPR (Xbp1(ΔIEC)) or autophagy function (Atg16l1(ΔIEC) or Atg7(ΔIEC)) in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn's-disease-like transmural ileitis if both mechanisms are compromised. Xbp1(ΔIEC) mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn's disease as a specific disorder of Paneth cells.

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells.

Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box-binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)-mediated increase in Lgr5(+) and Olfm4(+) ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)-related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors.

The unfolded protein response and its role in intestinal homeostasis and inflammation.

The unfolded protein response (UPR) is a signaling pathway from the endoplasmic reticulum (ER) to the nucleus that protects cells from the stress caused by misfolded or unfolded proteins [1, 2]. As such, ER stress is an ongoing challenge for all cells given the central biologic importance of secretion as part of normal physiologic functions. This is especially the case for cells that are highly dependent upon secretory function as part of their major duties. Within mucosal tissues, the intestinal epithelium is especially dependent upon an intact UPR for its normal activities [3]. This review will discuss the UPR and the special role that it provides in the functioning of the intestinal epithelium and, when dysfunctional, its implications for understanding mucosal homeostasis and intestinal inflammation, as occurs in inflammatory bowel disease (IBD).

NF-κB1 inhibits TLR-induced IFN-ß production in macrophages through TPL-2-dependent ERK activation.

Although NF-κB1 p50/p105 has critical roles in immunity, the mechanism by which NF-κB1 regulates inflammatory responses is unclear. In this study, we analyzed the gene expression profile of LPS-stimulated Nfkb1(-/-) macrophages that lack both p50 and p105. Deficiency of p50/p105 selectively increased the expression of IFN-responsive genes, which correlated with increased IFN-ß expression and STAT1 phosphorylation. IFN Ab-blocking experiments indicated that increased STAT1 phosphorylation and expression of IFN-responsive genes observed in the absence of p50/p105 depended upon autocrine IFN-ß production. Markedly higher serum levels of IFN-ß were observed in Nfkb1(-/-) mice than in wild-type mice following LPS injection, demonstrating that Nfkb1 inhibits IFN-ß production under physiological conditions. TPL-2, a mitogen-activated protein kinase kinase kinase stabilized by association with the C-terminal ankyrin repeat domain of p105, negatively regulates LPS-induced IFN-ß production by macrophages via activation of ERK MAPK. Retroviral expression of TPL-2 in Nfkb1(-/-) macrophages, which are deficient in endogenous TPL-2, reduced LPS-induced IFN-ß secretion. Expression of the C-terminal ankyrin repeat domain of p105 in Nfkb1(-/-) macrophages, which rescued LPS activation of ERK, also inhibited IFN-ß expression. These data indicate that p50/p105 negatively regulates LPS-induced IFN signaling in macrophages by stabilizing TPL-2, thereby facilitating activation of ERK.

Inhibition of Helicobacter hepaticus-induced colitis by IL-10 requires the p50/p105 subunit of NF-kappa B.

Defects within the innate immune system sensitize NF-kappaB-deficient (p50(-/-); p65(+/-)) mice to Helicobacter hepaticus (Hh)-induced colitis. Because IL-10 plays a central role in the inhibition of Hh-induced colitis, we hypothesized that the ability of IL-10 to inhibit the innate inflammatory response to Hh may be compromised in NF-kappaB-deficient mice. To test this hypothesis, we evaluated the ability of an IL-10-Ig fusion protein with IL-10-like properties to inhibit Hh-induced colitis in RAG-2(-/-) (RAG) and p50(-/-); p65(+/-); RAG-2(-/-) (3X/RAG) mice. As expected, IL-10-Ig efficiently inhibited the development of colitis in RAG mice. In contrast, the ability of IL-10-Ig to inhibit colitis was compromised in 3X/RAG mice. The defect in response to IL-10-Ig appeared to be primarily the result of the absence of the p50/p105 subunit, because the ability of IL-10-Ig to inhibit colitis was also compromised in p50(-/-); RAG-2(-/-) (p50/RAG) mice. Radiation chimeras demonstrated that the presence of p50/p105 within hemopoietic cells of the innate immune system was necessary for efficient inhibition of colitis by IL-10-Ig. Consistent with a defect in the suppressive effects of IL-10 in the absence of p50/p105, we found that the ability of IL-10 to control LPS-induced expression of IL-12 p40 was significantly compromised in macrophages lacking p50/p105. These results suggest that the absence of the p50/p105 subunit of NF-kappaB within hemopoietic cells of the innate immune system interferes with the ability of IL-10 to suppress inflammatory gene expression and Hh-induced colitis.

Defective activation of ERK in macrophages lacking the p50/p105 subunit of NF-kappaB is responsible for elevated expression of IL-12 p40 observed after challenge with Helicobacter hepaticus.

Helicobacter hepaticus is an enterohepatic Helicobacter species that induces lower bowel inflammation in susceptible mouse strains, including those lacking the p50/p105 subunit of NF-kappaB. H. hepaticus-induced colitis is associated with elevated levels of IL-12 p40 expression, and p50/p105-deficient macrophages express higher levels of IL-12 p40 than wild-type macrophages after challenge with H. hepaticus. However, the molecular mechanisms by which the p50/p105 subunit of NF-kappaB suppresses IL-12 p40 expression have not yet been elucidated. In this study we have demonstrated that H. hepaticus challenge of macrophages induces ERK activation, and this event plays a critical role in inhibiting the ability of H. hepaticus to induce IL-12 p40. Activation of ERK requires both p50/p105 and the MAPK kinase kinase, Tpl-2. Inhibition of the induction of IL-12 p40 by ERK was independent of c-Rel, a known positive regulator of IL-12 p40. Instead, it was linked to the induction of c-Fos, a known inhibitor of IL-12 p40 expression. These results suggest that H. hepaticus induces ERK activation by a pathway dependent upon Tpl-2 and p105, and that activation of ERK inhibits the expression of IL-12 p40 by inducing c-Fos. Thus, a defect in ERK activation could play a pivotal role in the superinduction of IL-12 p40 observed after challenge of macrophages lacking the p50/p105 subunit of NF-kappaB with H. hepaticus.

A role for NF-kappa B subunits p50 and p65 in the inhibition of lipopolysaccharide-induced shock.

To evaluate the possibility that NF-kappaB subunits p50 and p65 have a role in limiting the systemic inflammatory response induced by endotoxin, we compared the susceptibility of wild-type (WT), p65+/-, p50-/-, and p50-/-p65+/- (3X) mice to LPS-induced shock. Interestingly, whereas p65+/- mice were no more sensitive than WT mice to LPS-induced shock, 3X mice were exquisitely sensitive to the toxic effects of LPS. Mice lacking p50 alone displayed an intermediate phenotype. Sensitivity to LPS was a property of the innate immune system and was characterized by elevated circulating levels of TNF in both p50-/- and 3X mice. The ability of LPS to induce shock depended upon TNF, and 3X mice were significantly more sensitive to the toxic effects of TNF than were p50-deficient mice. The expression of several LPS-inducible proinflammatory genes, including IFN-gamma, was significantly higher within the spleens of p50-/- mice than in the spleens of WT mice, and interestingly, the expression of IFN-gamma was augmented still further within the spleens of 3X mice. These results demonstrate that NF-kappaB subunits p50 and p65 have critical inhibitory functions during the systemic response to LPS and raise the possibility that these functions could be essential in preventing mortality associated with systemic inflammatory response syndromes.

CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice.

Roles for host immune response in carcinogenesis are not well defined. Recent studies have shown that microbially driven inflammation can lead to colon cancer and that prior transfer of regulatory lymphocytes expressing CD4 and CD25 prevents the innate inflammatory events that lead to colon cancer in mice. To further examine the ability of regulatory lymphocytes to inhibit carcinogenesis, 129/SvEv Rag-2-deficient mice were inoculated by gastric gavage with Helicobacter hepaticus, an enteric bacterial pathogen of mice. Mice were then treated at 1, 3, or 12 months after infection with adoptive transfer of CD4(+)CD45RB(lo)CD25(+)-regulatory cells. Mice dosed with regulatory cells at 4 or 12 weeks after H. hepaticus infection had reduced severity of inflammatory bowel disease and significantly lower risk of colon cancer during the 8 month observation period, compared with infected mice that had not received cells. This suggested that regulatory cells were able to interrupt the ongoing innate immune events in the stepwise progression to cancer. Transfer of regulatory cells into chronically infected mice with established cancer reduced severity of colitis, epithelial dysplasia, and cancer, but did not eliminate all tumors. Regulatory cells lacking anti-inflammatory cytokine interleukin (IL)-10 were unable to inhibit inflammatory bowel disease, dysplasia, or cancer, showing that IL-10 was required for the protective effects of lymphocytes in this setting. Taken together, the data suggest that IL-10-mediated suppression of host innate inflammatory response was pivotal in interrupting carcinogenesis. Regulatory lymphocytes and cytokines may have implications for novel therapies for colon cancer in humans.

Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses.

Newer members of the B7-CD28 superfamily include the receptor PD-1 and its two ligands, PD-L1 and PD-L2. Here, we characterize the expression of PD-1, PD-L1, and PD-L2 in tissues of naive miceand in target organs from two models of autoimmunity, the pancreas from non-obese diabetic (NOD) mice and brain from mice with experimental autoimmune encephalomyelitis (EAE). In naive mice, proteiexpression of PD-1, PD-L1, and PD-L2 was detected in the thymus, while PD-1 and PD-L1 were detected in the spleen. PD-L1, but not PD-L2, was also detected at low levels on cardiac endothelium, pancreatic islets, and syncyciotrophoblasts in the placenta. In pre-diabetic NOD mice, PD-1 and PD-L1 were expressed on infiltrating cells in the pancreatic islets. Furthermore, PD-L1 was markedly up-regulated on islet cells. In brains from mice with EAE, PD-1, PD-L1, and PD-L2 were expressed on infiltrating inflammatory cells, and PD-L1 was up-regulated on endothelium within EAE brain. The distinct expression patterns of PD-L1 and PD-L2 led us to compare their transcriptional regulation in STAT4(-/-), STAT6(-/-), or NF-kappaB p50(-/-)p65(+/-) dendritic cells (DC).PD-L2, but not PD-L1, expression was dramatically reduced in p50(-/-)p65(+/-) DC. Thus, PD-L1 and PD-L2 exhibit distinct expression patterns and are differentially regulated on the transcriptional level.