IL-27 attenuates IL-23 mediated inflammatory arthritis.

Interleukin 27 has both pro-inflammatory and anti-inflammatory properties in autoimmunity. The anti-inflammatory effects of IL-27 are linked with inhibition of Th17 differentiation but the IL-27 effect on myeloid cells is less studied. Herein we demonstrate that IL-27 inhibits IL-23-induced inflammation associated not only with Th17 cells but also with myeloid cell infiltration in the joints and splenic myeloid populations of CD11b+ GR1+ and CD3-CD11b+CD11c-GR1- cells. The IL-27 anti-inflammatory response was associated with reduced levels of myeloid cells in the spleen and bone marrow. Overall, our data demonstrate that IL-27 has an immunosuppressive role that affects IL-23-dependent myelopoiesis in the bone marrow and its progression to inflammatory arthritis and plays a crucial role in controlling IL-23 driven joint inflammation by negatively regulating the expansion of myeloid cell subsets.

Time Series Analysis of Congestive Heart Failure Discharges in Florida (USA) Post Tropical Cyclones.

OBJECTIVES: The aim of this study was to analyze congestive heart failure (CHF) discharges in Florida (USA) post tropical cyclones from 2007 through 2017. METHODS: This was a retrospective longitudinal time series analysis of hospital CHF quarterly discharges across Florida using the Healthcare Cost and Utilization Project (HCUP) database. The autoregressive integrated moving average (ARIMA) model was used with correlated seasonal regressor variables such as cyclone frequency, maximum cyclone wind speed, average temperature, and reports of influenza-like illness (ILI). RESULTS: A total of 3,372,993 patients were identified, with average age in each quarter ranging 72.2 to 73.9 years and overall mortality ranging 4.3% to 6.4%. The CHF discharges within each year peaked from October through December and nadired from April through June with an increasing overall time trend. Significant correlation was found between CHF discharge and the average temperature (P <.001), with approximately 331.8 less CHF discharges (SE = 91.7) per degree of increase in temperature. However, no significant correlation was found between CHF discharges and frequency of cyclones, the maximum wind speed, and reported ILI. CONCLUSIONS: This study suggests that with the current methods and the HCUP dataset, there is no significant increase in overall CHF discharges in Florida as a result of recent previous cyclone occurrences.

Virtual Reality Training in Disaster Medicine: A Systematic Review of the Literature.

SUMMARY STATEMENT: Disaster medicine (DM) training aims to recreate stressful, mass casualty scenarios faced by medical professionals in the field with high fidelity. Virtual (VR) and augmented reality (AR) are well suited to disaster training as it can provide a safe, socially distant simulation with a high degree of realism. The purpose of this literature review was to summarize the current use of VR or AR for simulation training of healthcare providers in DM education. A systematic review of peer-reviewed articles was performed from January 1, 2000, to November 21, 2020, on PubMed, Embase, and OVID. Exclusion criteria included non-English articles, computer-generated models without human participants, or articles not relating to DM, VR or AR. Thirty-two articles were included. Triage accuracy was evaluated in 17 studies. Participants reported improved confidence and positive satisfaction after the simulations. The studies suggest VR or AR can be considered for disaster training in addition to other, more traditional simulation methods. More research is needed to create a standardized educational model to incorporate VR and AR into DM training and to understand the relationship between disaster simulation and improved patient care.

Trend Analysis on Road Traffic Collision Occurrence in Nigeria.

OBJECTIVES: Road traffic collisions (RTC) result in a significant number of preventable deaths worldwide. In 2010, the United Nations General Assembly launched, "The Decade of Action for Road Safety (2011-2020)" with the stated goal to "reduce road traffic deaths and injuries by 50% by 2020." This study aims to analyze trends in RTC numbers and subsequent deaths with respect to road safety laws in Nigeria and to suggest suitable interventions. METHODS: Annual reports for the period 2007-2017 were obtained from the Federal Road Safety Corps of Nigeria. These reports were analyzed for trends in RTC, including reported causes, fatalities, injuries, and casualties. RESULTS: Overall total injuries, casualties, and fatalities increased by 74.7%, 61.2%, and 9.6%, respectively. Analysis showed that the 3 main causes of RTC were speed violation, loss of control, and dangerous driving. CONCLUSIONS: Although current trends do not suggest that Nigeria will accomplish its initial goal of decreasing fatalities by 50% by 2020, there has been a reduction in the number of crashes resulting from dangerous driving. Further interventions such as implementing automated speed monitoring, collaboration, and data sharing between federal and regional agencies, and improving the state of road networks should be implemented to decrease fatalities further.

Developing Telemedicine Curriculum Competencies for Graduate Medical Education: Outcomes of a Modified Delphi Process.

PURPOSE: Telemedical applications have only recently begun to coalesce into the field of telemedicine due to varying definitions of telemedicine and issues around reimbursement. This process has been accelerated by the COVID-19 pandemic and the ensuing expansion of telemedicine delivery. This article demonstrates the development of a set of proposed competencies for a telemedicine curriculum in graduate medical education. METHOD: A modified Delphi process was used to create a panel of competencies. This included a systematic review of the telemedicine literature through November 2019 to create an initial set of competencies, which were analyzed and edited by a focus group of experts in January 2020. Initial competencies were distributed in a series of 3 rounds of surveys to a group of 23 experts for comments and rating from April to August 2020. Competencies that obtained a score of 4.0 or greater on a 5-point Likert scale in at least 2 rounds were recommended. RESULTS: Fifty-five competencies were developed based on the systematic review. A further 32 were added by the expert group for a total of 87. After 3 rounds of surveys, 34 competencies reached the recommendation threshold. These were 10 systems-based practice competencies, 7 professionalism, 6 patient care, 4 practice-based learning and improvement, 4 interpersonal and communication skills, and 3 medical knowledge competencies. CONCLUSIONS: Half (17/34) of the competencies approved by the focus group and surveyed expert panel pertained to either systems-based practice or professionalism. Both categories exhibit more variation between telemedicine and in-person practice than other categories. The authors offer a set of proposed educational competencies that can be used in the development of curricula for a wide range of providers and are based on the best evidence and expert opinion available.

Crisis Standards of Care Implementation at the State Level in the United States.

INTRODUCTION: In 2009, the Institute of Medicine published guidelines for implementation of Crisis Standards of Care (CSC) at the state level in the United States (US). Based in part on the then concern for H1N1 pandemic, there was a recognized need for additional planning at the state level to maintain health system preparedness and conventional care standards when available resources become scarce. Despite the availability of this framework, in the years since and despite repeated large-scale domestic events, implementation remains mixed. PROBLEM: Coronavirus disease 2019 (COVID-19) rejuvenates concern for how health systems can maintain quality care when faced with unrelenting burden. This study seeks to outline which states in the US have developed CSC and which areas of care have thus far been addressed. METHODS: An online search was conducted for all 50 states in 2015 and again in 2020. For states without CSC plans online, state officials were contacted by email and phone. Public protocols were reviewed to assess for operational implementation capabilities, specifically highlighting guidance on ventilator use, burn management, sequential organ failure assessment (SOFA) score, pediatric standards, and reliance on influenza planning. RESULTS: Thirty-six states in the US were actively developing (17) or had already developed (19) official CSC guidance. Fourteen states had no publicly acknowledged effort. Eleven of the 17 public plans had updated within five years, with a majority addressing ventilator usage (16/17), influenza planning (14/17), and pediatric care (15/17), but substantially fewer addressing care for burn patients (9/17). CONCLUSION: Many states lacked publicly available guidance on maintaining standards of care during disasters, and many states with specific care guidelines had not sufficiently addressed the full spectrum of hazard to which their health care systems remain vulnerable.

Effect of Road Safety Laws on Deaths and Injuries from Road Traffic Collisions in Colombia.

INTRODUCTION: Colombia is the fourth largest country in South America. It is an upper middle-income country with an estimated population of 49.2 million people, and road traffic collisions (RTCs) are the second most common cause of traumatic death. The United Nations (UN) proclaimed 2011 to 2020 as the "Decade of Action for Road Safety." In this context, the government of Colombia established the National Road Safety Plan (PNSV) for the period 2011-2021, aiming to reduce RTC-related deaths by 26%. Some road safety laws (RSLs) were implemented before the PNSV, but their impact on deaths and injuries is still not known. STUDY OBJECTIVE: The aim of this study was to evaluate whether these RSLs have had a long-term effect on road safety in the country. METHODS: Data on RTC casualties, deaths, and injuries from January 1, 2001 through December 31, 2017 were collated from official Colombian governmental publications. Three different periods were considered for analysis: 2001-2010 to evaluate the Transit Code; 2011-2017 to evaluate the PNSV; and 2001-2017 to evaluate a composite of the full study period. Analyses of trends in deaths and injuries were related to dates of new RSLs. RESULTS: A total of 102,723 deaths (12.7%) and 707,778 injuries (87.3%) were reported from 2001 through 2017. The Transit Code period (2001-2010) showed a 10.1% decline in deaths, 16.6% decline in injuries, and rates per 100,000 inhabitants and per 10,000 registered vehicles also declined. During the period of the PNSV (2011-2017), there was an increase in the number of deaths by 16.6%, injuries decreased by 1.7%, and death rates per 100,000 inhabitants also increased. During the total study period, a 12.4% reduction in the total number of casualties was achieved, and death and injury rates per 100,000 inhabitants decreased by 12.4% and 27.5%, respectively. DISCUSSION: Despite the introduction of the PNSV, RTCs remain the second most common cause of preventable death in Colombia. Overall, while the absolute number of RTCs and deaths has been increasing, the rate of RTCs per 10,000 registered vehicles has been decreasing. This suggests that although the goals of the PNSV may not be realized, some of the laws emanating from it may be having a beneficial effect. Further study is required over a protracted period to determine the longer-term impact of these initiatives.

Creating a Novel Disaster Medicine Virtual Reality Training Environment.

INTRODUCTION: Disasters are high-acuity, low-frequency events which require medical providers to respond in often chaotic settings. Due to this infrequency, skills can atrophy, so providers must train and drill to maintain them. Historically, drilling for disaster response has been costly, and thus infrequent. Virtual Reality Environments (VREs) have been demonstrated to be acceptable to trainees, and useful for training Disaster Medicine skills. The improved cost of virtual reality training can allow for increased frequency of simulation and training. PROBLEM: The problem addressed was to create a novel Disaster Medicine VRE for training and drilling. METHODS: A VRE was created using SecondLife (Linden Lab; San Francisco, California USA) and adapted for use in Disaster Medicine training and drilling. It is easily accessible for the end-users (trainees), and is adaptable for multiple scenario types due to the presence of varying architecture and objects. Victim models were created which can be role played by educators, or can be virtual dummies, and can be adapted for wide ranging scenarios. Finally, a unique physiologic simulator was created which allows for dummies to mimic disease processes, wounds, and treatment outcomes. RESULTS: The VRE was created and has been used extensively in an academic setting to train medical students, as well as to train and drill disaster responders. CONCLUSIONS: This manuscript presents a new VRE for the training and drilling of Disaster Medicine scenarios in an immersive, interactive experience for trainees.

A dignitary medicine curriculum developed using a modified Delphi methodology.

BACKGROUND: Dignitary medicine is an emerging field of training that involves the specialized care of diplomats, heads of state, and other high-ranking officials. In an effort to provide guidance on training in this nascent field, we convened a panel of experts in dignitary medicine and using the Delphi methodology, created a consensus curriculum for training in dignitary medicine. METHODS: A three-round Delphi consensus process was performed with 42 experts in the field of dignitary medicine. Predetermined scores were required for an aspect of the curriculum to advance to the next round. The scores on the final round were used to determine the components of the curriculum. Scores below the threshold to advance were dropped in the subsequent round. RESULTS: Our panel had a high degree of agreement on the required skills needed to practice dignitary medicine, with active practice in a provider's baseline specialty, current board certification, and skills in emergency care and resuscitation being the highest rated skills dignitary medicine physicians need. Skills related to vascular and emergency ultrasound and quality improvement were rated the lowest in the Delphi analysis. No skills were dropped from consideration. CONCLUSIONS: The results of our work can form the basis of formal fellowship training, continuing medical education, and publications in the field of dignitary medicine. It is clear that active medical practice and knowledge of resuscitation and emergency care are critical skills in this field, making emergency medicine physicians well suited to practicing dignitary medicine.

Use of Dimensional Analysis in the X-, Y-, and Z-Axis to Predict Occurrence of Injury in Human Stampede.

BACKGROUND: Human stampedes (HS) may result in mass casualty incidents (MCI) that arise due to complex interactions between individuals, collective crowd, and space, which have yet to be described from a physics perspective. HS events were analyzed using basic physics principles to better understand the dynamic kinetic variables that give rise to HS. METHODS: A literature review was performed of medical and nonmedical sourced databases, Library of Congress databases, and online sources for the term human stampedes resulting in 25,123 references. Filters were applied to exclude nonhuman events. Retrieved references were reviewed for a predefined list of physics terms. Data collection involved recording frequency of each phrase and physics principle to give the final proportions of each predefined principle used a single-entry method for each of the 105 event reports analyzed. Data analysis was performed using the R statistics packages "tidyverse", "psych", "lubridate", and "Hmisc" with descriptive statistics used to describe the frequency of each observed variable. RESULTS: Of the 105 reports of HS resulting in injury or death reviewed, the following frequency of terms were found: density change in a limited capacity, 45%; XY-axis motion failure, 100%; loss of proxemics, 100%; deceleration with average velocity of zero, 90%; Z-axis displacement pathology (falls), 92%; associated structure with nozzle effect, 93%; and matched fluid dynamic of high pressure stagnation of mass gathering, 100%. CONCLUSIONS: Description or reference to principles of physics was seen in differing frequency in 105 reports. These include XY-axis motion failure of deceleration that leads to loss of human to human proxemics, and high stagnation pressure resulting in the Z-axis displacement effect (falls) causing injury and death. Real-time video-analysis monitoring of high capacity events or those with known nozzle effects for loss of proxemics and Z-axis displacement pathology offers the opportunity to prevent mortality from human stampedes.

Core Disaster Medicine Education (CDME) for Emergency Medicine Residents in the United States.

OBJECTIVES: Disaster Medicine (DM) education for Emergency Medicine (EM) residents is highly variable due to time constraints, competing priorities, and program expertise. The investigators' aim was to define and prioritize DM core competencies for EM residency programs through consensus opinion of experts and EM professional organization representatives. METHODS: Investigators utilized a modified Delphi methodology to generate a recommended, prioritized core curriculum of 40 DM educational topics for EM residencies. RESULTS: The DM topics recommended and outlined for inclusion in EM residency training included: patient triage in disasters, surge capacity, introduction to disaster nomenclature, blast injuries, hospital disaster mitigation, preparedness, planning and response, hospital response to chemical mass-casualty incident (MCI), decontamination indications and issues, trauma MCI, disaster exercises and training, biological agents, personal protective equipment, and hospital response to radiation MCI. CONCLUSIONS: This expert-consensus-driven, prioritized ranking of DM topics may serve as the core curriculum for US EM residency programs.

Disaster Medicine: A Comprehensive Review of the Literature From 2016.

OBJECTIVE: The Society of Academic Emergency Medicine Disaster Medicine Interest Group, the Office of the Assistant Secretary for Preparedness and Response - Technical Resources, Assistance Center, and Information Exchange (ASPR TRACIE) team, and the National Institutes of Health Library searched disaster medicine peer-reviewed and gray literature to identify, review, and disseminate the most important new research in this field for academics and practitioners. METHODS: MEDLINE/PubMed and Scopus databases were searched with key words. Additional gray literature and focused hand search were performed. A Level I review of titles and abstracts with inclusion criteria of disaster medicine, health care system, and disaster type concepts was performed. Eight reviewers performed Level II full-text review and formal scoring for overall quality, impact, clarity, and importance, with scoring ranging from 0 to 20. Reviewers summarized and critiqued articles scoring 16.5 and above. RESULTS: Articles totaling 1176 were identified, and 347 were screened in a Level II review. Of these, 193 (56%) were Original Research, 117 (34%) Case Report or other, and 37 (11%) were Review/Meta-Analysis. The average final score after a Level II review was 11.34. Eighteen articles scored 16.5 or higher. Of the 18 articles, 9 (50%) were Case Report or other, 7 (39%) were Original Research, and 2 (11%) were Review/Meta-Analysis. CONCLUSIONS: This first review highlighted the breadth of disaster medicine, including emerging infectious disease outbreaks, terror attacks, and natural disasters. We hope this review becomes an annual source of actionable, pertinent literature for the emerging field of disaster medicine.

The Gillette Stadium Experience: A Retrospective Review of Mass Gathering Events From 2010 to 2015.

OBJECTIVE: Mass gathering events can substantially impact public safety. Analyzing patient presentation and transport rates at various mass gathering events can help inform staffing models and improve preparedness. METHODS: A retrospective review of all patients seeking medical attention across a variety of event types at a single venue with a capacity of 68,756 from January 2010 through September 2015. RESULTS: We examined 232 events with a total of 8,260,349 attendees generating 8157 medical contacts. Rates were 10 presentations and 1.6 transports per 10,000 attendees with a non-significant trend towards increased rates in postseason National Football League games. Concerts had significantly higher rates of presentation and transport than all other event types. Presenting concern varied significantly by event type and gender, and transport rate increased predictably with age. For cold weather events, transport rates increased at colder temperatures. Overall, on-site physicians did not impact rates. CONCLUSIONS: At a single venue hosting a variety of events across a 6-year period, we demonstrated significant variations in presentation and transport rates. Weather, gender, event type, and age all play important roles. Our analysis, while representative only of our specific venue, may be useful in developing response plans and staffing models for similar mass gathering venues. (Disaster Med Public Health Preparedness. 2018;12:752-758).

Ca2+-Dependent Regulation of NFATc1 via KCa3.1 in Inflammatory Osteoclastogenesis.

In inflammatory arthritis, the dysregulation of osteoclast activity by proinflammatory cytokines, including TNF, interferes with bone remodeling during inflammation through Ca2+-dependent mechanisms causing pathological bone loss. Ca2+-dependent CREB/c-fos activation via Ca2+-calmodulin kinase IV (CaMKIV) induces transcriptional regulation of osteoclast-specific genes via NFATc1, which facilitate bone resorption. In leukocytes, Ca2+ regulation of NFAT-dependent gene expression oftentimes involves the activity of the Ca2+-activated K+ channel KCa3.1. In this study, we evaluate KCa3.1 as a modulator of Ca2+-induced NFAT-dependent osteoclast differentiation in inflammatory bone loss. Microarray analysis of receptor activator of NF-κB ligand (RANKL)-activated murine bone marrow macrophage (BMM) cultures revealed unique upregulation of KCa3.1 during osteoclastogenesis. The expression of KCa3.1 in vivo was confirmed by immunofluorescence staining on multinucleated cells at the bone surface of inflamed mouse joints. Experiments on in vitro BMM cultures revealed that KCa3.1-/- and TRAM-34 treatment significantly reduced the expression of osteoclast-specific genes (p < 0.05) alongside decreased osteoclast formation (p < 0.0001) in inflammatory (RANKL+TNF) and noninflammatory (RANKL) conditions. In particular, live cell Ca2+ imaging and Western blot analysis showed that TRAM-34 pretreatment decreased transient RANKL-induced Ca2+ amplitudes in BMMs by ∼50% (p < 0.0001) and prevented phosphorylation of CaMKIV. KCa3.1-/- reduced RANKL+/-TNF-stimulated phosphorylation of CREB and expression of c-fos in BMMs (p < 0.01), culminating in decreased NFATc1 protein expression and transcriptional activity (p < 0.01). These data indicate that KCa3.1 regulates Ca2+-dependent NFATc1 expression via CaMKIV/CREB during inflammatory osteoclastogenesis in the presence of TNF, corroborating its role as a target candidate for the treatment of bone erosion in inflammatory arthritis.

Disaster Education: A Survey Study to Analyze Disaster Medicine Training in Emergency Medicine Residency Programs in the United States.

BACKGROUND: The increase in natural and man-made disasters occurring worldwide places Emergency Medicine (EM) physicians at the forefront of responding to these crises. Despite the growing interest in Disaster Medicine, it is unclear if resident training has been able to include these educational goals. Hypothesis This study surveys EM residencies in the United States to assess the level of education in Disaster Medicine, to identify competencies least and most addressed, and to highlight effective educational models already in place. METHODS: The authors distributed an online survey of multiple-choice and free-response questions to EM residency Program Directors in the United States between February 7 and September 24, 2014. Questions assessed residency background and details on specific Disaster Medicine competencies addressed during training. RESULTS: Out of 183 programs, 75 (41%) responded to the survey and completed all required questions. Almost all programs reported having some level of Disaster Medicine training in their residency. The most common Disaster Medicine educational competencies taught were patient triage and decontamination. The least commonly taught competencies were volunteer management, working with response teams, and special needs populations. The most commonly identified methods to teach Disaster Medicine were drills and lectures/seminars. CONCLUSION: There are a variety of educational tools used to teach Disaster Medicine in EM residencies today, with a larger focus on the use of lectures and hospital drills. There is no indication of a uniform educational approach across all residencies. The results of this survey demonstrate an opportunity for the creation of a standardized model for resident education in Disaster Medicine. Sarin RR , Cattamanchi S , Alqahtani A , Aljohani M , Keim M , Ciottone GR . Disaster education: a survey study to analyze disaster medicine training in emergency medicine residency programs in the United States. Prehosp Disaster Med. 2017;32(4):368-373.

T Cell-Independent Mechanisms Associated with Neutrophil Extracellular Trap Formation and Selective Autophagy in IL-17A-Mediated Epidermal Hyperplasia.

IL-17A has been strongly associated with epidermal hyperplasia in many cutaneous disorders. However, because IL-17A is mainly produced by αß and γδT cells in response to IL-23, the role of T cells and IL-23 has overshadowed any IL-17A-independent actions. In this article, we report that IL-17A gene transfer induces epidermal hyperplasia in Il23r-/-Rag1-/-- and Tcrδ-deficient mice, which can be prevented by neutrophil depletion. Moreover, adoptive transfer of CD11b+Gr-1hi cells, after IL-17A gene transfer, was sufficient to phenocopy the disease. We further show that the IL-17A-induced pathology was prevented in transgenic mice with impaired neutrophil extracellular trap formation and/or neutrophils with conditional deletion of the master regulator of selective autophagy, Wdfy3. Our data demonstrate a novel T cell-independent mechanism that is associated with neutrophil extracellular trap formation and selective autophagy in IL-17A-mediated epidermal hyperplasia.

Autophagy-linked FYVE containing protein WDFY3 interacts with TRAF6 and modulates RANKL-induced osteoclastogenesis.

Recently, autophagy-related proteins were shown to regulate osteoclast mediated bone resorption, a critical process in autoimmune diseases such as rheumatoid arthritis. However, the role of autophagy-linked FYVE containing protein, WDFY3, in osteoclast biology remains elusive. WDFY3 is a master regulator in selective autophagy for clearing ubiquitinated protein aggregates and has been linked with rheumatoid arthritis. Herein, we used a series of WDFY3 transgenic mice (Wdfy3(lacZ) and Wdfy3(loxP)) to investigate the function of WDFY3 in osteoclast development and function. Our data demonstrate that WDFY3 is highly expressed at the growth plate of neonatal mice and is expressed in osteoclasts in vitro cultures. Osteoclasts derived from WDFY3 conditional knockout mice (Wdfy3(loxP/loxP)-LysM-Cre(+)) demonstrated increased osteoclast differentiation as evidenced by higher number and enlarged size of TRAP(+) multinucleated cells. Western blot analysis also revealed up-regulation of TRAF6 and an increase in RANKL-induced NF-κB signaling in WDFY3-deficient bone marrow-derived macrophages compared to wild type cultures. Consistent with these observations WDFY3-deficient cells also demonstrated an increase in osteoclast-related genes Ctsk, Acp5, Mmp9 and an increase of dentine resorption in in vitro assays. Importantly, in vivo RANKL gene transfer exacerbated bone loss in WDFY3 conditional knockout mice, as evidenced by elevated serum TRAP, CTX-I and micro-CT analysis of distal femurs compared to wild type littermates. Taken together, our data highlight a novel role for WDFY3 in osteoclast development and function, which can be exploited for the treatment of musculoskeletal diseases.

T cell-extrinsic CD18 attenuates antigen-dependent CD4+ T cell activation in vivo.

The ß2 integrins (CD11/CD18) are heterodimeric leukocyte adhesion molecules expressed on hematopoietic cells. The role of T cell-intrinsic CD18 in trafficking of naive T cells to secondary lymphoid organs and in Ag-dependent T cell activation in vitro and in vivo has been well defined. However, the T cell-extrinsic role for CD18, including on APC, in contributing to T cell activation in vivo is less well understood. We examined the role for T cell-extrinsic CD18 in the activation of wild-type CD4(+) T cells in vivo through the adoptive transfer of DO11.10 Ag-specific CD4(+) T cells into CD18(-/-) mice. We found that T cell-extrinsic CD18 was required for attenuating OVA-induced T cell proliferation in peripheral lymph nodes (PLN). The increased proliferation of wild-type DO11.10 CD4(+) T cells in CD18(-/-) PLN was associated with a higher percentage of APC, and these APC demonstrated an increased activation profile and increased Ag uptake, in particular in F4/80(+) APC. Depletion of F4/80(+) cells both reduced and equalized Ag-dependent T cell proliferation in CD18(-/-) relative to littermate control PLN, demonstrating that these cells play a critical role in the enhanced T cell proliferation in CD18(-/-) mice. Consistently, CD11b blockade, which is expressed on F4/80(+) macrophages, enhanced the proliferation of DO11.10 CD4(+) T cells in CD18(+/-) PLN. Thus, in contrast to the T cell-intrinsic essential role for CD18 in T cell activation, T cell-extrinsic expression of CD18 attenuates Ag-dependent CD4(+) T cell activation in PLN in vivo.

Crosstalk among IL-23 and DNAX activating protein of 12 kDa-dependent pathways promotes osteoclastogenesis.

IL-23 has been well studied in the context of T cell differentiation; however, its role in the differentiation of myeloid progenitors is less clear. In this paper, we describe a novel role of IL-23 in myeloid cell differentiation. Specifically, we have identified that in human PBMCs, IL-23 induces the expression of MDL-1, a PU.1 transcriptional target during myeloid differentiation, which orchestrates osteoclast differentiation through activation of DNAX activating protein of 12 kDa and its ITAMs. The molecular events that lead to the differentiation of human macrophages to terminally differentiated osteoclasts are dependent on spleen tyrosine kinase and phospholipase Cγ2 phosphorylation for the induction of intracellular calcium flux and the subsequent activation of master regulator osteoclast transcription factor NFATc1. IL-23-elicited osteoclastogenesis is independent of the receptor activator of NF-κB ligand pathway and uses a unique myeloid DNAX activating protein of 12 kDa-associated lectin-1(+)/DNAX activating protein of 12 kDa(+) cell subset. Our data define a novel pathway that is used by IL-23 in myeloid cells and identify a major mechanism for the stimulation of osteoclastogenesis in inflammatory arthritis.