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Objective: Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren's syndrome (pSS)., Methods: In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration., Results: Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8 + CD103 + CD69 + cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8 + CD103 + Trm contributed to the secretion of granzyme-B and interferon-γ, CD8 + Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of CD69, ITGAE, GZMB, GZMK and HLA-DRB1 among CD3 + CD8 + SG T cells. In the SG of ESS, CD8 + CD69 + CD103 + Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow., Conclusions: CD103 + CD8 + Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted., Competing Interests: Competing interests: RT has filed provisional patents surrounding technology for targeting DCs for antigen-specific tolerance (US patent 9017697 B2: 2006, PCT/AU2013/000303) and is developing immunotherapy to target DCs to suppress autoimmune disease in collaboration with CSL. AB-M and AB are employees of CSL. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

BACKGROUNDAntigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under "sub-immunogenic" conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-κB inhibitor 1,25-dihydroxycholecalciferol.METHODSA double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71-specific (Cit-Vim-specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate.RESULTSDEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim-specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181-treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim-specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181.CONCLUSIONThe safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA.TRIAL REGISTRATIONAnzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.FUNDINGInnovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported by European Union's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations; Arthritis Queensland; National Health and Medical Research Council (NHMRC) Senior Research Fellowship; and NHMRC grant 2008287.

Antigen-specific T cells can serve as a response biomarker in non-clinical or clinical immunotherapy studies in autoimmune disease. There are protocols with optimized multimer staining methods to detect peptide (p)MHCII+ CD4+ T cells, and some qualified and validated protocols for pMHCI+ CD8+ T cells. However, no protocol is fully or partially qualified to enumerate and characterize antigen-specific pMHCII+ CD4+ T cells from patient samples. Implementing such an assay requires a desired level of specificity and precision, in terms of assay repeatability and reproducibility. In transgenic type II collagen (CII)-immunized HLA-DR1/DR4 humanized mouse models of collagen-induced arthritis (CIA), CII259-273-specific T cells dominantly expand. Therefore antigen-specific T cells recognizing this epitope presented by rheumatoid arthritis (RA)-associated risk HLA-DR allomorphs are of interest to understand disease progression and responses to immunotherapy in RA patients. Using HLA-DRB1∗04:01 or ∗01:01-collagen type II (CII)259-273 tetramers, we evaluated parameters influencing precision and reproducibility of an optimized flow cytometry-based method for antigen-specific CD4+ T cells and eight specific subpopulations with and without tetramer positivity. We evaluated specificity, precision, and reproducibility for research environments and non-regulated laboratories. The assay has excellent overall precision with %CV<25% for intra-assay repeatability, inter-analyst precision, and inter-assay reproducibility. The precision of the assay correlated negatively with the cell viability after thawing, indicating that post-thaw viability is a critical parameter for reproducibility. This assay is suitable for longitudinal analysis of treatment response and disease activity outcome in RA patients, and adaptable for translational or immunotherapy clinical trial settings., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Increasingly earlier identification of individuals at high risk of rheumatoid arthritis (RA) (eg, with autoantibodies and mild symptoms) improves the feasibility of preventing or curing disease. The use of antigen-specific immunotherapies to reinstate immunological self-tolerance represent a highly attractive strategy due to their potential to induce disease resolution, in contrast to existing approaches that require long-term treatment of underlying symptoms.Preclinical animal models have been used to understand disease mechanisms and to evaluate novel immunotherapeutic approaches. However, models are required to understand critical processes supporting disease development such as the breach of self-tolerance that triggers autoimmunity and the progression from asymptomatic autoimmunity to joint pain and bone loss. These models would also be useful in evaluating the response to treatment in the pre-RA period.This review proposes that focusing on immune processes contributing to initial disease induction rather than end-stage pathological consequences is essential to allow development and evaluation of novel immunotherapies for early intervention. We will describe and critique existing models in arthritis and the broader field of autoimmunity that may fulfil these criteria. We will also identify key gaps in our ability to study these processes in animal models, to highlight where further research should be targeted., Competing Interests: Competing interests: GM, RT, CMUH, DCW, DS, MB, PG and JMB all received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777357. DCW is the founder and serves as a consultant to Apitope International NV. RT reports additional grants from Arthritis Queensland, and an NHMRC senior research fellowship during the conduct of the study; grants from NHMRC grants 1083192 and 1071822, past funding from Janssen Biotech Inc to Uniquest outside the submitted work; In addition, RT has patent 9,017,697 B2: 2006 issued, a grant from JDRF Australia and US The Leona M. and Harry B. Helmsley Charitable Trust for antigen-specific immunotherapy in type 1 diabetes, and investment from CSL to UniQuest to develop and commercialise antigen-specific immunotherapy in Sjogren's syndrome. DS and MB report grants from Medical University of Vienna during the conduct of the study. HDL and DFT are both employees and shareholders of GSK (Pharma partner in RTCure Consortium)., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Dendritic cells (DCs) are the key professional antigen-presenting cells which bridge innate and adaptive immune responses, inducing the priming and differentiation of naive to effector CD4 + T cells, the cross-priming of CD8 + T cells and the promotion of B cell antibody responses. DCs also play a critical role in the maintenance of immune homeostasis and tolerance. DC-T cell interactions underpin the generation of an autoimmune response in rheumatoid arthritis (RA). Here we describe the function of DCs and review evidence for DC and T cell involvement in RA pathogenesis, in particular through the presentation of self-peptide by DCs that triggers differentiation and activation of autoreactive T cells. Finally, we discuss the emerging field of targeting the DC-T cell interaction for antigen-specific immunotherapy of RA., (© 2018 British Society for Immunology.)

Background: Sports-related concussions (SRCs) have gained increased societal interest in the past decade. The National Collegiate Athletic Association (NCAA) has implemented legislation and rule changes to decrease the incidence and risk of head injury impacts. The "targeting" rule forbids initiating contact with the crown of a helmet and targeting defenseless players in the head and neck area; however, there are concerns that this rule change has unintentionally led to an increased incidence of lower extremity injuries., Purpose/hypothesis: The purpose of this study was to evaluate the change in lower extremity injury rates in NCAA football during the 2009-2010 to 2014-2015 seasons. We hypothesized that the lower extremity injury rate has increased across the time period., Study Design: Descriptive epidemiology study., Methods: Sixty-eight NCAA football programs provided 153 team-seasons of data to the NCAA Injury Surveillance Program. Lower extremity injuries (ie, hip/groin, upper leg/thigh, knee, lower leg/Achilles, foot/toes) and SRCs sustained during NCAA football games were examined. We calculated injury rates per 1000 athlete-exposures (AEs) for lower extremity injuries and SRCs. Rate ratios (RRs) compared injury rates between the 2009-2010 to 2011-2012 and 2012-2013 to 2014-2015 seasons., Results: Overall, 2400 lower extremity injuries were reported during the 2009-2010 to 2014-2015 seasons; most were to the knee (33.6%) and ankle (28.5%) and caused by player contact (59.2%). The lower extremity injury rate increased in 2012-2013 to 2014-2015 compared with 2009-2010 to 2011-2012 (23.55 vs 20.45/1000 AEs, respectively; RR, 1.15; 95% CI, 1.06-1.25). This finding was retained when restricted to injuries due to player contact (RR, 1.19; 95% CI, 1.07-1.32) but not for injuries due to noncontact/overuse (RR, 0.96; 95% CI, 0.80-1.14). When examining player contact injury rates by anatomic site, only ankle injuries had an increase (RR, 1.36; 95% CI, 1.13-1.64). The SRC rate also increased in 2012-2013 to 2014-2015 compared with 2009-2010 to 2011-2012 (3.52 vs 2.63/1000 AEs, respectively; RR, 1.34; 95% CI, 1.08-1.66)., Conclusion: The lower extremity injury rate has increased in NCAA football athletes. Similarly, SRC rates have increased, although this may be caused by concurrent policies related to better education, identification, and management. Targeting rule changes may be contributing to increased rates of player contact-related ankle injuries. Alongside continued surveillance research to examine longitudinal time trends, more in-depth individual-level examinations of how targeting rule changes influence coaching and player behaviors are warranted., (© 2016 The Author(s).)

Objectives: Introducing medical students to wilderness medicine provides skills in leadership, teamwork, improvisation, and managing medical emergencies; however, wilderness medicine (WM) education is typically reserved for senior medical students and often requires expensive travel. Here, we describe the Winter Wilderness Medicine Race (WWMR). The race was held at a large allopathic medical school and targeted towards preclinical medical students. Race planning was performed by senior medical students with the supervision of doctors from the Department of Emergency Medicine. We hypothesized that this intervention in medical education would enhance students' WM knowledge, and build teamwork and improvisational skills., Methods: The research involved a one day WM race that required teams of first- and second-year medical students to navigate a 5-km course and complete medical scenarios. Races that were held annually between 2011 and 2014 are included in the study. The educational effectiveness of the race was evaluated by pre- and post-race knowledge assessments of the medical students participating in a WWMR. Qualitative data regarding student perceptions of the skills learned were obtained by focus group interviews. Wilderness medicine provides skills in leadership, teamwork, improvisation and managing medical emergencies, Results: Between 2011 and 2014, 122 preclinical medical students from a Midwestern US allopathic medical school participated in the study. Overall, the mean scores for pre- and post-race knowledge assessments were 48 and 85 per cent, respectively, a 37 per cent increase in scores (p < 0.0001). Participants cited improvisational and communication skills as the most important educational feature of the race., Conclusions: The Winter Wilderness Medicine Race (WWMR) enhanced preclinical medical students' wilderness medicine knowledge, teamwork skills and improvisational abilities., (© 2015 John Wiley & Sons Ltd.)

Psychopharmacologists are interested in delay and probability discounting because the tendency to discount the value of future and uncertain rewards has been linked with drug dependency. However, relatively little is known about the long-term stability of discounting measures typically studied in clinical psychopharmacology. To evaluate the stability of discounting over a 3-month period, the authors compared points of subjective equality (indifference points) with those collected from the same subjects 3 months earlier. Seven delay periods, ranging from 1 week to 25 years, and 7 probability values, ranging from .95 to .05, were assessed in an undergraduate sample (n=22, delay discounting; n=18, probability discounting). The authors examined both differential stability (stability of individual differences) and absolute stability (stability of the group mean) of delay and probability discounting measures as well as their respective indifference points. The results demonstrate that standard delay and probability discounting parameters (e.g., hyperbolic k and area under the curve) had both differential stability and absolute stability across 3 months. Moreover, most indifference points in the delay and probability discounting tasks demonstrated both differential and absolute stability. All together, these results suggest that delay and probability parameters are stable enough to predict future behavior, such as substance abuse. Additional findings indicated that a hyperbolic function fitted the data better than an exponential function and that delay and probability discounting parameters were not significantly correlated.

Averageness is purportedly the result of stabilizing selection maintaining the population mean, whereas facial paedomorphosis is a product of directional selection driving the population mean towards an increasingly juvenile appearance. If selection is predominantly stabilizing, intermediate phenotypes reflect high genetic quality and mathematically average faces should be found attractive. If, on the other hand, directional selection is strong enough, extreme phenotypes reflect high genetic quality and juvenilized faces will be found attractive. To compare the effects of stabilizing and directional selection on facial paedomorphosis (juvenilization), graphic morphing and editing techniques were used to alter the appearance of composite faces to make them appear more or less juvenile. Both facial models and judges of attractiveness were from the CSU-Long Beach campus. Although effect sizes for both preferences were large, the effect for averageness was nearly twice that found for juvenilization, an indication that stabilizing selection influences preferences for facial paedomorphosis more so than directional selection in contemporary humans.