Early reports suggest that chimeric antigen receptor (CAR)-T therapy has remarkable potential for treating autoimmune disease. Current approaches rely on autologous CAR-T cells, creating a bottleneck to the broad deployment of this therapy. In this issue of Cell, Wang et al.1 report the first use of allogeneic CAR-T cells in three patients with systemic autoimmune disease.

AbstractCD4+ T cells recognising citrullinated self-epitopes presented by HLA-DRB1 bearing the shared susceptibility epitope (SE) are implicated in rheumatoid arthritis (RA). However, the underlying T cell receptor (TCR) determinants of epitope specificity towards distinct citrullinated peptide antigens, including vimentin-64cit59-71 and α-enolase-15cit10-22 remain unclear. Using HLA-DR4-tetramers, we examine the T cell repertoire in HLA-DR4 transgenic mice and observe biased TRAV6 TCR gene usage across these two citrullinated epitopes which matches with TCR bias previously observed towards the fibrinogen β−74cit69-81 epitope. Moreover, shared TRAV26-1 gene usage is evident in four α-enolase-15cit10-22 reactive T cells in three human samples. Crystal structures of mouse TRAV6+ and human TRAV26-1+ TCR-HLA-DR4 complexes presenting vimentin-64cit59-71 and α-enolase-15cit10-22, respectively, show three-way interactions between the TCR, SE, citrulline, and the basis for the biased selection of TRAV genes. Position 2 of the citrullinated epitope is a key determinant underpinning TCR specificity. Accordingly, we provide a molecular basis of TCR specificity towards citrullinated epitopes.

Dr Schumacher was a force in rheumatology for more than half a century through his multiple roles as a researcher, clinician, mentor, and educator. He is not likely to be soon forgotten by the rheumatology community; however, it is hoped that this chapter can provide a faithful recollection that will help bring his memory to life for some and that rings true to those who knew him and learned from him.

Psoriasis is a chronic skin disease characterized by hyperproliferative epidermal lesions infiltrated by autoreactive T cells. Individuals expressing the human leukocyte antigen (HLA) C*06:02 allele are at highest risk for developing psoriasis. An autoreactive T cell clone (termed V alpha 3S1/V beta 13S1) isolated from psoriatic plaques is selective for HLA-C*06:02, presenting a peptide derived from the melanocyte-specific autoantigen ADAMTSL5 (VRSRRCLRL). Here we determine the crystal structure of this psoriatic TCR-HLA-C*06:02 ADAMTSL5 complex with a stabilized peptide. Docking of the TCR involves an extensive complementary charge network formed between negatively charged TCR residues interleaving with exposed arginine residues from the self-peptide and the HLA-C*06:02 alpha 1 helix. We probed these interactions through mutagenesis and activation assays. The charged interface spans the polymorphic region of the C1/C2 HLA group. Notably the peptide-binding groove of HLA-C*06:02 appears exquisitely suited for presenting highly charged Arg-rich epitopes recognized by this acidic psoriatic TCR. Overall, we provide a structural basis for understanding the engagement of melanocyte antigen-presenting cells by a TCR implicated in psoriasis while simultaneously expanding our knowledge of how TCRs engage HLA-C.

Aim: Patients admitted to hospital for abdominal surgery often experience gastrointestinal dysfunction. Many studies have reported outcomes following gastrointestinal dysfunction, yet there is no unified definition of recovery or a validated patient-reported outcome measure (PROM). The first stage of PROM development requires formation of a conceptual framework to identify key themes to patients. The aim of this study was to utilize semistructured interviews to identify core themes and concepts relevant to patients to facilitate development of a conceptual framework.Method: Adult patients admitted to hospital for major gastrointestinal, urological or gynaecological surgery, in an emergency or elective setting, were eligible to participate. Patients treated nonoperatively for small bowel obstruction were also eligible. Interviews were conducted by telephone, audio-recorded, transcribed, coded and analysed using NVivo software by two researchers and reviewed by lay members of the steering group. Interviews continued until data saturation was reached. Ethical approval was gained prior to interviews (21/WA/0231).Results: Twenty nine interviews were completed (17 men, median age 64 years) across three specialties (20 gastrointestinal, six gynaecological, three urological). Two overarching themes of 'general recovery' and 'gastrointestinal symptoms' were identified. General recovery included three themes: 'life impact', 'mental impact', including anxiety, and 'physical impact', including fatigue. Gastrointestinal symptoms included three themes: 'abdominal symptoms' such as pain, 'diet and appetite' and 'expulsory function', such as stool frequency. A total of 18 gastrointestinal symptoms were identified during patient recovery-many of which lasted several weeks following discharge.Conclusion: This study reports a range of gastrointestinal and nongastrointestinal symptoms experienced by patients during early gastrointestinal recovery. Identified symptoms have been synthesized into a conceptual framework to enable development of a definitive PROM for early gastrointestinal recovery.

Objective CD4+ T cells are implicated in rheumatoid arthritis (RA) pathology from the strong association between RA and certain HLA class II gene variants. This study was undertaken to examine the synovial T cell receptor (TCR) repertoire, T cell phenotypes, and T cell specificities in small joints of RA patients at time of diagnosis before therapeutic intervention. Methods Sixteen patients, of whom 11 patients were anti–citrullinated protein antibody (ACPA)–positive and 5 patients were ACPA–, underwent ultrasound‐guided synovial biopsy of a small joint (n = 13) or arthroscopic synovial biopsy of a large joint (n = 3), followed by direct sorting of single T cells for paired sequencing of the αβ TCR together with flow cytometry analysis. TCRs from expanded CD4+ T cell clones of 4 patients carrying an HLA–DRB1*04:01 allele were artificially reexpressed to study antigen specificity. Results T cell analysis demonstrated CD4+ dominance and the presence of peripheral helper T–like cells in both patient groups. We identified >4,000 unique TCR sequences, as well as 225 clonal expansions. Additionally, T cells with double α‐chains were a recurring feature. We identified a biased gene usage of the V β chain segment TRBV20‐1 in CD4+ cells from ACPA+ patients. In vitro stimulation of T cell lines expressing selected TCRs with an extensive panel of citrullinated and viral peptides identified several different virus‐specific TCRs (e.g., human cytomegalovirus and human herpesvirus 2). Still, the majority of clones remained orphans with unknown specificity. Conclusion Minimally invasive biopsies of the RA synovium allow for single‐cell TCR sequencing and phenotyping. Clonally expanded, viral‐reactive T cells account for part of the diverse CD4+ T cell repertoire. TRBV20‐1 bias in ACPA+ patients suggests recognition of common antigens. image

Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen receptor (CAR) T therapy throughout oncology. However, evidence from clinical and preclinical studies underscores the potential of CAR T therapy beyond oncology in treating autoimmunity, chronic infections, cardiac fibrosis, senescence-associated disease and other conditions. Concurrently, the deployment of new technologies and platforms provides further opportunity for the application of CAR T therapy to noncancerous pathologies. Here we review the rationale behind CAR T therapy, current challenges faced in oncology, a synopsis of preliminary reports in noncancerous diseases, and a discussion of relevant emerging technologies. We examine potential applications for this therapy in a wide range of contexts. Last, we highlight concerns regarding specificity and safety and outline the path forward for CAR T therapy beyond cancer.

CAR T therapy has revolutionized the treatment of hematologic cancers. In their recent Nature Medicine paper, Mackensen et al. report the use of CART cells to treat systemic lupus erythematosus in five patients. This provides enthusiasm to further explore CAR T therapy beyond oncology.

Antibodies targeting the activation marker CD83 can achieve immune suppression by targeting antigen-presenting mature dendritic cells (DC). This study investigated the immunosuppressive mechanisms of anti-CD83 antibody treatment in mice and tested its efficacy in a model of autoimmune rheumatoid arthritis. A rat anti-mouse CD83 IgG2a monoclonal antibody, DCR-5, was developed and functionally tested in mixed leukocyte reactions, demonstrating depletion of CD83+ conventional (c)DC, induction of regulatory DC (DCreg), and suppression of allogeneic T cell proliferation. DCR-5 injection into mice caused partial splenic cDC depletion for 2–4 days (mostly CD8+ and CD83+ cDC affected) with a concomitant increase in DCreg and regulatory T cells (Treg). Mice with collagen induced arthritis (CIA) treated with 2 or 6 mg/kg DCR-5 at baseline and every three days thereafter until euthanasia at day 36 exhibited significantly reduced arthritic paw scores and joint pathology compared to isotype control or untreated mice. While both doses reduced anti-collagen antibodies, only 6 mg/kg achieved significance. Treatment with 10 mg/kg DCR-5 was ineffective. Immunohistological staining of spleens at the end of CIA model with CD11c, CD83, and FoxP3 showed greater DC depletion and Treg induction in 6 mg/kg compared to 10 mg/kg DCR-5 treated mice. In conclusion, DCR-5 conferred protection from arthritis by targeting CD83, resulting in selective depletion of mature cDC and subsequent increases in DCreg and Treg. This highlights the potential for anti-CD83 antibodies as a targeted therapy for autoimmune diseases.

Riboflavin is an essential cofactor in many enzymatic processes and in the production of flavin adenine dinucleotide (FAD). Here, we report that the partial depletion of riboflavin through knockdown of the C. elegans riboflavin transporter 1 (rft-1) promotes metabolic health by reducing intracellular flavin concentrations. Knockdown of rft-1 significantly increases lifespan in a manner dependent upon AMP-activated protein kinase (AMPK)/aak-2, the mitochondrial unfolded protein response, and FOXO/daf-16. Riboflavin depletion promotes altered energetic and redox states and increases adiposity, independent of lifespan genetic dependencies. Riboflavin-depleted animals also exhibit the activation of caloric restriction reporters without any reduction in caloric intake. Our findings indicate that riboflavin depletion activates an integrated hormetic response that promotes lifespan and healthspan in C. elegans.

Obesity is a widespread public health problem with profound medical consequences and its burden is increasing worldwide. Obesity causes significant morbidity and mortality and is associated with conditions including cardiovascular disease and diabetes mellitus. Conventional treatment options are insufficient, or in the case of bariatric surgery, quite invasive. The etiology of obesity is complex, but at its core is often a caloric imbalance with an inability to burn off enough calories to exceed caloric intake, resulting in storage. Interventions such as dieting often lead to decreased resting energy expenditure (REE), with a rebound in weight (“yo-yo effect” or weight cycling). Strategies that increase REE are attractive treatment options. Brown fat tissue engages in nonshivering thermogenesis whereby mitochondrial respiration is uncoupled from ATP production, increasing REE. Medications that replicate brown fat metabolism by mitochondrial uncoupling (e.g., 2,4-dinitrophenol) effectively promote weight loss but are limited by toxicity to a narrow therapeutic range. This review explores the possibility of a new therapeutic approach to engineer autologous T cells into acquiring a thermogenic phenotype like brown fat. Engineered autologous T cells have been used successfully for years in the treatment of cancers (chimeric antigen receptor T cells), and the principle of engineering T cells ex vivo and transferring them back to the patient is established. Engineering T cells to acquire a brown fat-like metabolism could increase REE without the risks of pharmacological mitochondrial uncoupling. These thermogenic T cells may increase basal metabolic rate and are therefore a potentially novel therapeutic strategy for obesity.

Œ:Ultrasound is increasingly used by physicians at the bedside to diagnose and treat a variety of conditions and is particularly useful in the resource-limited setting. The purpose of this study was to determine whether point-of-care ultrasound (POCUS) performed by physicians changed the diagnosis or treatment of patients in mobile clinics in rural Uganda. Patients presenting to mobile clinics in Uganda were assessed by physicians and, when appropriate, POCUS was performed. When available, a radiologist reviewed ultrasound images in real time. A de-identified questionnaire was completed for each ultrasound and reviewed retrospectively. A total of 177 ultrasounds were performed. A radiologist reviewed 50% of the ultrasounds. In 73% of patients, the findings either confirmed (50%) or changed (23%) a diagnosis. In 53% of patients, the ultrasound findings changed the treatment plan. POCUS positively impacted patient care in rural Ugandan clinics by improving diagnostic capabilities and influencing treatment plans.

Individuals expressing HLA-DR4 bearing the shared susceptibility epitope (SE) have an increased risk of developing rheumatoid arthritis (RA). Posttranslational modification of self-proteins via citrullination leads to the formation of neoantigens that can be presented by HLA-DR4 SE allomorphs. However, in T cell-mediated autoimmunity, the interplay between the HLA molecule, posttranslationally modified epitope(s), and the responding T cell repertoire remains unclear. In HLA-DR4 transgenic mice, we show that immunization with a Fibβ-74cit69-81 peptide led to a population of HLA-DR4Fibβ-74cit69-81 tetramer+ T cells that exhibited biased T cell receptor (TCR) β chain usage, which was attributable to selective clonal expansion from the preimmune repertoire. Crystal structures of pre- and postimmune TCRs showed that the SE of HLA-DR4 represented a main TCR contact zone. Immunization with a double citrullinated epitope (Fibβ-72,74cit69-81) altered the responding HLA-DR4 tetramer+ T cell repertoire, which was due to the P2-citrulline residue interacting with the TCR itself. We show that the SE of HLA-DR4 has dual functionality, namely, presentation and a direct TCR recognition determinant. Analogous biased TCR β chain usage toward the Fibβ-74cit69-81 peptide was observed in healthy HLA-DR4+ individuals and patients with HLA-DR4+ RA, thereby suggesting a link to human RA.

Background:Many surgical techniques are used to treat symptomatic neuroma, but options are limited for digital neuromas because of a paucity of soft-tissue coverage and/or the absence of the terminal nerve end. The authors assessed factors that influence patient-reported outcomes after surgery for symptomatic digital neuroma.Methods:The authors retrospectively identified 29 patients with 33 symptomatic digital neuromas that were treated surgically. Patients completed the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity and Pain Interference scales, a numeric rating scale for pain, and the PROMIS Depression scale at a median follow-up of 7.6 years postoperatively (range, 3.2 to 16.8 years). Surgical treatment for neuroma included excision with nerve repair/reconstruction (n=13; 39 percent), neuroma excision alone (n=10; 30 percent), and excision and implantation (n=10; 30 percent). Multivariable linear regression was performed to identify the factors that independently influenced patient-reported outcomes.Results:The mean postoperative PROMIS Upper Extremity score was 45.2 ± 11.2, the mean Pain Interference score was 54.3 ± 10.7, and the mean numeric rating scale pain score was 3 (interquartile range, 1 to 5). Compared with other treatment techniques, neuroma excision with nerve repair/reconstruction was associated with lower numeric rating scale pain scores; lower Pain Interference scores, corresponding to less daily impact of pain; and higher Upper Extremity scores, reflecting better upper extremity function. Older age and higher Depression scores were associated with lower Upper Extremity scores and higher Pain Interference scores. Smoking was associated with higher Pain Interference and numeric rating scale pain scores.Conclusions:Neuroma excision followed by nerve repair/reconstruction resulted in better outcomes compared with neuroma excision alone with or without implantation. Patient age and psychosocial factors influenced patient-reported outcomes.CLINICAL QUESTION/LEVEL OF EVIDENCE:Risk, III.

OBJECTIVE:In rheumatoid arthritis, whether women are less likely to achieve low disease activity is unclear. We evaluated sex differences in remission and low disease activity, comparing different clinical and imaging measures. METHODS:We used data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry and from 2 clinical trials. Remission and low disease activity were defined using composite scores, individual items (tender joints, swollen joints, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP] level, and evaluator/patient global assessment), and magnetic resonance imaging (MRI). In the VARA registry, we assessed the likelihood of point remission at any time during follow-up using logistic regression, and time to sustained remission (2 consecutive visits) using Cox proportional hazards models. In the clinical trials, logistic regression models evaluated the likelihood of low clinical and MRI activity at 52 weeks. RESULTS:Among 2,463 patients in VARA, women (10.2%) were less likely to be in Disease Activity Score in 28 joints (DAS28)-ESR remission in follow-up (odds ratio [OR] 0.71 [95% confidence interval (95% CI) 0.55-0.91]; P < 0.01) and had a longer time to sustained DAS28-ESR remission. This difference was not observed for DAS28-CRP, Clinical Disease Activity Index, or Routine Assessment of Patient Index Data 3. Women were more likely to achieve favorable individual components except for an ESR <30 mm/hour (OR 0.72 [95% CI 0.57-0.90]; P < 0.01). Among 353 trial participants (83.7% women), women had reduced rates of DAS28-ESR remission (OR 0.39 [95% CI 0.21-0.72]; P = 0.003) but similar rates of low MRI synovitis and osteitis. CONCLUSION:The comparison of remission rates between men and women varies based on the disease activity measure, with sex-specific differences in ESR resulting in reliably lower rates of remission among women. There were no differences in MRI measures.

The benefits of sonography utilization in low-resource communities has been thoroughly demonstrated in the literature.1-3 As ultrasound units have become smaller and more portable, the feasibility of bringing these imaging devices into more remote areas is becoming a reality. One factor that limits ultrasound use in austere environments is battery life. Although solar power has been used for oxygen delivery5,6 in resource-limited settings, its use in sonography has not been previously described. This report describes the use of a Lumify (Philips; Amsterdam, Netherlands) for a month-long trip into a remote Himalayan region of India powered exclusively with an Anker (Shenzhen, China) solar panel for the entirety of the trip. According to the Palmetto Health Institutional Review Board, this does not qualify as "research" as defined by the US Department of Health and Human Services and therefore does not meet the requirements for institutional review board review.

Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA323-339 and calcitriol targeted dLN PD-L1hi DCs of immunized mice and reduced their MHC class II expression. OVA323-339/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3+ and IL-10+ peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture's vasculitis models with suppression of antigen-specific memory T cell differentiation and function. Accordingly, peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.

Objectives. In PsA management, remission and low disease activity represent preferential treatment targets. We aimed at evaluating the predictive value and clinical use of initial therapeutic response for subsequent achievement of these targets. Methods. Based on data of 216 patients enrolled in a randomized controlled trial of golimumab (GO-REVEAL), we performed diagnostic testing analyses using 3-and 6-month disease activity as tests for treatment outcomes to understand the implications of early response. In regression analyses, we estimated the probabilities for achieving at least LDA. Disease activity was measured by the disease activity index for PsA (DAPSA). Results. Three-month DAPSA levels were excellent tests for disease activity at 6 months (and at 1 year), with areas under the receiver operating characteristic curves of 0.92 (and 0.88, respectively). The estimated probability for 6-month LDA could be quantified as <22% if patients did not reach at least moderate disease activity after 3 months on golimumab. Similar data were seen for early DAPSA response: patients achieving a DAPSA 85% at 3 months had an 84% probability for 6-month LDA or REM. All results were validated in an independent trial cohort of patients treated with infliximab (IMPACT 2). Conclusion. Three months after implementation of therapy in PsA, it is already possible to evaluate the potential for accomplishing therapeutic goals. This substantiates the choice of the 3-month assessment as essential for treatment adaptations.

The HLA-DRB1 locus is strongly associated with rheumatoid arthritis (RA) susceptibility, whereupon citrullinated self-peptides bind to HLA-DR molecules bearing the shared epitope (SE) amino acid motif. However, the differing propensity for citrullinated/non-citrullinated self-peptides to bind given HLA-DR allomorphs remains unclear. Here, we used a fluorescence polarization assay to determine a hierarchy of binding affinities of 34 self-peptides implicated in RA against three HLA-DRB1 allomorphs (HLA-DRB1*04:01/*04:04/*04:05) each possessing the SE motif. For all three HLA-DRB1 allomorphs, we observed a strong correlation between binding affinity and citrullination at P4 of the bound peptide ligand. A differing hierarchy of peptide-binding affinities across the three HLA-DRB1 allomorphs was attributable to the β-chain polymorphisms that resided outside the SE motif and were consistent with sequences of naturally presented peptide ligands. Structural determination of eight HLA-DR4-self-epitope complexes revealed strict conformational convergence of the P4-Cit and surrounding HLA β-chain residues. Polymorphic residues that form part of the P1 and P9 pockets of the HLA-DR molecules provided a structural basis for the preferential binding of the citrullinated self-peptides to the HLA-DR4 allomorphs. Collectively, we provide a molecular basis for the interplay between citrullination of self-antigens and HLA polymorphisms that shape peptide-HLA-DR4 binding affinities in RA.