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Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis. Psoriatic arthritis (PsA) commonly affects patients with skin psoriasis, but its pathogenesis is still unclear. Here the authors use two types of single-cells data, mass cytometry and RNA sequencing, to describe the expansion and diversity of synovial, but not peripheral blood, CD8 T cells from PsA patients to provide a molecular immune landscape for PsA.

Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo . MAIT cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus. This activation—driving cytokine release and Granzyme B upregulation—is TCR-independent but dependent on IL-18 in synergy with IL-12, IL-15 and/or interferon-α/β. IL-18 levels and MAIT cell activation correlate with disease severity in acute dengue infection. Furthermore, HCV treatment with interferon-α leads to specific MAIT cell activation in vivo in parallel with an enhanced therapeutic response. Moreover, TCR-independent activation of MAIT cells leads to a reduction of HCV replication in vitro mediated by IFN-γ. Together these data demonstrate MAIT cells are activated following viral infections, and suggest a potential role in both host defence and immunopathology. Mucosal Associated Invariant T cells have been implicated in response to bacterial pathogens. Here the authors show that in human viral infections, these cells are activated by IL-18 in cooperation with other pro-inflammatory cytokines, producing interferon gamma and granzyme B.

IL-23 is considered a critical regulator of IL-17 in Th17 cells; however, its requirement for inducing IL-17 production in other human immune subsets remains incompletely understood. Mucosal associated invariant T (MAIT) cells uniformly express retinoic acid receptor-related orphan receptor gamma t (RORγt) but only a minor population have been shown to produce IL-17A. Here we show that IL-17F is the dominant IL-17 isoform produced by MAIT cells, not IL-17A. For optimal MAIT cell derived IL-17A and IL-17F production, T cell receptor (TCR) triggering, IL-18 and monocyte derived IL-12 signaling is required. Unlike Th17 cells, this process is independent of IL-23 signaling. Using an in vitro skin cell activation assay, we demonstrate that dual neutralization of both IL-17A and IL-17F resulted in greater suppression of inflammatory proteins than inhibition of IL-17A alone. Finally, we extend our findings by showing that other innate-like lymphocytes such as group 3 innate lymphoid cells (ILC3) and gamma delta (γδ) T cells are also capable of IL-23 independent IL-17A and IL-17F production. These data indicate both IL-17F and IL-17A production from MAIT cells may contribute to tissue inflammation independently of IL-23, in part explaining the therapeutic disconnect between targeting IL-17 or IL-23 in certain inflammatory diseases.

Background Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE. Methods RNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target. Results We demonstrated that the plasma cell/plasmablast-related genes CD38 , XBP1 , IRF4 , PRDM1 , IGJ and TNFSF13B are significantly up-regulated in synovial biopsies from patients with arthralgia, undifferentiated arthritis (UA), early RA and established RA as compared to healthy controls and control patients with osteoarthritis. In addition, the highest CD38 expression was observed on plasma cells and plasmablasts compared to natural killer (NK) cells, classical dendritic cells (DCs), plasmacytoid DCs (pDCs) and T cells, in blood from healthy controls and patients with SLE and RA. Furthermore, IHC showed CD38 staining in the same region as CD3 and CD138 staining in synovial tissue biopsies from patients with early RA. Most importantly, our data show for the first time that daratumumab effectively depletes plasma cells/plasmablasts in PBMC from patients with SLE and RA in a dose-dependent manner ex vivo. Conclusion These results indicate that CD38 may be a potential target for RA disease interception and daratumumab should be evaluated clinically for the treatment of both RA and SLE.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.

Background The thyroid gland is an uncommon site for metastatic deposits from non-thyroid malignancies, occurring in only 1.4 - 3% of surgical specimens where malignancy is suspected. It is even rarer for the source of thyroid metastases to be of colorectal origin. In most cases reported, colorectal metastases in the thyroid occurs many years later after the primary colorectal cancer has been diagnosed and treated. In this unique case, a primary sigmoid carcinoma metastasised to the thyroid gland and presented synchronously as a thyroid nodule. Case presentation We describe a case of a 64-year-old Caucasian woman who presented with clinical features of metastatic cancer of unknown origin. Her medical history included underlying hyperthyroidism. She had a large pelvic mass adjacent to the sigmoid colon, a left lower lobe lung mass and a suspicious nodule in the left thyroid lobe. A fine-needle aspiration biopsy of the thyroid nodule was performed, which remarkably showed malignant cells originating from primary colorectal cancer on immunohistochemical staining. The patient was managed with palliative chemotherapy given the poor prognosis due to disseminated colorectal malignancy. Conclusions Colorectal adenocarcinoma metastases can rarely present as a metastatic thyroid nodule. Fine-needle aspiration should be performed in suspicious thyroid nodules and may be the least invasive way of identifying a metastatic colorectal or other non-thyroidal malignancy in patients presenting with an unknown primary. The pathologist should be vigilant to this possibility and specific immunohistochemical markers should be used to ensure accurate diagnosis. In thyroid metastases, the prognosis is ultimately determined by the primary tumour but thyroidectomy still has a role in alleviating compressive symptoms and can potentially improve survival in selected cases.

BackgroundA major gap in the management of sarcoidosis is the lack of accessible and objective methods to measure disease activity. Since 90% of patients have pulmonary involvement, we explored if a disease activity score based on thoracic CT scans could address this clinical issue.MethodsHigh-resolution CT scans from 100 consecutive patients with sarcoidosis at a regional sarcoidosis service were scored for extent of CT abnormalities known to relate to granuloma or lymphocytic infiltration from published CT-pathological studies. These individual abnormality scores were then correlated against serum ACE, sIL-2R and change in FVC to identify CT abnormalities that reflect contemporaneous disease activity. The sum of these scores, or CT Activity Score (CTAS), was then validated against FVC response to treatment.FindingsCT extent scores for nodularity, ground-glass opacification, interlobular septal thickening and consolidation correlated significantly with at least one of the disease activity parameters and were used to form CTAS. CTAS was found to predict FVC response to treatment at 1 year and was highly reproducible between radiologists. An abbreviated CTAS (aCTAS), constructed from presence or absence of the four CT abnormalities, also showed significant correlation with FVC response to treatment. CTAS and aCTAS also correlated with response to treatment in the fibrotic subgroup.InterpretationCTAS provides a concept for an objective and reproducible CT scoring method to quantify disease activity in sarcoidosis. The score can potentially be used to stratify patients according to disease activity, determine response to treatment and establish if fibrotic sarcoidosis is active.

BackgroundWhile highly efficacious for numerous cancers, immune checkpoint inhibitors (ICIs) can cause unpredictable and potentially severe immune-related adverse events (irAEs), underscoring the need to understand irAE biology.MethodsWe used a multidimensional approach incorporating single-cell RNA sequencing, mass cytometry, multiplex cytokine assay, and antinuclear antibody (ANA) profiling to characterize the peripheral immune landscape of patients receiving ICI therapy according to irAE development.ResultsAnalysis of 162 patients revealed that individuals who developed clinically significant irAEs exhibited a baseline proinflammatory, autoimmune-like state characterized by a significantly higher abundance of CD57+ T and natural killer (NK) T cells, plasmablasts, proliferating and activated CXCR3+ lymphocytes, CD8+ effector and terminal effector memory T cells, along with reduced NK cells and elevated plasma ANA levels. In irAE cases, we identified distinct baseline proinflammatory gene signatures, including markedly higher expression of IL1B and CXCL8 in monocytes and CXCR3, TNF, and IFNG in T/NK cells. TNF signaling was the most enriched pathway, while immunosuppressive genes SIGLEC7 and CXCR4 were downregulated. Following ICI initiation, these patients exhibited an enhanced shift toward an activated and inflammatory immune phenotype, including monocyte reprogramming characterized by upregulation of IL18 and elevated gene expression levels of CXCL10. Conversely, post-treatment levels of CXCL8 were decreased in irAE patients. Notably, in patients who did not develop clinically significant irAE, we identified increased baseline abundance of a TGFBIhigh myeloid cluster enriched in immunosuppressive markers such as STAB1. In addition, patients without irAE exhibited upregulation of TNF and AIRE, accompanied by distinct myeloid protumorigenic reprogramming.ConclusionsA pre-existing activated, autoimmune-like proinflammatory state drives the development of irAE during ICI therapy through three key axes: increased plasmablast/ANA, heightened interferon-gamma/CXCL10/CXCR3 axis, and amplified TNF signaling. These findings may serve as potential peripheral immune biomarkers for predicting irAE and provide biological insights into the mechanisms governing and mitigating irAE.

Reliance on telehealth increased dramatically during the COVID-19 pandemic, introducing new opportunities to consider the use of telehealth across the cancer control continuum. However, patient, clinician, and staff perspectives about the types of cancer care appointments that are considered appropriate and the clinical care needs to support expanded remote care services are limited. Understanding older adults' diverse technology needs and perspectives is especially important given that they comprise a large and growing proportion of patients with cancer. This study aimed to describe the perceptions and experiences of older patients with cancer and their clinical care team members regarding the expansion of telehealth use across the cancer control continuum and to solicit suggestions about how to support telehealth use for cancer care delivery. Using a convergent mixed methods design, we surveyed and interviewed patients aged ≥60 years, clinicians, and staff at a comprehensive cancer center in the southern United States between December 2020 and November 2021. Interview questions were rooted in the sociotechnical model, which proposes 8 interrelated dimensions representing factors influencing the design, use, and outcomes associated with health information technologies. Patient survey domains included telehealth experience and satisfaction and factors affecting telehealth perceptions and use; clinician survey domains included contexts of telehealth appropriateness, training, and barriers and facilitators to telehealth service provision. Survey data were analyzed using descriptive statistics. Qualitative data were thematically analyzed using a combined deductive and inductive approach. We received completed surveys from 128 patients (567 invited) and 106 clinicians and staff (146 invited). We completed 14 patient (29 invited) and 20 clinician and staff (22 invited) interviews. Across all participants, most agreed or strongly agreed that multiple cancer care appointment types should be offered via telehealth, including discussing treatment side effects (75/102, 73.5% of patients and 66/94, 70.2% of clinicians and staff), results communication (71/102, 69.6% of patients and 65/94, 69.1% of clinicians and staff), and treatment follow-up (67/102, 65.7% of patients and 52/93, 55.9% of clinicians and staff). In interviews, participants elaborated on factors influencing the appropriateness of telehealth versus in-person appointments, including symptom severity, type of cancer, and purpose of the appointment. Many patient and staff suggestions focused on ways to address digital literacy gaps, while clinicians recommended improving clinic workflows, infrastructure, and training. Overall, clinicians, staff, and older patients with cancer all responded positively toward expanding telehealth use across multiple cancer and appointment types across the cancer control continuum. Older adults with cancer are generally interested in telehealth for cancer care, especially if strategies to address digital literacy gaps are incorporated. Clinicians and staff members expressed specialized training and infrastructure needs to optimize telehealth uptake and service delivery.