The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling.

We found upregulation of expression of the microRNA miR-155 in primary effector and effector memory CD8(+) T cells, but low miR-155 expression in naive and central memory cells. Antiviral CD8(+) T cell responses and viral clearance were impaired in miR-155-deficient mice, and this defect was intrinsic to CD8(+) T cells, as miR-155-deficient CD8(+) T cells mounted greatly diminished primary and memory responses. Conversely, miR-155 overexpression augmented antiviral CD8(+) T cell responses in vivo. Gene-expression profiling showed that miR-155-deficient CD8(+) T cells had enhanced type I interferon signaling and were more susceptible to interferon's antiproliferative effect. Inhibition of the type I interferon-associated transcription factors STAT1 or IRF7 resulted in enhanced responses of miR-155-deficient CD8(+) T cells in vivo. We have thus identified a previously unknown role for miR-155 in regulating responsiveness to interferon and CD8(+) T cell responses to pathogens in vivo.

Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus.

Innate lymphoid cells (ILCs), a heterogeneous cell population, are critical in orchestrating immunity and inflammation in the intestine, but whether ILCs influence immune responses or tissue homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed the alloantigen Thy-1 (CD90), interleukin 2 (IL-2) receptor a-chain (CD25), IL-7 receptor a-chain (CD127) and the IL-33 receptor subunit T1-ST2. Notably, mouse ILCs accumulated in the lung after infection with influenza virus, and depletion of ILCs resulted in loss of airway epithelial integrity, diminished lung function and impaired airway remodeling. These defects were restored by administration of the lung ILC product amphiregulin. Collectively, our results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis after infection with influenza virus.

Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection.

T cell exhaustion is common during chronic infections. Although CD4(+) T cells are critical for controlling viral load during chronic viral infections, less is known about their differentiation and transcriptional program. We defined the phenotypic, functional, and molecular profiles of exhausted CD4(+) T cells. Global transcriptional analysis demonstrated a molecular profile distinct from effector and memory CD4(+) T cells and also from exhausted CD8(+) T cells, though some common features of CD4(+) and CD8(+) T cell exhaustion were revealed. We have demonstrated unappreciated roles for transcription factors (TFs) including Helios, type I interferon (IFN-I) signaling, and a diverse set of coinhibitory and costimulatory molecules during CD4(+) T cell exhaustion. Moreover, the signature of CD4(+) T cell exhaustion was found to be distinct from that of other CD4(+) T cell lineage subsets and was associated with TF heterogeneity. This study provides a framework for therapeutic interventions targeting exhausted CD4(+) T cells.

Bystander chronic infection negatively impacts development of CD8(+) T cell memory.

Epidemiological evidence suggests that chronic infections impair immune responses to unrelated pathogens and vaccines. The underlying mechanisms, however, are unclear and distinguishing effects on priming versus development of immunological memory has been challenging. We investigated whether bystander chronic infections impact differentiation of memory CD8(+) T cells, the hallmark of protective immunity against intracellular pathogens. Chronic bystander infections impaired development of memory CD8(+) T cells in several mouse models and humans. These effects were independent of initial priming and were associated with chronic inflammatory signatures. Chronic inflammation negatively impacted the number of bystander CD8(+) T cells and their memory development. Distinct underlying mechanisms of altered survival and differentiation were revealed with the latter regulated by the transcription factors T-bet and Blimp-1. Thus, exposure to prolonged bystander inflammation impairs the effector to memory transition. These data have relevance for immunity and vaccination during persisting infections and chronic inflammation.

The Effects of Autologous Fat Transfer in an In Vitro Model of Basal Joint Osteoarthritis.

PURPOSE: Basal joint osteoarthritis (OA) is a highly prevalent and debilitating condition. Recent clinical evidence suggests that autologous fat transfer (AFT) may be a promising, minimally invasive treatment for this condition. However, the mechanism of action is not fully understood. It is theorized that AFT reduces inflammation in the joint, functions to regenerate cartilage, or acts as a mechanical buffer. The purpose of this study was to better understand the underlying mechanism of AFT using an in vitro model. We hypothesize that the addition of stromal vascular fraction (SVF) cells will cause a reduction in markers of inflammation. METHODS: Articular chondrocytes were expanded in culture. Liposuction samples were collected from human subjects and processed similarly to AFT protocols to isolate SVF rich in adipose-derived stem cells. A control group was treated with standard growth media, and a positive control group (OA group) was treated with inflammatory cytokines. To mimic AFT, experimental groups received inflammatory cytokines and either a low or high dose of SVF. Expression of relevant genes was measured, including interleukin (IL)-1ß, IL-1 receptor antagonist, and matrix metalloproteinases (MMP). RESULTS: Compared to the OA group, significant decreases in IL-1ß, MMP3, and MMP13 expression on treatment day 3 were found in the high-dose SVF group, while MMP13 expression was also significantly decreased in the low-dose SVF group on day 3. CONCLUSIONS: In this study, we found that SVF treatment reduced expression of IL-1ß, MMP3, and MMP13 in an in vitro model of OA. These results suggest that an anti-inflammatory mechanism may be responsible for the clinical effects seen with AFT in the treatment of basal joint OA. CLINICAL RELEVANCE: An anti-inflammatory mechanism may be responsible for the clinical benefits seen with AFT for basal joint arthritis.

Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory.

Exhausted CD8(+) T cells function poorly and are negatively regulated by inhibitory receptors. Transcriptional profiling has identified gene expression changes associated with exhaustion. However, the transcriptional pathways critical to the differences between exhausted and functional memory CD8(+) T cells are unclear. We thus defined transcriptional coexpression networks to define pathways centrally involved in exhaustion versus memory. These studies revealed differences between exhausted and memory CD8(+) T cells including the following: lack of coordinated transcriptional modules of quiescence during exhaustion, centrally connected hub genes, pathways such as transcription factors, genes involved in regulation of immune responses, and DNA repair genes, as well as differential connectivity for genes including T-bet, Eomes, and other transcription factors. These data identify pathways involved in CD8(+) T cell exhaustion, and highlight the context-dependent nature of transcription factors in exhaustion versus memory.

Commensal bacteria calibrate the activation threshold of innate antiviral immunity.

Signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. However, the mechanisms by which commensal bacteria regulate protective immunity after exposure to systemic pathogens remain poorly understood. Here, we demonstrate that antibiotic-treated (ABX) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic LCMV or mucosal influenza virus. Furthermore, ABX mice exhibited severe bronchiole epithelial degeneration and increased host mortality after influenza virus infection. Genome-wide transcriptional profiling of macrophages isolated from ABX mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages from ABX mice exhibited defective responses to type I and type II IFNs and impaired capacity to limit viral replication. Collectively, these data indicate that commensal-derived signals provide tonic immune stimulation that establishes the activation threshold of the innate immune system required for optimal antiviral immunity.

TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation.

CD4(+) T-helper type 2 (T(H)2) cells, characterized by their expression of interleukin (IL)-4, IL-5, IL-9 and IL-13, are required for immunity to helminth parasites and promote the pathological inflammation associated with asthma and allergic diseases. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, indicating that TSLP is a critical regulator of T(H)2 cytokine-associated inflammatory diseases. In support of genetic analyses, exaggerated TSLP production is associated with asthma, atopic dermatitis and food allergies in patients, and studies in murine systems demonstrated that TSLP promotes T(H)2 cytokine-mediated immunity and inflammation. However, the mechanisms through which TSLP induces T(H)2 cytokine responses remain poorly defined. Here we demonstrate that TSLP promotes systemic basophilia, that disruption of TSLP-TSLPR interactions results in defective basophil responses, and that TSLPR-sufficient basophils can restore T(H)2-cell-dependent immunity in vivo. TSLP acted directly on bone-marrow-resident progenitors to promote basophil responses selectively. Critically, TSLP could elicit basophil responses in both IL-3-IL-3R-sufficient and -deficient environments, and genome-wide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited basophils. Furthermore, activated human basophils expressed TSLPR, and basophils isolated from eosinophilic oesophagitis patients were distinct from classical basophils. Collectively, these studies identify previously unrecognized heterogeneity within the basophil cell lineage and indicate that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating basophil haematopoiesis and eliciting a population of functionally distinct basophils that promote T(H)2 cytokine-mediated inflammation.

Defective CD8 T cell responses in aged mice are due to quantitative and qualitative changes in virus-specific precursors.

Aging is associated with suboptimal CD8 T cell responses to viral infections. It is not clear whether these poor responses are due to environmental influences or quantitative and qualitative changes in the pool of responding CD8 T cells. Our studies demonstrated several deleterious age-related changes in the pool of Ag-specific CD8 T cells that respond to infection. The majority of CD8 T cells from uninfected aged mice was CD44(Hi) and had increased expression of inhibitory receptors including PD1, LAG3, 2B4, and CD160. These aged CD44(Hi) CD8 T cells were transcriptionally similar to exhausted CD8 T cells found during chronic infections. In addition, the number of virus-specific precursors in aged mice prior to infection was decreased up to 10-fold, and many of these Ag-specific precursors had high expression of CD44 and PD1. Finally, TCR transgenic studies demonstrated that the CD44(Hi) Ag-specific CD8 T cells from unimmunized aged and young mice were qualitatively inferior compared with CD44(Lo) CD8 T cells from aged or young donors. Thus, a decrease in precursor frequency as well as qualitative changes of CD8 T cells during aging are directly related to impaired immunity.

Knotless Suture Anchor Suspensionplasty for Basal Joint Arthritis A Prospective Case Series with Short-Term Outcomes.

BACKGROUND: The mainstay of surgical treatment for advanced basal joint arthritis is arthroplasty. Many differ- ent techniques of basal joint arthroplasty exist, but none has been determined to be superior to the others, and most methods used to maintain the post-trapeziectomy space require postoperative immobilization or pin fixation. In this article, we describe a knotless suture anchor suspen- sionplasty (KSAS) technique and present a prospective case series with short-term outcomes. The KSAS technique utilizes a suspension construct to maintain the post-trapeziectomy space, allowing for early mobilization without the need for pin fixation or casting. METHODS: Twenty-five patients underwent trapeziectomy with KSAS. Visual analog scale (VAS) for pain scores and Quick Disabilities of the Arm, Shoulder, and Hand (qDASH) scores were recorded preoperatively and at multiple post- operative points. Grip and pinch strengths were recorded. Maintenance of the post-trapeziectomy space and subsidence were determined by comparing preoperative and postopera- tive radiographs. RESULTS: VAS pain scores were significantly reduced from baseline at all postoperative time points with a reduction from 6.54 to 1.47 at 20 to 24 weeks (p < 0.001). qDASH scores were also significantly decreased from baseline at all time points except for 1 week postoperatively with a re- duction from 57.71 to 12.27 at 20 to 24 weeks (p < 0.001). Grip strength improved from 80.43% compared to the non- operative side preoperatively to 90.36% at 6 months status post KSAS (p < 0.05). Radiographically, subsidence was 35.11% at final follow-up. CONCLUSIONS: Our data suggest that KSAS is a safe, effective, and reproducible basal joint arthroplasty tech- nique that allows for early mobilization while sufficiently maintaining the post-trapeziectomy space enough to prevent impingement of the first metacarpal on the scaphoid. Al- though there are limitations to this prospective case series, the data presented here warrant long-term outcome studies utilizing this technique.

Common Complications of Distal Radial Fractures.

Distal radial fractures are associated with good outcomes; however, although they occur at low rates, complications can significantly impair treatment success. Therefore, the treating surgeon should be aware of potential complications associated with each treatment type and how to best prevent them. Although certain patient-specific and fracture-specific factors may increase the risk of adverse outcomes, most are nonmodifiable risk factors at the time of presentation, so it is imperative that every effort is made to mitigate these risk factors to prevent long-term morbidity. Patients should be well-informed about these complications and potential symptoms so that they can be addressed expeditiously.

Hot Topics in Hand and Wrist Surgery.

The field of hand surgery continues to evolve in new and exciting directions. Advances in diagnosis and management for common complaints and complex injuries allow higher-level care, while still being cognizant of the cost of health care delivery. Indications and protocols for past paradigm shifts, such as volar locked plating for distal radial fractures, continue to be honed, and the outcomes seen for modern flexor tendon repairs are impressive. Open questions remain, but promising results for scaphoid nonunion surgery and peripheral nerve reconstruction with processed allograft will continue to shed light on these unsolved problems.

High-Energy Fractures of the Pelvis and Acetabulum in Pediatric Patients.

Fractures of the pelvis and acetabulum, although uncommon in the pediatric cohort, represent a range of injuries with similarities to those seen in the adult cohort but with key differences that are important for the treating physician to be aware of to allow for systematic evaluation and management of these potentially life-threatening injuries. As the pediatric skeleton matures, changes in anatomy and physiology influence injury pattern, diagnosis, treatment, and complications. High-energy fractures of the pediatric pelvis are particularly concerning given the reported mortality rates ranging from 3.2% to 18%, with severe fracture patterns being associated with visceral injury in up to 60% of patients. The unique complexity of pediatric patients requires a multidisciplinary team to fully address their care. A systematic approach to the initial evaluation and diagnosis of pediatric patients with fractures of the acetabulum or pelvic ring aids in choosing between surgical and nonsurgical management of these fractures and avoiding complications unique to the maturing skeleton. We present such an approach to assist the practitioner who infrequently treats these uncommon injuries.

Dorsal Plating for Intra-articular Middle Phalangeal Base Fractures With Volar Instability.

Background: Intra-articular middle phalangeal base fractures with volar instability are rare injuries with scant literature on optimal management. Our purpose is to describe our method of dorsal plating and report postoperative outcomes. Methods: This study is a retrospective case review of 5 patients with intra-articular middle phalangeal base fractures with volar proximal interphalangeal joint instability, measuring subjective, clinical, and radiographic outcomes. Results: Patient age averaged 38.2 years (range, 23-56 years), and 80% were male. Sporting injuries were the most common mechanism (80%). Time to surgery averaged 7 days, and postoperative follow-up duration averaged 19.6 months (median 8 months). All fractures were intra-articular at the proximal interphalangeal joint with volar instability. There were no complications and no patients required secondary surgery. Grip strength was maintained and range of motion was good, based on the American Society for Surgery of the Hand Total Active Motion score. Average Quick Disability of the Arm, Shoulder and Hand was 0.5 (range, 0-2.3), 100% of patients were satisfied, and average visual analog pain score was 1.2. Patients returned to work at a median of 4 days. There was radiographic union at an average of 6.6 weeks (range, 6-7 weeks) in all fractures. Conclusions: Dorsal plating using a 1.5-mm modular hand plate is a viable option for rigid fixation of intra-articular middle phalangeal base fractures with volar instability. This fixation method allows for early range of motion without complications in this case series. All fractures united, and patients had minimal functional deficits and were able to maintain good range of motion.

Establishing an evidence base for critical laboratory value thresholds.

OBJECTIVES: Critical values denote laboratory test results indicating a life-threatening situation. The outcomes of this premise have not been rigorously evaluated. METHODS: Five years of inpatient admissions were examined for critical or "near-critical" results (total admissions = 165,066; total test results = 872,503). In-hospital mortality was examined as a function of time and degree of test result abnormality. RESULTS: Some critical value thresholds appropriately identified patients at risk for death (eg, elevated potassium). Other thresholds were too conservative (elevated hematocrit, hemoglobin) or not conservative enough (elevated lactate). Mortality risk for most critical values was time dependent, but some critical values showed no temporal effect on mortality (elevated activated partial thromboplastin time [APTT], international normalized ratio [INR], and glucose). Following an initial critical result, further worsening was associated with increased mortality. Prior hospital admission within 30 days was a predictor of lower mortality for some (elevated APTT, INR, potassium, and sodium; low glucose, hematocrit, hemoglobin, and potassium) but not other critical values (elevated lactate, glucose, hematocrit, and hemoglobin; low sodium). CONCLUSIONS: Only a subset of laboratory critical value thresholds was optimally chosen for increased risk of in-hospital mortality, with a time urgency for most but not all critical values. For many tests, a prior hospital admission imparted a decreased risk of in-hospital death.