MHC class I and II peptide homology regulates the cellular immune response.

Mammalian immune responses are initiated by "danger" signals--immutable molecular structures known as PAMPs. When detected by fixed, germline encoded receptors, pathogen-associated molecular pattern (PAMPs) subsequently inform the polarization of downstream adaptive responses depending upon identity and localization of the PAMP. Here, we report the existence of a completely novel "PAMP" that is not a molecular structure but an antigenic pattern. This pattern--the incidence of peptide epitopes with stretches of 100% sequence identity bound to both dendritic cell (DC) major histocompatibility (MHC) class I and MHC class II--strongly induces TH 1 immune polarization and activation of the cellular immune response. Inherent in the existence of this PAMP is the concomitant existence of a molecular sensor complex with the ability to scan and compare amino acid sequence identities of bound class I and II peptides. We provide substantial evidence implicating the multienzyme aminoacyl-tRNA synthetase (mARS) complex and its AIMp1 structural component as the key constituents of this complex. The results demonstrate a wholly novel mechanism by which T-helper (TH ) polarization is governed and provide critical information for the design of vaccination strategies intended to provoke cell-mediated immunity.

CD8+CD161+ T-Cells: Cytotoxic Memory Cells With High Therapeutic Potential.

NK1.1 and its human homolog CD161 are expressed on NK cells, subsets of CD4+ and CD8+ T cells, and NKT cells. While the expression of NK1.1 is thought to be inhibitory to NK cell function, it is reported to play both costimulatory and coinhibitory roles in T-cells. CD161 has been extensively studied and characterized on subsets of T-cells that are MR1-restricted, IL-17 producing CD4+ (TH17 MAIT cells) and CD8+ T cells (Tc17 cells). Non-MAIT, MR1-independent CD161-expressing T-cells also exist and are characterized as generally effector memory cells with a stem cell like phenotype. Gene expression analysis of this enigmatic subset indicates a significant enhancement in the expression of cytotoxic granzyme molecules and innate like stress receptors in CD8+NK1.1+/CD8+CD161+ cells in comparison to CD8+ cells that do not express NK1.1 or CD161. First identified and studied in the context of viral infection, the role of CD8+CD161+ T-cells, especially in the context of tumor immunology, is still poorly understood. In this review, the functional characteristics of the CD161-expressing CD8+ T cell subset with respect to gene expression profile, cytotoxicity, and tissue homing properties are discussed, and application of this subset to immune responses against infectious disease and cancer is considered.

Open Repair of Acute Type A Intramural Hematoma in 3 Patients.

Acute aortic syndrome encompasses classic aortic dissection and less common aortic phenomena, including intramural hematoma (IMH), a hemorrhage within the aortic media that occurs without a discrete intimal tear. We reviewed our experience with treating acute type A IMH to better understand this acute aortic syndrome. A review of our clinical database identified 1,902 proximal aortic repairs that were performed from January 2006 through December 2018; of these, 266 were for acute aortic syndrome, including 3 (1.1%) for acute type A IMH. Operative technique varied considerably. All IMH repairs involved hemiarch or total arch replacement. In all 3 patients, the IMH extended distally into the descending thoracic aorta. There were no operative deaths or major adverse events (stroke, paraplegia, paraparesis, or renal failure necessitating dialysis) that persisted to hospital discharge. Length of hospitalization ranged from 5 to 20 days. All 3 patients were alive at follow-up (range, 2-6 yr) and needed no aortic reintervention after their index or staged repairs. In our experience, repair of acute type A IMH was infrequent and could be either simple or complex. Despite our limited experience with this disease, we found that it can be repaired successfully in urgent and emergency cases. Following treatment guidelines for aortic dissection appears to be a reasonable strategy for treating IMH.

Beyond T-Cells: Functional Characterization of CTLA-4 Expression in Immune and Non-Immune Cell Types.

The immune response consists of a finely-tuned program, the activation of which must be coupled with inhibitory mechanisms whenever initiated. This ensures tight control of beneficial anti-pathogen and anti-tumor responses while preserving tissue integrity, promoting tissue repair, and safeguarding against autoimmunity. A cogent example of this binary response is in the mobilization of co-stimulatory and co-inhibitory signaling in regulating the strength and type of a T-cell response. Of particular importance is the costimulatory molecule CD28 which is countered by CTLA-4. While the role of CD28 in the immune response has been thoroughly elucidated, many aspects of CTLA-4 biology remain controversial. The expression of CD28 is largely constrained to constitutive expression in T-cells and as such, teasing out its function has been somewhat simplified by a limited and specific expression profile. The expression of CTLA-4, on the other hand, while reported predominantly in T-cells, has also been described on a diverse repertoire of cells within both lymphoid and myeloid lineages as well as on the surface of tumors. Nonetheless, the function of CTLA-4 has been mostly described within the context of T-cell biology. The focus on T-cell biology may be a direct result of the high degree of amino acid sequence homology and the co-expression pattern of CD28 and CTLA-4, which initially led to the discovery of CTLA-4 as a counter receptor to CD28 (for which a T-cell-activating role had already been described). Furthermore, observations of the outsized role of CTLA-4 in Treg-mediated immune suppression and the striking phenotype of T-cell hyperproliferation and resultant disease in CTLA-4-/- mice contribute to an appropriate T-cell-centric focus in the study of CTLA-4. Complete elucidation of CTLA-4 biology, however, may require a more nuanced understanding of its role in a context other than that of T-cells. This makes particular sense in light of the remarkable, yet limited utility of anti-CTLA-4 antibodies in the treatment of cancers and of CTLA-4-Ig in autoimmune disorders like rheumatoid arthritis. By fully deducing the biology of CTLA-4-regulated immune homeostasis, bottlenecks that hinder the widespread applicability of CTLA-4-based immunotherapies can be resolved.

Hybrid thoracoabdominal aortic aneurysm repair: is the future here?

Open surgical repair has been the gold standard for thoracoabdominal aortic aneurysm (TAAA) repair for more than 6 decades, but 2 additional options have emerged: total endovascular TAAA repair and a hybrid approach that combines open and endovascular repair. Despite the optimism for an endovascular approach, long-term results for these repairs are still lacking. Some of the issues with this emerging technology include the risk of paraplegia after extensive endovascular repair, the need for multiple reinterventions, continuous stent-graft surveillance, endograft branch stenosis, as well as the significant learning curve. Interest in a hybrid approach has resurged despite the non-superior results compared to open TAAA. Commonly, the focus of the hybrid approach is now on performing a less extensive open TAAA repair, which is then extended with a stent-graft or vice versa. Moreover, this approach is now often performed in two stages in an effort to decrease the associated spinal cord ischemia. Open surgical repair after endovascular aortic repair is increasingly being performed to address serious complications, such as infection or fistula, that cannot be repaired by further endovascular intervention. As with any new technology, there will be an increase in the number of procedure-related complications and a decrease in the number of surgeons who can perform the traditional open operation with good results.

Extent II Thoracoabdominal Aortic Aneurysm Repair: How I Do It.

The primary risks associated with thoracoabdominal aortic aneurysm (TAAA) repair-namely operative death, paraplegia, and renal failure necessitating dialysis-are commonly related to the distal ischemia that occurs during aortic clamping and the disruption of vital branching arteries. Our technique for open TAAA repair has evolved over the course of 3 decades, from the unheparinized, simple "clamp-and-sew" approach learned directly from E. Stanley Crawford himself to a contemporary, multimodal strategy that uses an array of surgical adjuncts. Today, our approach to TAAA repair is largely standardized and based on the Crawford extents of TAAA repair, but we have maintained flexibility to explore new techniques and to adapt to the specific needs of patients. To protect the spinal cord, we routinely use mild passive hypothermia, cerebrospinal fluid drainage, left heart bypass, and reimplantation of crucial intercostal or lumbar arteries. The renal arteries are perfused with cold solution to protect the kidneys from ischemic damage, and the celiac axis and superior mesenteric artery are perfused with isothermic blood from the left heart bypass circuit, which minimizes the duration of abdominal-organ ischemia. The most extensive repair, Crawford extent II repair, typically replaces the aorta from just beyond the left subclavian artery to the aortic bifurcation; unsurprisingly, it commonly poses greater operative risk than do less extensive TAAA repairs (extent I, III, and IV). Subsequently, most surgical adjuncts used today were developed to ameliorate risk in extent II repair. Here, we provide a detailed description of our approach to open extent II TAAA repair.

Total aortic arch replacement: current approach using the trifurcated graft technique.

Since the pioneering work of DeBakey, Cooley, and colleagues more than 50 years ago, surgical treatment of aneurysms involving the transverse aortic arch has been associated with substantial morbidity and mortality. Over the past 15 years, techniques for replacing the diseased aortic arch have evolved substantially. Previously, our approach to these operations involved femoral cannulation, profound-to-deep hypothermic circulatory arrest and retrograde cerebral perfusion, and the island technique for reattaching the brachiocephalic vessels. In contrast, we currently use innominate artery cannulation, deep-to-moderate hypothermic circulatory arrest with antegrade cerebral perfusion, bilateral cerebral monitoring with near-infrared spectroscopy, and the trifurcated graft (Y-graft) technique for reattaching the arch branches. Cannulating the innominate artery to provide an inflow site for cardiopulmonary bypass has facilitated the use of antegrade cerebral perfusion as a cerebral protection strategy; the left common carotid artery is additionally perfused to provide bilateral cerebral perfusion. Despite having a systemic circulatory arrest time that often exceeds 60 minutes, these improved perfusion strategies make it possible to consistently avoid cerebral circulatory arrest all together. A moderate temperature target of between 18 and 23 °C is now used; this appears to reduce the risk of hypothermic coagulopathy and improve hemostasis. Y-graft techniques, such as the trifurcated graft approach, have the advantages of eliminating residual aortic arch tissue and being easily tailored to the needs of the individual patient. This report describes total aortic arch replacement in patients with aneurysms that are confined to the ascending aorta and transverse aortic arch.