Aire in Autoimmunity.

The role of the autoimmune regulator (Aire) in central immune tolerance and thymic self-representation was first described more than 20 years ago, but fascinating new insights into its biology continue to emerge, particularly in the era of advanced single-cell genomics. We briefly describe the role of human genetics in the discovery of Aire, as well as insights into its function gained from genotype-phenotype correlations and the spectrum of Aire-associated autoimmunity-including insights from patients with Aire mutations with broad and diverse implications for human health. We then highlight emerging trends in Aire biology, focusing on three topic areas. First, we discuss medullary thymic epithelial diversity and the role of Aire in thymic epithelial development. Second, we highlight recent developments regarding the molecular mechanisms of Aire and its binding partners. Finally, we describe the rapidly evolving biology of the identity and function of extrathymic Aire-expressing cells (eTACs), and a novel eTAC subset called Janus cells, as well as their potential roles in immune homeostasis.

Extrathymic AIRE-Expressing Cells: A Historical Perspective.

Since its discovery, Aire has been the topic of numerous studies in its role as a transcriptional regulator in the thymus where it promotes the "promiscuous" expression of a large repertoire of tissue-restricted antigens (TRAs) that are normally expressed only in the immune periphery. This process occurs in specialized medullary thymic epithelial cells (mTECs) and mediates the elimination of self-reactive T cells or promotes their conversion to the Foxp3+ regulatory T cell lineage, both of which are required for the prevention of autoimmunity. In recent years, there has been increasing interest in the role of extrathymic Aire expression in peripheral organs. The focus has primarily been on the identification of the cellular source(s) and mechanism(s) by which extrathymic AIRE affects tolerance-related or other physiological processes. A cadre of OMICs tools including single cell RNA sequencing and novel transgenic models to trace Aire expression to perform lineage tracing experiments have shed light on a phenomenon that is more complex than previously thought. In this chapter, we provide a deeper analysis of how extrathymic Aire research has developed and progressed, how cellular sources were identified, and how the function of AIRE was determined. Current data suggests that extrathymic AIRE fulfills a function that differs from what has been observed in the thymus and strongly argues that its main purpose is to regulate transcriptional programs in a cell content-dependent manner. Surprisingly, there is data that also suggests a non-transcriptional role of extrathymic AIRE in the cytoplasm. We have arrived at a potential turning point that will take the field from the classical understanding of AIRE as a transcription factor in control of TRA expression to its role in immunological and non-immunological processes in the periphery.

Evaluation of circulating tumor cell clusters for pan-cancer noninvasive diagnostic triaging.

BACKGROUND: Histopathologic examination (HPE) of tumor tissue obtained by invasive biopsy is the standard for cancer diagnosis but is resource-intensive and has been associated with procedural risks. The authors demonstrate that immunocytochemistry (ICC) profiling of circulating ensembles of tumor-associated cells (C-ETACs) can noninvasively provide diagnostic guidance in solid organ cancers. METHODS: The clinical performance of this approach was tested on blood samples from 30,060 individuals, including 9416 individuals with known cancer; 6725 symptomatic individuals with suspected cancer; and 13,919 asymptomatic individuals with no prior diagnosis of cancer. C-ETACs were harvested from peripheral blood and profiled by ICC for organ-specific and subtype-specific markers relevant to the cancer type. ICC profiles were compared with HPE diagnoses to determine concordance. RESULTS: The presence of malignancy was confirmed by the detection of C-ETACs in 91.8% of the 9416 individuals with previously known cancer. Of the 6725 symptomatic individuals, 6025 were diagnosed with cancer, and 700 were diagnosed with benign conditions; C-ETACs were detected in 92.6% of samples from the 6025 individuals with cancer. In a subset of 3509 samples, ICC profiling of C-ETACs for organ-specific and subtype-specific markers was concordant with HPE findings in 93.1% of cases. C-ETACs were undetectable in 95% of samples from the 700 symptomatic individuals who had benign conditions and in 96.3% of samples from the 13,919 asymptomatic individuals. CONCLUSIONS: C-ETACs were ubiquitous (>90%) in various cancers and provided diagnostically relevant information in the majority (>90%) of cases. This is the first comprehensive report on the feasibility of ICC profiling of C-ETACs to provide pan-cancer diagnostic guidance with accuracy comparable to that of HPE.

Arthroscopic shoulder stabilization Differential treatment strategy with Suretac, Fastak, holmium: YAG laser and electrosurgery.

The goal for arthroscopic stabilization of anterior glenohumeral instability is to achieve an outcome equivalent to or better than open procedures. A number of arthroscopic procedures have been advocated to reestablish continuity of the inferior glenohumeral ligament complex (IGHLC) with the glenoid. Implantable suture anchors were developed to avoid the problems associated with arthroscopic staple capsulorrhaphy like iatrogenic injury of the glenoid or humeral surface, loosening and migration of the staple. Several transosseous techniques include the need for an accessory posterior incision, the possibility of neurovascular injury (Suprascapular or axillary nerve), and the loosening of the repair after tying over the fascia of the infraspinatus posteriorly. The preferred techniques are cannulated, absorbable fixation device (Suretac) and easy implantable suture anchors made of titanium (Fastak). Even in the hands of experienced arthroscopists, unacceptably high recurrence rates for arthroscopic shoulder stabilization have been reported, due to the steep learning curve for both technical performance and patient selection. Our experience suggests, that if proper selection criteria are employed, normal patients and overhead-athletes may benefit from the advantages of an arthroscopic repair without accepting an increased risk for recurrence. We performed a prospective analysis of 105 shoulders, who underwent arthroscopic stabilization with Suretac or Fastak between 4/96 and 7/98. 48 shoulders were available for followup at least one year. The redislocation rate was 6.25 % (3 shoulders) and the rate of subluxation without dislocation also was 6.25 %, but none of the shoulders required a second open stabilization. The reason for redislocation or subluxation were 5/6 traumatic injuries, participating in contact sports or in one case a generalized ligamentous laxity. In combination with the LACS-Procedure or the Electro thermally assisted capsular shift (ETACS) not only the capsular detachment but also the capsular redundancy may be adressed and a lower failure rate can be expected.