Ankylosing spondylitis (AS) is a potentially disabling form of seronegative spondyloarthritis. The main symptom of AS is inflammatory spinal pain; with time, some patients develop ankylosis and spinal immobility. The pathology mainly affects the entheses, where ligaments, tendons and capsules are attached to the bone. Three processes are observed at the entheses: inflammation, bone erosion and syndesmophyte (spur) formation. Tumor necrosis factor is an important mediator of the inflammatory processes, but this proinflammatory cytokine is not closely involved in bone erosion or syndesmophyte formation. The major causative factors of AS are genetic, with the gene encoding HLA-B27 being the most important genetic factor. Several other susceptibility genes have also been identified. An enormous number of papers have been published and many diverse hypotheses have been generated regarding the pathogenesis of AS. This Review outlines the key areas of current research in this field, describes several hypotheses regarding the pathogenesis of AS, which are under intense investigation, and concludes with a dissection of the processes involved in bone erosion and syndesmophyte formation.

Pathogenesis of ankylosing spondylitis

The pathogenetic role of HLA-B27 and its subtypes

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

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Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Dynamical characterization of two differentially disease associated MHC class I proteins in complex with viral and self-peptides.

HLA-B27 and the Pathogenesis of Spondyloarthropathies

Conformational dimorphism of self−peptides and molecular mimicry in a disease−associated HLA−B27 subtype

Recently, a flexible DROP-IN gamma-probe was introduced for robot-assisted radioguided surgery, using traditional low-energy SPECT-isotopes. In parallel, a novel approach to achieve sensitive radioguidance using beta-emitting PET isotopes has been proposed. Integration of these two concepts would allow to exploit the use of PET tracers during robot-assisted tumor-receptor-targeted. In this study, we have engineered and validated the performance of a novel DROP-IN beta particle (DROP-INβ) detector. Seven prostate cancer patients with PSMA-PET positive tumors received an additional intraoperative injection of ~ 70 MBq 68Ga-PSMA-11, followed by robot-assisted prostatectomy and extended pelvic lymph node dissection. The surgical specimens from these procedures were used to validate the performance of our DROP-INβ probe prototype, which merged a scintillating detector with a housing optimized for a 12-mm trocar and prograsp instruments. After optimization of the detector and probe housing via Monte Carlo simulations, the resulting DROP-INβ probe prototype was tested in a robotic setting. In the ex vivo setting, the probe—positioned by the robot—was able to identify 68Ga-PSMA-11 containing hot-spots in the surgical specimens: signal-to-background (S/B) was > 5 when pathology confirmed that the tumor was located  3). The rotational freedom of the DROP-IN design and the ability to manipulate the probe with the prograsp tool allowed the surgeon to perform autonomous beta-tracing. This study demonstrates the feasibility of beta-radioguided surgery in a robotic context by means of a DROP-INβ detector. When translated to an in vivo setting in the future, this technique could provide a valuable tool in detecting tumor remnants on the prostate surface and in confirmation of PSMA-PET positive lymph nodes.

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Roberto Moretti

Papers

Conformational dimorphism of self−peptides and molecular mimicry in a disease−associated HLA−B27 subtype

A DROP-IN beta probe for robot-assisted 68 Ga-PSMA radioguided surgery: first ex vivo technology evaluation using prostate cancer specimens

Dosimetric evaluation of gas pockets electron density in online adaptive mrgrt

PO-1705 Characterization of injectable marker in a low tesla MR-Linac for online tracking of liver tumour

Multi-treatment dosimetric evaluation: 90y-radioembolization with previous mr-guided external beam radiation therapy