HLA-DO increases bacterial superantigen binding to human MHC molecules by inhibiting dissociation of class II-associated invariant chain peptides

HLA-DO (H2-O in mice) is an intracellular non-classical MHC class II molecule (MHCII). It forms a stable complex with HLA-DM (H2-M in mice) and shapes the MHC class II-associated peptide repertoire. Here, we tested the impact of HLA-DO and H2-O on the binding of superantigens (SAgs), which has been shown previously to be sensitive to the structural nature of the class II-bound peptides. We found that the binding of staphylococcal enterotoxin (SE) A and B, as well as toxic shock syndrome toxin 1 (TSST-1), was similar on the HLA-DO⁺ human B cell lines 721.45 and its HLA-DO⁻ counterpart. However, overexpressing HLA-DO in MHC class II⁺ HeLa cells (HeLa-CIITA-DO) improved binding of SEA and TSST-1. Accordingly, knocking down HLA-DO expression using specific siRNAs decreased SEA and TSST-1 binding. We tested directly the impact of the class II-associated invariant chain peptide (CLIP), which dissociation from MHC class II molecules is inhibited by overexpressed HLA-DO. Loading of synthetic CLIP on HLA-DR⁺ cells increased SEA and TSST-1 binding. Accordingly, knocking down HLA-DM had a similar effect. In mice, H2-O deficiency had no impact on SAgs binding to isolated splenocytes. Altogether, our results demonstrate that the sensitivity of SAgs to the MHCII–associated peptide has physiological basis and that the effect of HLA-DO on SEA and TSST-1 is mediated through the inhibition of CLIP release.     

Importance of ablating all potential right atrial flutter circuits in postcardiac surgery patients

OBJECTIVES: In patients with atrial flutter (AFL) and postoperative right atrial incisional scars, we sought to assess if the use of additional ablative lesions that targeted all potential re-entrant circuits, regardless of the presenting type of flutter, would prevent long-term recurrence. BACKGROUND: Patients with AFL and incisional scars have a complex atrial substrate that may promote multiple mechanisms of intra-atrial re-entry. METHODS: Twenty-nine patients with single right atrial incisional scars undergoing ablation for scar-dependent (n = 15) and cavotricuspid isthmus (CTI)-dependent (n = 14) flutter were studied. RESULTS: In the scar-dependent group, 9 of 15 (60%) patients had inducible or spontaneous CTI-dependent flutter immediately after ablation. In the group with CTI flutter, 7 of 14 (50%) patients had scar-related flutter immediately after ablation. If a second type of flutter was found during the initial ablation, a second ablation was performed either along the isthmus (scar-dependent group) or from the scar to another anatomic boundary (isthmus-dependent group). Patients were followed for 24 +/- 5 months and 18 +/- 6 months in the scar- and CTI-dependent groups, respectively. In the scar-dependent group, five of six (83%) who underwent only a single flutter line had recurrence at 3 +/- 1 months. In the isthmus-dependent group, three of seven (42%) patients who had only one flutter line performed had recurrence at 5 +/- 3 months. There was no flutter recurrence in patients who initially received two different flutter lines or in patients who subsequently underwent a second flutter line at follow-up. CONCLUSIONS: In patients with postoperative right atrial incisional scar and flutter, multiple ablation lines that target both scar-related and classic isthmuses appear necessary to prevent long-term recurrence.     

Anesthesia and the developing brain: a way forward for clinical research

It is now well established that many general anesthetics have a variety of effects on the developing brain in animal models. In contrast, human cohort studies show mixed evidence for any association between neurobehavioural outcome and anesthesia exposure in early childhood. In spite of large volumes of research, it remains very unclear if the animal studies have any clinical relevance; or indeed how, or if, clinical practice needs to be altered. Answering these questions is of great importance given the huge numbers of young children exposed to general anesthetics. A recent meeting in Genoa brought together researchers and clinicians to map a path forward for future clinical studies. This paper describes these discussions and conclusions. It was agreed that there is a need for large, detailed, prospective, observational studies, and for carefully designed trials. It may be impossible to design or conduct a single study to completely exclude the possibility that anesthetics can, under certain circumstances, produce long‐term neurobehavioural changes in humans; however , observational studies will improve our understanding of which children are at greatest risk, and may also suggest potential underlying etiologies, and clinical trials will provide the strongest evidence to test the effectiveness of different strategies or anesthetic regimens with respect to better neurobehavioral outcome.