The proximal extension of acute type A aortic dissection is associated with ascending aortic wall degeneration.

Background: Aortic root involvement during acute type A aortic dissection (ATAAD) may depend on ascending aortic wall degeneration. Surgical decision-making for extended resection of the aortic root is clinically made without histopathology. The aim of the study was to investigate whether the degree of degeneration of the ascending aortic wall found in patients with ATAAD is associated with the aortic root involvement. Methods: Collectively, 141 consecutive patients undergoing ATAAD surgery at Tampere University Heart Hospital were investigated. The ascending aortic wall resected in surgery was processed for 11 different variables that describe medial and adventitial degeneration. In addition, atherosclerosis and inflammation were separately evaluated. Patients undergoing aortic root replacement were compared with those with supracoronary reconstruction of the ascending aorta with/without aortic valve surgery (root-sparing surgery) during a mean 4.9-year follow-up. Results: Aortic root replacement together with the ascending aortic replacement was performed in 39% of the patients (n=55). The mean age for all patients was 65 years [standard deviation (SD 13)]. Many patients with aortic root replacement had moderate to severe aortic valve regurgitation (85.5%). Most of the patients with aortic root-sparing surgery included a supracoronary tube prosthesis (89.5%), while nine patients also had aortic valve replacement. The degree of mucoid extracellular matrix accumulation was more prominent in patients with aortic root replacement compared to patients with root-sparing surgery (2.1 SD 0.4 vs. 1.9 SD 0.4, P=0.04, respectively). During follow-up, there were 52 deaths among patients (log rank P=0.79). Conclusions: Histopathology of the ascending aorta during ATAAD reveals distinctive aortic wall degeneration in patients with aortic root involvement vs. not. The degree of mucoid extracellular matrix accumulation assessed postoperatively is associated with the choice of surgical procedure in many patients.

Aortic elastic fiber degeneration during acute type a aortic dissection and reverse aortic remodeling.

BACKGROUND: Progression of proximal or distal aortic dilatation is defined as reverse aortic remodeling after surgery for acute type A aortic dissection (ATAAD) that may be dependent on aortic wall degeneration. METHODS: We investigated whether aortic wall degeneration is associated with reverse aortic remodeling leading to aortic reoperation after surgery for ATAAD. Altogether, 141 consecutive patients undergoing surgery for ATAAD at Tampere were evaluated. The resected ascending aortic wall at surgery was processed for 42 degenerative, atherosclerotic and inflammatory histological variables. Patients undergoing aortic reoperations (Redos) were compared with those without aortic reoperations (Controls) during a mean 4.9-year follow-up. RESULTS: Redos were younger than Controls (56 and 66 years, respectively, P < 0.001), and had less frequently previous cardiac surgery prior to ATAAD. Initial surgery encompassed replacement of the ascending aorta in the majority. There were 21 Redos in which one patient died during follow-up as compared with 51 deaths in Controls (log Rank P = 0.002). Histology of the aortic wall revealed increased elastic fiber fragmentation, loss, and disorganization in Redos as compared with Controls (2.1 ± 0.5 vs. 1.9 ± 0.5, Point score unit (PSU), P = 0.043 and 1.7 ± 0.8 vs. 1.2 ± 0.8, PSU, P = 0.016, respectively). Moderate atherosclerosis occurred less often in Redos vs. Controls (9.5% vs. 33%, PSU, P = 0.037, respectively). CONCLUSIONS: According to this exploratory study, histopathology reveals distinctive aortic wall degeneration during ATAAD. Reverse aortic remodeling after ATAAD is associated with the presence of ascending aortic wall elastic fiber fragmentation, loss and disorganization during ATAAD.

Peptide immunization excludes antigen-specific T cells from splenic lymphoid compartments.

Using adoptive transfer of TCR-transgenic T cells, we examined the homing of transgenic T cells to splenic compartments in situ. After systemic immunization with peptide or protein antigen, the location of clonotypic T cells, cytokine production, cell surface markers, and apoptosis were assessed. There were distinct differences in the splenic homing of CD4(+) TCR-transgenic T cells in mice immunized with peptide as compared to mice immunized with whole-protein antigen. T cells in peptide-immunized mice were found almost exclusively in the splenic red pulp, but not in the T and B cell zones (white pulp), while the majority of T cells immunized with whole protein were found in the white pulp. Many more Fas ligand-expressing and apoptotic cells were present after peptide immunization than after whole-protein immunization. Localization of IL-4-, IL-2- and IFN-gamma-producing cells to the lymphocyte-containing splenic white pulp was only observed with whole-protein immunization. The unique homing and increased apoptosis of immune cells post peptide immunization may help explain the ineffectiveness of many peptide vaccines. Linkage of the same peptide epitope to a carrier protein increased white pulp T cell localization and decreased apoptosis, suggesting a strategy to enhance peptide vaccine responses.

A dominant negative mutant beta 2-microglobulin blocks the extracellular folding of a major histocompatibility complex class I heavy chain.

The major histocompatibility complex class I (MHC1) molecule plays a crucial role in cytotoxic lymphocyte function. beta 2-Microglobulin (beta 2m) has been demonstrated to be both a structural component of the MHC1 complex and a chaperone-like molecule for MHC1 folding. beta 2m binding to an isolated alpha 3 domain of MHC1 heavy chain at micromolar concentrations has been shown to accurately model the biochemistry and thermodynamics of beta 2m-driven MHC1 folding. These results suggested a model in which the chaperone-like role of beta 2m is dependent on initial binding to the alpha 3 domain interface of MHC1 with beta 2m. Such a model predicts that a mutant beta 2m molecule with an intact MHC1 alpha 3 domain interaction but a defective MHC1 alpha 1 alpha 2 domain interaction would block beta2m-driven folding of MHC1. In this study we generated such a beta 2m mutant and demonstrated that it blocks MHC1 folding by normal beta 2m at the expected micromolar concentrations. Our data support an initial interaction of beta 2m with the MHC1 alpha 3 domain in MHC1 folding. In addition, the dominant negative mutant beta 2m can block T-cell functional responses to antigenic peptide and MHC1.