The Impact of T Cell Intrinsic Antigen Adaptation on Peripheral Immune Tolerance

Overlapping roles have been ascribed for T cell anergy, clonal deletion, and regulation in the maintenance of peripheral immunological tolerance. A measurement of the individual and additive impacts of each of these processes on systemic tolerance is often lacking. In this report we have used adoptive transfer strategies to tease out the unique contribution of T cell intrinsic receptor calibration (adaptation) in the maintenance of tolerance to a systemic self-antigen. Adoptively transferred naïve T cells stably calibrated their responsiveness to a persistent self-antigen in both lymphopenic and T cell–replete hosts. In the former, this state was not accompanied by deletion or suppression, allowing us to examine the unique contribution of adaptation to systemic tolerance. Surprisingly, adapting T cells could chronically help antigen-expressing B cells, leading to polyclonal hypergammaglobulinemia and pathology, in the form of mild arthritis. The helper activity mediated by CD40L and cytokines was evident even if the B cells were introduced after extended adaptation of the T cells. In contrast, in the T cell–replete host, neither arthritis nor autoantibodies were induced. The containment of systemic pathology required host T cell–mediated extrinsic regulatory mechanisms to synergize with the cell intrinsic adaptation process. These extrinsic mechanisms prevented the effector differentiation of the autoreactive T cells and reduced their precursor frequency, in vivo

CO(2) laser treatment of laryngeal stenoses after reconstructive laryngectomies with cricohyoidopexy, cricohyoidoepiglottopexy or tracheohyoidoepiglottopexy.

Supracricoid laryngectomy with cricohyoidopexy (CHP) or cricohyoidoepiglottopexy (CHEP) is a conservative laryngeal surgery tailored to T1b-T2-T3 glottic-supraglottic carcinomas. Tracheohyoidopexy (THP) and tracheohyoidoepiglottopexy (THEP) allow a chance of conservative surgery also for selected transglottic carcinomas. These techniques are comprehensively named reconstructive laryngectomies (RLs). Post RL laryngeal stenosis not due to carcinoma persistence or recurrence is an unusual occurrence. The aim of the present study has been to analyse retrospectively and describe the treatment of the cases of laryngeal stenosis after RL, which occurred in Vittorio Veneto Otolaryngological Department in a 6 year period. In the period between 1999 and 2004, 225 patients underwent RL in our Department. In 18 of them (8%) a laryngeal stenosis after RL was diagnosed. The same evidence was shown in 2 patients who underwent RL in other Institutions. All patients underwent CO(2) laser surgical treatment of the laryngeal stenosis. The 14 patients who underwent RL-CHEP, the 5 patients who underwent THEP and the patient who underwent CHP were treated on average with CO(2) laser 1.2 (range 1-2), 4.2 (range 2-7), and 2 times, respectively. Decannulation was possible in all patients but one after CO(2) laser treatment of the stenosis in a mean period of 3.4 months. Laryngeal stenoses after RLs can be successfully treated with CO(2) laser excision with a very limited morbility. The only reasonable contra-indication to CO(2) laser excision could be a cranio-caudal length of the laryngeal stenotic tract longer than 1 cm: in this occurrence diagnosed after THP or THEP, an external surgical approach could be preferred

The arthritogenic T cell receptor and its ligand in a model of spontaneous arthritis

International audienc

Different modes of pathogenesis in T-cell-dependent autoimmunity: clues from two TCR transgenic systems

International audienceT lymphocytes constantly flirt with reactivity to self peptides, a price they pay for their ability to recognize foreign peptides presented by self-MHC molecules, and autoreactivity in the T compartment occasionally gives rise to autoimmune disease. Pathology from T-cell autoimmunity can manifest itself through radically different strategies, as we have observed recently in two transgenic models. In the BDC2.5 diabetes model, T cells express a transgene-encoded T-cell receptor (TCR) with reactivity against a pancreatic antigen. This leads to a massive, if often controlled, infiltration of the pancreatic islets. Target cell destruction then results from the local consequences of this local immune/inflammatory process. On the other hand, the arthritic manifestations of the KRN transgenic model are indirect: the transgenic TCR confers a broad autoreactivity, through which T cells stimulate B cells to produce arthritogenic immunoglobulins. These molecules are then sufficient to produce the disease, even in the complete absence of any lymphocytes. Although important questions subsist in this model--how the KRN T cells interfere with B-cell tolerance, what the target of arthritogenic IgG is--its implication is that an isolated T-cell dysregulation may manifest itself through an Ig-mediated disease