HSP60 as a Target of Anti-Ergotypic Regulatory T Cells

The 60 kDa heat shock protein (HSP60) has been reported to influence T-cell responses in two ways: as a ligand of toll-like receptor 2 signalling and as an antigen. Here we describe a new mechanism of T-cell immuno-regulation focused on HSP60: HSP60 is up-regulated and presented by activated T cells (HSP60 is an ergotope) to regulatory (anti-ergotypic) T cells. Presentation of HSP60 by activated T cells was found to be MHC-restricted and dependent on accessory molecules - CD28, CD80 and CD86. Anti-ergotypic T cells responded to T-cell HSP60 by proliferation and secreted IFNγ and TGFβ1. In vitro, the anti-ergotypic T cells inhibited IFNγ production by their activated T-cell targets. In vivo, adoptive transfer of an anti-ergotypic HSP60-specific T-cell line led to decreased secretion of IFNγ by arthritogenic T cells and ameliorated adjuvant arthritis (AA). Thus, the presentation of HSP60 by activated T cells turns them into targets for anti-ergotypic regulatory T cells specific for HSP60. However, the direct interaction between the anti-ergotypic T regulators (anti-HSP60) and the activated T cells also down-regulated the regulators. Thus, by functioning as an ergotope, HSP60 can control both the effector T cells and the regulatory HSP60-specific T cells that control them

Genetic Covariance Structure of Reading, Intelligence and Memory in Children

This study investigates the genetic relationship among reading performance, IQ, verbal and visuospatial working memory (WM) and short-term memory (STM) in a sample of 112, 9-year-old twin pairs and their older siblings. The relationship between reading performance and the other traits was explained by a common genetic factor for reading performance, IQ, WM and STM and a genetic factor that only influenced reading performance and verbal memory. Genetic variation explained 83% of the variation in reading performance; most of this genetic variance was explained by variation in IQ and memory performance. We hypothesize, based on these results, that children with reading problems possibly can be divided into three groups: (1) children low in IQ and with reading problems; (2) children with average IQ but a STM deficit and with reading problems; (3) children with low IQ and STM deficits; this group may experience more reading problems than the other two

The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events

MHC class II-restricted recognition of activated T cells by HSP60-specific T-cells.

<p>A. Anti-ergotypic proliferative response of Anti-HSP60 or Anti-MBP T cell lines. Proliferative responses are presented as the ΔCPM±SEM of quadruplicate cultures. B. Anti-ergotypic proliferative response of Anti-p277 or Anti-MBP T cell lines. Proliferative responses are presented as the ΔCPM±SEM of quadruplicate cultures. C. Monoclonal antibodies to MHC-II/RT1.B, MHC-II/RT1.D or MHC-I were assayed for their ability to block the anti-ergotypic proliferative response of the Anti-HSP60 and the Anti-p277 T cell lines. Results are presented as the percent of inhibition of proliferation±SEM of quadruplicate cultures. D. IFNγ (IFNg), TGFβ1 (TGFb1), IL-10 and IL-4 were quantified in the culture supernatants after 72 hr of stimulation of the Anti-MBP, Anti-p277 or Anti-HSP60 T cell lines with 10⁵ activated or resting, irradiated, A2b cells per well. The results are presented as pg/ml±SEM of triplicate cultures. Three to five independent experiments produced similar results.</p

HSP60-specific Anti-ergotypic T-cells control arthritogenic T-cells <i>in vitro</i>.

<p>LNC from Mt immunized rats (2.5×10⁵ per well) were activated with Mt176-90 for 72 hr in the presence of Anti-p277 or Anti-MBP T-cells (5×10⁴ per well). The secretion of IFNγ was determined by ELISA, the results are presented as pg/ml±SEM of triplicate cultures. The differences between the groups were significant (p<0.05) for antigen concentrations higher than 0.1 µg/ml. Three independent experiments produced similar results.</p

HSP60-specific anti-ergotypic T-cells control arthritogenic T-cells <i>in vivo</i>.

<p>A and B. Anti-MBP or Anti-p277 T cells were injected ip into naïve Lewis rats and three days later AA was induced. Twenty-six days after AA induction, at the peak of AA, the AA clinical score (A) and the hind paw diameter (B) were determined. The bars represent the mean values ± SEM for each group of 8 rats. C. LNC were collected on day 26 after AA induction and the secretion of IFNγ upon stimulation with Mt176-90 was studied. The results are presented as pg/ml±SEM of triplicate cultures. Three independent experiments produced similar results. * p<0.05 and ** p<0.005 compared to the Anti-MBP group.</p