Defects in Regulation of Local Immune Responses Resulting in Atherosclerosis

Atherosclerosis is nowadays generally accepted as an inflammatory disease but the mechanism of its origin and development have not yet been fully clarified. The present review focuses on the role of the local immune system as one of the key players in the pathogenesis of the complex process. Its part represented by vascular-associated lymphoid tissue (VALT) within the arterial wall participates directly in the vascular wall's homeostatis. Its inordinate activation during ontogenic development of an individual, this formerly defensive and physiologic mechanism transform into a pathological process resulting in an impairing inflammation. Hsp60, CRP and oxidized or otherwise modified LDL are serious candidates for triggering these pathological changes. The principal role is played by anti-Hsp60 antibodies and by shear stress originating on the surface of endothelium due to blood flow. The experimental and clinical data supporting this immunological hypothesis of atherosclerosis are discussed

Long-Term Consequences of Fetal Angiotensin II Receptor Antagonist Exposure

Fetal angiotensin II receptor antagonist exposure is associated with major complications and even death when administered during pregnancy. Neonates frequently require intensive care treatment, and mortality is high. Despite this well-known risk potential, a considerable number of women still receive angiotensin II receptor antagonists during pregnancy to treat arterial hypertension. Although clinical symptoms in the neonatal period are well described, few reports address long-term follow-up after fetal exposure to angiotensin II receptor antagonists. We here report on a patient who was unwittingly exposed to olmesartan medoxomil during pregnancy. After birth, the neonate presented with mild clinical symptoms, mainly affecting the kidneys. However, neurodevelopmental follow-up revealed a delay in motor development with muscular hypotonia and failure to thrive at age 2 years. This case highlights the fact that, despite not causing neurological symptoms in the neonatal period, fetal angiotensin II receptor antagonist exposure during pregnancy might lead to neurodevelopmental impairment in later life

Lymphoid neogenesis in chronic rejection: Evidence for a local humoral alloimmune response

Recent advances indicate that, in various chronic inflammatory disorders, the activation of the immune system is triggered locally rather than in lymphoid organs. In this study, we have evaluated whether the humoral alloimmune response involved in chronic rejection is elicited within the graft. We used the rat aortic interposition model and microdissected the adventitia of the graft. Over time, the T cell infiltrate shifted toward a B helper phenotype. B lymphocyte clusters were detected and were the site of intense proliferation and apoptosis. Simultaneously, adventitial vascular endothelium acquired a high endothelial venule phenotype. Similar features were evidenced in the interstitium of chronically allografts (hearts and kidneys). Strikingly, ganocultured graft interstitial tissue was found to be the site of production of antibodies directed against donor MHC-I molecules. These findings, therefore, document the appearance of germinal centers in chronically rejected tissues. This lymphoid neogenesis implies that the graft is not only the target of the alloimmune response but also a site where this response actually develops, so as to optimize the communication between the targeted tissue and the immune effectors

Spatial Differences in the Presence of FOXP3+ and GranzymeB+ T Cells between the Intra- and Extravascular Compartments in Renal Allograft Vasculopathy

BACKGROUND: Allograft vasculopathy (AV) and native atherosclerosis (NA) share the presence of a T-cell mediated inflammatory response, but differ in overall plaque morphology and growth rate. We studied the distribution and frequency of regulatory- and cytotoxic T cells in the arterial intima lesions in both conditions. METHODOLOGY/PRINCIPAL FINDINGS: The study is based on vessels of 15 explanted human renal allografts with AV and 10 carotid artery plaques obtained at surgery. Distribution and frequency of cytotoxic- and regulatory T cells, as identified by the expression of Granzyme B (GrB) and FOXP3 was established in NA and AV. Furthermore, we compared the distribution of these cells in AV with the perivascular, interstitial renal tissue using immunohistochemistry. The total number of T cells was much higher in AV than in NA lesions (711±135 and 37±8 CD3/mm(2) respectively, p<0.005, mean, ± SEM). Total numbers of FOXP3(+) regulatory cells were also significantly increased in AV (36±10 and 0.9±0.3 FOXP3(+)/mm(2) p<0.05), but relative numbers, expressed as a percentage of the total number of CD3(+) T cells ((FOXP3(+)/CD3(+)) ×100), were not significantly different (4.6%±0.9 and 2.7%±0.6). GrB(+) cells were rare in NA, but significantly increased numbers of GrB(+) cells were found in AV lesions (85±24 and 0.2±0.1 GrB(+)/mm(2), p<0.05). Perivascular tissues in the allografts showed a higher relative frequency of FOXP3(+) cells than adjacent intimal lesions (14.0%±2.7 and 4.6%±0.9, respectively, p<0.05), but a lower frequency of GrB(+) cytotoxic T cells (16.1%±2.7 and 22.6%±3.6, p<0.05). CONCLUSIONS: Similar to NA, AV is characterized by a low frequency of intimal FOXP3(+) regulatory T cells. Moreover, significant spatial differences exist in the distribution of functional T cell subsets between the intra- and extravascular micro-environments of the graft