Biomedical subjects

Ruth Y Lan

Publications and source records attributed to Ruth Y Lan.

4 recordsLinked to original sources

PubMed2006

Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis.

CD4+CD25high regulatory T cells (Tregs) play a critical role in self-tolerance, as seen in murine autoimmunity. Studies on Tregs in human autoimmunity have focused primarily on peripheral blood samples. A study targeting diseased tissue should identify direct relationships between Tregs and autoimmunity. Peripheral blood samples were collected from 91 patients with primary biliary cirrhosis (PBC), 28 immediate relatives, and 41 healthy controls, and Treg frequencies were determined as a percentage of CD4+CD25high T cells in CD4+TCR-alphabeta+ T cells. A tissue-targeted determination of frequency and distribution of FoxP3+ Tregs was also performed on 90 different liver tissue specimens exhibiting PBC (n = 52), chronic hepatitis C (CHC) (n = 30), and autoimmune hepatitis (AIH) (n = 8). Treg suppression studies were performed on 50 PBC patients and 27 controls. Patients with PBC demonstrated a relative reduction of Tregs compared with controls (P < .0002). Interestingly, a deficiency in CD4+CD25+ Tregs was also found in the daughters and sisters of PBC patients compared with controls (P < .0007). However, functional studies did not reveal a global PBC Treg defect. The level of FoxP3-expressing Tregs was markedly lower in affected PBC portal tracts compared with CHC and AIH (P < .001). In addition, the CD8+T cell/FoxP3+ Treg ratio was significantly higher in livers of late-stage PBC compared with those of CHC (P < .001) and early-stage AIH (P < .001). In conclusion, these data provide support for a genetic modulation of Treg frequency and illustrate the role Tregs play in the loss of tolerance in PBC.

Autoimmunity↗

PubMed2006

IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis.

Recently, we identified a child born with a genetic deficiency of IL-2 receptor alpha (IL-2Ralpha, CD25) expression who had several clinical manifestations of primary biliary cirrhosis (PBC). In addition, there has been suggestive evidence in both patients with PBC and their first-degree relatives that a deficiency of regulatory T cells (Tregs) is an integral component for susceptibility to PBC. Based on these observations, we generated IL-2Ralpha/CD25 deficient (IL-2Ralpha(-/-)) mice and wild-type littermate controls and followed them longitudinally for the natural history of liver immunopathology and appearance of antimitochondrial antibodies (AMAs). The analyses included immunohistochemical staining of liver and portal tract infiltrates as well as FACS profiles of lymphoid subpopulations in liver and spleen. In addition, serum cytokine profiles were quantitated. Importantly, IL-2Ralpha(-/-), but not littermate controls, develop portal inflammation and biliary ductular damage similar to human patients with PBC. CD4(+) and CD8(+) T cells predominate among portal cell infiltrates and sera reflect a Th1 cytokine bias with increased levels of IFN-gamma, TNF-alpha, IL-2 and IL-12p40. Of importance is the finding that the IL-2Ralpha(-/-) mice not only develop significantly increased serum levels of IgG and IgA, but they also develop AMAs with specificity for PDC-E2, which maps to the inner lipoyl domain of the autoantigen, all characteristics which are hallmarks of human PBC. In conclusion, the IL-2Ralpha(-/-) mice should facilitate studies of the early events in PBC and especially the tantalizing connection between Treg deficiency and autoimmunity specifically directed to mitochondrially located PDC-E2 and subsequent biliary ductular cell damage.

Animals↗

PubMed2005

Increased levels of chemokine receptor CXCR3 and chemokines IP-10 and MIG in patients with primary biliary cirrhosis and their first degree relatives.

Infiltrating memory T cells play an important role in the destruction of the biliary tract in primary biliary cirrhosis (PBC) and inflammatory chemokines control lymphocyte traffic through their interactions with T cell chemokine receptors. In the present study, we measured plasma levels of chemokines interferon-gamma-inducible protein-10 (IP-10) and monokine induced by gamma interferon (MIG), and also studied the expression of CXCR3 chemokine receptors in 105 subjects, including 53 patients with PBC, 26 first degree relatives and 26 healthy controls. Interestingly, plasma IP-10 and MIG levels in PBC were increased significantly compared to controls and appeared to increase with disease progression. By immunohistochemistry, IP-10 and MIG expressions were evident in the portal areas in PBC. Further, the frequency of CXCR3-expressing cells in peripheral blood was also significantly higher in PBC, and CXCR3-positive cells were also found in the portal areas of diseased livers, primarily on CD4+ cells. Finally, the daughters and sisters of PBC patients also demonstrated increased plasma levels of IP-10 and MIG, but, in contrast, displayed normal frequency of CXCR3+ expressing peripheral blood lymphocytes. Our data imply a role for specific chemokine-chemokine receptor interactions in the pathogenesis of PBC and also highlight the familial risk factor.

Adult↗

PubMed2005

Regulatory T cells: development, function and role in autoimmunity.

The crucial role of regulatory cells in self-tolerance and autoimmunity has been clearly established in numerous types of regulatory cells, the majority of which are CD4(+) T cells. Much focus has been placed on thymically derived CD4(+)CD25(+) regulatory T cells, given that the depletion of this subset in murine models results in the spontaneous development of autoimmune diseases. These naturally occurring regulatory T cells are found to be functionally mature in the thymus, and exert suppression in a contact-dependent manner. Another important category of immunosuppressive cells consists of conditionally induced regulatory T cells such as Tr1, Th3, and various other CD4(+) lymphocytes. Understanding the development and regulatory functions of immunoregulatory cells may elucidate the etiology for loss of self-tolerance. This review will summarize the characteristics, developmental pathways, and functions of regulatory T cells, as well as their role in human autoimmune diseases including multiple sclerosis, rheumatoid arthritis, Myasthenia Gravis, Kawasaki disease, autoimmune polyglandular syndrome type II, type 1 diabetes, autoimmune lymphoproliferative syndrome, and systemic lupus erythematosus.

Autoimmune Diseases↗