CD80 and CTLA-4 as diagnostic and prognostic markers in adult-onset minimal change disease: a retrospective study
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Minimal change disease (MCD) is a form of idiopathic nephrotic syndrome. Compared to children, adult-onset MCD patients are reported to have delayed responses to glucocorticoid treatment. Several studies of children have suggested detecting urinary CD80 levels to diagnose MCD. There are no effective diagnostic methods to distinguish steroid-sensitive MCD from steroid-resistant MCD unless treatments are used.In a total of 55 patients with biopsy-proven MCD and 26 patients with biopsy-proven idiopathic membranous nephropathy, CD80 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) levels in serum, urine and renal tissue were analyzed.Steroid-sensitive MCD patients in remission had lower urinary CD80 levels and higher CTLA-4 levels than patients in relapse (156.65 ± 24.62 vs 1066.40 ± 176.76 ng/g creatinine; p < 0.0001), (728.73 ± 89.93 vs 151.70 ± 27.01 ng/g creatinine; p < 0.0001). For MCD patients in relapse, mean urinary CD80 level was higher, and CTLA-4 level was lower for those who were steroid-sensitive than those who were steroid-resistant (1066.40 ± 176.76 vs. 203.78 ± 30.65 ng/g creatinine; p < 0.0001), but the mean urinary CTLA-4 level was lower (151.70 ± 27.01 vs. 457.83 ± 99.45 ng/g creatinine; p < 0.0001). CD80 expression in glomeruli was a sensitive marker to diagnose MCD. The absent or minimal expression of CTLA-4 in glomeruli could distinguish steroid-sensitive MCD from steroid-resistant MCD.Glucocorticoid treatment may result in complete remission for only MCD patients with strongly positive CD80 expression and negative CTLA-4 expression in glomeruli, or higher urinary CD80 level and lower CTLA-4 level.Keywords:
CTLA-4
CTLA-4 is a critical gatekeeper of T-cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA-4 in SLE. Our results reveal increased CTLA-4 expression in FOXP3(-) responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA-4 was unable to regulate T-cell proliferation, lipid microdomain formation and phosphorylation of TCR-zeta following CD3/CD28 co-stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co-stimulation, there was no parallel increase in CTLA-4 expression, which would normally provide a break on T-cell proliferation. These defects were associated with exclusion of CTLA-4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA-4 dysfunction as a potential cause for abnormal T-cell activation in patients with SLE, which could be targeted for therapy.
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CTLA-4 is an inhibitory protein that contributes to immune homeostasis and tolerance, a role that has led to its exploitation as a therapeutic in several clinical settings including cancer and autoimmune disease. Development of CTLA-4 therapies focused largely on the full-length receptor isoform but other CTLA-4 isoforms are also expressed, including a secretable form of CTLA-4 (soluble CTLA-4 [sCTLA-4]). The contribution of sCTLA-4 to immune regulation has been less well studied, primarily because it was identified some years after the original description of CTLA-4. Here, we examine how sCTLA-4 might contribute to immune regulation and ask whether it might be a biomarker to inform current CTLA-4 therapies or represent a novel CTLA-4 target for future therapeutics.
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Recently, systemic administration of a human monoclonal antibody directed against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expressed on circulating T cells in patients with chronic lymphocytic leukaemia (CLL) has been considered. Also, CLL cells have been shown to express CTLA-4, increased levels of which in the leukaemic compartment are a predictor of good clinical outcome. Since both CLL and Treg microenvironment cells can be targeted by the CTLA-4 blocking antibody in this immunotherapy approach, the investigation of the functional effect of CTLA-4 blockade on CLL cells might be of potential clinical relevance. The main aim of this study was to examine the effect of CTLA-4 blockade on proliferation activity and apoptosis of CLL cells in patients with low and high CTLA-4 expression. We found that in the high CTLA-4-expressing CLL group, CTLA-4 blockade on the CLL cell surface resulted in a significant increase in the median percentages of Ki67(+) cells and a tendency to decrease in the proportion of apoptotic cells. In contrast, in the low CTLA-4 expressors, CTLA-4 blockade did not affect the proliferation activity or the frequency of apoptosis. This study reports for the first time the different effect of CTLA-4 blockade on CLL cells in CLL patients depending on the levels of CTLA-4 expression. CTLA-4 blockade seems to induce pro-survival signals in leukaemic cells from CLL patients exhibiting high CTLA-4 expression, suggesting that an immunotherapy approach based on the systemic use of monoclonal anti-CTLA-4 antibodies could be an unfavourable strategy for some CLL patients.
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Journal Article THE RELIABILITY OF DIETARY HISTORY FROM THE DISTANT PAST Get access TIM BYERS, TIM BYERS Reprint requests to Dr. Tim Byers Search for other works by this author on: Oxford Academic PubMed Google Scholar JAMES MARSHALL, JAMES MARSHALL Search for other works by this author on: Oxford Academic PubMed Google Scholar EVELYN ANTHONY, EVELYN ANTHONY Search for other works by this author on: Oxford Academic PubMed Google Scholar ROGER FIEDLER, ROGER FIEDLER Search for other works by this author on: Oxford Academic PubMed Google Scholar MARIA ZIELEZNY MARIA ZIELEZNY Search for other works by this author on: Oxford Academic PubMed Google Scholar American Journal of Epidemiology, Volume 125, Issue 6, June 1987, Pages 999–1011, https://doi.org/10.1093/oxfordjournals.aje.a114638 Published: 01 June 1987 Article history Received: 09 April 1986 Revision received: 23 September 1986 Published: 01 June 1987
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Research addressing the association between daily and retrospective symptom reports suggests that retrospective reports are typically inflated. The present study examined the association between daily posttraumatic stress disorder (PTSD) symptom reports over 1 month and a corresponding retrospective report (PTSD Checklist [PCL]; Weathers et al., 1993) for both total scores and symptom clusters. The authors hypothesized that greater PTSD symptom instability and greater depression would be associated with poorer agreement between daily and retrospective reports. Data were collected from 132 female college students who were sexually assaulted. Multilevel modeling indicated very strong agreement between mean daily and retrospective reports for total scores and symptom clusters, with pseudo-R 2 ranging from .55 to .77. Depression symptoms did not moderate this association, but daily–retrospective agreement was lowest for the avoidance cluster, which was also the most unstable. Finally, retrospective recall for each symptom cluster showed acceptable specificity to the corresponding daily symptom clusters. Overall, these findings suggest that retrospective memories for global PTSD symptoms and symptom clusters, as assessed by the PCL, are consistent with daily reports over a 1-month period. Implications for clinical assessment methodology are discussed.
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Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4),a second counterreceptor for the B7 family of costimulatory molecules,functions as a negative regulator of T-cell activation.CTLA-4 is pivotal in infections diseases and tumors,while the relationship between CTLA-4 and regulatory T cells has not been elucidated.This review summarized the concept and the function of CTLA-4,focusing its role in diseases.The relationship between CTLA-4 and regulatory T cells,as well as the prospects of CTLA-4 antibody in clinical treatment were also discussed.
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CTLA-4; Regulatory T cells; Immunology tolerance; Relationship
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Immune deficiency disorders are a heterogeneous group of diseases of variable genetic aetiology. While the hallmark of immunodeficiency is susceptibility to infection, it is increasingly clear that autoimmunity is prevalent, suggestive of a more general immune dysregulation in some cases. With the increasing use of genetic technologies, the underlying causes of immune dysregulation are beginning to emerge. Here we provide a review of the heterozygous mutations found in the immune checkpoint protein CTLA-4, identified in cases of common variable immunodeficiency disorders (CVID) with accompanying autoimmunity. Study of these mutations provides insights into the biology of CTLA-4 as well as suggesting approaches for rational treatment of these patients.
Immune Dysregulation
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Common Variable Immunodeficiency
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Primary Immunodeficiency
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Immune checkpoint
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Immune Dysregulation
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CTLA-4 blockade with monoclonal antibodies can lead to cancer regression in patients with metastatic melanoma (MM). CTLA-4 gene polymorphisms may influence the response to anti-CTLA-4 antibodies although few data are available regarding this issue. We analyzed six CTLA-4 single nucleotide polymorphisms (−1661A>G, −1577G>A, −658C>T, −319C>T, +49A>G, and CT60G>A) in 14 Italian MM patients and 45 healthy subjects. We found a significant association between the −1577G/A and CT60G/A genotypes and improved overall survival (Pc < 0.006, Bonferroni corrected), further confirmed by the diplotype analysis (−1577&CT60 GG-AA diplotype, p < 0.001). A positive trend toward an association between these genotypes and response to therapy was also observed.
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