scholarly journals Soluble CD163 Identifies Those at Risk for Increased Hepatic Inflammation & Fibrosis

2021 ◽  
Author(s):  
Kenneth E Sherman ◽  
Heidi L Meeds ◽  
Susan D Rouster ◽  
Enass A Abdel-Hameed ◽  
Jacqueline Hernandez ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Kupffer Cell ◽  
Immune Activation ◽  
Cell Activation ◽  
Drug Effects ◽  
Activation Markers ◽  
Soluble Cd163 ◽  
Systemic Immune Activation ◽  
Hcv Coinfection

Abstract Background Liver disease remains a significant cause of morbidity and mortality in HIV-infected persons. Soluble CD163 is a marker of Kupffer cell activation that is highly associated with development of hepatic fibrosis. The relative contributions of HIV-associated systemic immune activation versus other etiologies of injury are poorly characterized. Methods We utilized subjects in the Miami Adult Studies on HIV (MASH) cohort to evaluate 464 participants including 361 PLWH and 103 HCV/HIV uninfected controls. Subjects underwent testing for hepatic fibrosis using both MRE and ELF. Steatosis was evaluated by MRI-PDFF. Immune activation markers and cytokines were quantitated using Luminex methodologies. Results Participants with HIV with or without HCV coinfection had higher levels of sCD163 than uninfected controls (p<0.05). Soluble sCD163 was highly associated with elevated ALT, a key marker of inflammation/injury and with hepatic fibrosis. Hepatic steatosis was also associated with a cytokine pattern suggestive of Kupffer cell activation, but was not associated with an increase in sCD14 or sCD27. Conclusions Injury and resultant hepatic fibrosis occur by distinct though overlapping mechanistic pathways. In PLWH, sCD163 is highly associated with both injury and fibrosis suggesting that persistent systemic immune activation is a major contributor to long term outcomes, adding to damage caused by alcohol, steatosis and other hepatotoxic drug effects.

Abstract MP41: A Role Of Isolevuglandins In Systemic Lupus Erythematosus Associated Autoimmunity And Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
David M Patrick ◽  
Nestor de la Visitacion ◽  
Michelle J Ormseth ◽  
Charles Stein ◽  
Sean S Davies ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Immune Cell ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Immune Cell Activation ◽  
Systemic Immune Activation

Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions that disproportionately affect women. SLE has heterogeneous manifestations and treatment is limited to the use of non-specific global immunosuppression. Importantly, there is an increased prevalence of hypertension in women with SLE compared to healthy controls. Isolevuglandins (IsoLGs) are oxidation products of fatty acids that form as a result of reactive oxygen species. These molecules adduct covalently to lysine residues of proteins. Adducted proteins are then presented as autoantigens to T-cells resulting in immune cell activation. Previous studies have shown an essential role of IsoLGs in immune cell activation and the development of hypertension in animal models. We hypothesize that isoLGs are important for the development of hypertension and systemic immune activation in SLE. We first examined isoLG adduct accumulation within monocytes of human subjects with SLE compared to healthy controls. By flow cytometry, we found marked accumulation of isoLG adducts within CD14 + monocytes (34.2% ± 12.4% vs 3.81% ± 2.1% of CD14 + , N = 10-11, P <0.05). We confirmed this increase in isoLG adducts by mass spectrometry. To determine a causative role of isoLG adducts in immune activation and hypertension in SLE, we employed the B6.SLE123 and NZBWF1 mouse models of SLE. Animals were treated with the isoLG scavenger 2-hydroxybenzylamine (2-HOBA) or vehicle beginning at 7 weeks and were sacrificed at 32 weeks of age. C57BL/6 and NZW were used as controls. Importantly, treatment with 2-HOBA attenuated blood pressure in both mouse models (systolic BP 136.2 ± 5.6 mmHg for B6.SLE123 vs 120.9 ± 4.46 mmHg for B6.SLE123 +2HOBA; 164.7 ± 24.4 mmHg for NZBWF1 vs 136.9 ± 14.9 mmHg for NZBWF1 +2HOBA, N = 6-8, P < 0.05). Moreover, treatment with 2-HOBA reduced albuminuria and renal injury in the B6.SLE123 model (albumin/creatinine ratio 33.8 ± 2.0 x 10 -2 μg/mg for B6.SLE123 vs 5.5 ± 0.9 x 10 -2 μg/mg for B6.SLE123 +2HOBA, N = 7-9, P < 0.05). Finally, immune cell accumulation in primary and secondary lymphoid organs is significantly attenuated by 2-HOBA. These studies suggest a critical role of isoLG adduct accumulation in both systemic immune activation and hypertension in SLE.

scholarly journals Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4+T Cell Activation during Antiretroviral Treatment

2014 ◽  
Vol 88 (14) ◽  
pp. 7818-7827 ◽  
Author(s):  
Sara Gianella ◽  
Marta Massanella ◽  
Douglas D. Richman ◽  
Susan J. Little ◽  
Celsa A. Spina ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Immune Activation ◽  
Genital Tract ◽  
Cell Activation ◽  
Future Studies ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Dna Reservoir

ABSTRACTAsymptomatic cytomegalovirus (CMV) replication occurs frequently in the genital tract in untreated HIV-infected men and is associated with increased immune activation and HIV disease progression. To determine the connections between CMV-associated immune activation and the size of the viral reservoir, we evaluated the interactions between (i) asymptomatic seminal CMV replication, (ii) levels of T cell activation and proliferation in blood, and (iii) the size and transcriptional activity of the HIV DNA reservoir in blood from 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. We found that asymptomatic CMV shedding in semen was associated with significantly higher levels of proliferating and activated CD4+T cells in blood (P< 0.01). Subjects with detectable CMV in semen had approximately five times higher average levels of HIV DNA in blood CD4+T cells than subjects with no CMV. There was also a trend for CMV shedders to have increased cellular (multiply spliced) HIV RNA transcription (P= 0.068) compared to participants without CMV, but it is unclear if this transcription pattern is associated with residual HIV replication. In multivariate analysis, the presence of seminal plasma CMV (P= 0.04), detectable 2-long terminal repeat (2-LTR), and lower nadir CD4+(P< 0.01) were independent predictors of higher levels of proviral HIV DNA in blood. Interventions aimed at reducing seminal CMV and associated immune activation may be important for HIV curative strategies. Future studies of anti-CMV therapeutics will help to establish causality and determine the mechanisms underlying these described associations.IMPORTANCEAlmost all individuals infected with HIV are also infected with cytomegalovirus (CMV), and the replication dynamics of the two viruses likely influence each other. This study investigated interactions between asymptomatic CMV replication within the male genital tract, levels of inflammation in blood, and the size of the HIV DNA reservoir in 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. In support of our primary hypothesis, shedding of CMV DNA in semen was associated with increased activation and proliferation of T cells in blood and also significantly higher levels of HIV DNA in blood cells. These results suggest that CMV reactivation might play a role in the maintenance of the HIV DNA reservoir during suppressive ART and that it could be a target of pharmacologic intervention in future studies.

Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized prostate cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2563-2563
Author(s):  
Nadeem A. Sheikh ◽  
Johnna D. Wesley ◽  
Nikole Perdue ◽  
Frances P. Stewart ◽  
Lawrence Fong
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Immune Activation ◽  
Cell Activation ◽  
Localized Prostate Cancer ◽  
Cellular Immunotherapy ◽  
Activation Markers ◽  
Immune System Activation

2563 Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). NeoACT (Study P07-1) was undertaken to investigate neoadjuvant sipuleucel-T treatment in subjects with localized prostate cancer. Methods: In this open-label, phase 2 study (NCT00715104), subjects with localized prostate cancer received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to radical prostatectomy (RP). Following RP, subjects were randomized 1:1 to receive / not receive a sipuleucel-T booster infusion 12 weeks post-RP. Cellular composition, antigen presenting cell (APC) activation, cytokines, and T and B cell activation were profiled before and after each culture with PA2024, the fusion protein containing prostatic acid phosphatase used to generate sipuleucel-T. Results: Of the 42 enrolled subjects (median age: 61 years; 98% Caucasian), 38 received all 3 infusions of sipuleucel-T, and 15 subjects received a booster infusion. Consistent with sipuleucel-T in mCRPC, CD54 upregulation (APC activation) was greater at the second and third infusions relative to the first (p<0.001). The expression of early T cell activation markers (CD134, CD137, CD278 and CD279) were increased in pre-culture cells obtained after the first infusion, and further increased after culture. Activated mature B cells (CD20+CD27+IgD+CD86+) increased following culture in all 3 products (p<0.01); memory B cells (CD20+CD27+IgD-CD86+) were progressively increased following the first infusion (p<0.05 third vs. first product). TNF-α, IFN-γ, IL-2 were secreted at higher levels during culture of the second and third products (all p<0.001). The observed increases in CD54 upregulation, early T cell activation markers, and memory and activated mature B cells were maintained at booster treatment. Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune system activation that was consistent with boosting of an immune response primed with the first infusion. Immune activation was maintained at the booster infusion 3 months following initial sipuleucel-T treatment.

scholarly journals The Effect of Rosuvastatin on Markers of Immune Activation in Treatment-Naive Human Immunodeficiency Virus-Patients

2015 ◽  
Vol 3 (1) ◽  
Author(s):  
Robyn G. M. Weijma ◽  
Eric R. A. Vos ◽  
Jaap Ten Oever ◽  
Muriel Van Schilfgaarde ◽  
Lea M. Dijksman ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Activation Markers ◽  
Cell Ratio ◽  
Immunodeficiency Virus ◽  
Treatment Naïve

Abstract Background.  Immune activation has been implicated in the excess mortality in human immunodeficiency virus (HIV)-infected patients, due to cardiovascular diseases and malignancies. Statins may modulate this immune activation. We assessed the capacity of rosuvastatin to mitigate immune activation in treatment-naive HIV-infected patients. Methods.  In a randomized double-blind placebo-controlled crossover study, we explored the effects of 8 weeks of rosuvastatin 20 mg in treatment-naive male HIV-infected patients (n = 28) on immune activation markers: neopterin, soluble Toll-like receptor (TLR)2, sTLR4, interleukin (IL)-6, IL-1Ra, IL-18, d-dimer, highly sensitive C-reactive protein, and CD38 and/or human leukocyte antigen-DR expression on T cells. Baseline data were compared with healthy male controls (n = 10). Furthermore, the effects of rosuvastatin on HIV-1 RNA, CD4/CD8 T-cell count, and low-density lipoprotein cholesterol were examined and side effects were registered. Results.  T-cell activation levels were higher in patients than in controls. Patients had higher levels of circulating IL-18, sTLR2, and neopterin (all P &lt; .01). Twenty patients completed the study. Rosuvastatin increased the CD4/CD8 T-cell ratio (P = .02). No effect on other markers was found. Conclusions.  Patients infected with HIV had higher levels of circulating neopterin, IL-18, sTLR2, and T-cell activation markers. Rosuvastatin had a small but significant positive effect on CD4/CD8 T-cell ratio, but no influence on other markers of T-cell activation and innate immunity was identified (The Netherlands National Trial Register [NTR] NTR 2349, http://www.trialregister.nl/trialreg/index.asp).

Soluble CD163, a marker of Kupffer cell activation, is related to portal hypertension in patients with liver cirrhosis

2012 ◽  
Vol 36 (2) ◽  
pp. 173-180 ◽  
Author(s):  
H. Grønbaek ◽  
T. D. Sandahl ◽  
C. Mortensen ◽  
H. Vilstrup ◽  
H. J. Møller ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Kupffer Cell ◽  
Cell Activation ◽  
Soluble Cd163

Soluble CD163 (sCD163): Biomarker of Kupffer Cell Activation in Liver Disease

2017 ◽  
pp. 321-348
Author(s):  
Holger Jon Møller ◽  
Konstantin Kazankov ◽  
Sidsel Rødgaard-Hansen ◽  
Marlene Christina Nielsen ◽  
Thomas D. Sandahl ◽  
...  
Keyword(s):  
Liver Disease ◽  
Kupffer Cell ◽  
Cell Activation ◽  
Soluble Cd163

Soluble CD163 (sCD163): Biomarker of Kupffer Cell Activation in Liver Disease

2016 ◽  
pp. 1-28 ◽  
Author(s):  
Holger Jon Møller ◽  
Konstantin Kazankov ◽  
Sidsel Rødgaard-Hansen ◽  
Marlene Christina Nielsen ◽  
Thomas D. Sandahl ◽  
...  
Keyword(s):  
Liver Disease ◽  
Kupffer Cell ◽  
Cell Activation ◽  
Soluble Cd163
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