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Development of cytomegalovirus (CMV) immune recovery uveitis is associated with Th17 cell depletion and poor systemic CMV-specific T cell responses.

ABSTRACT: the immune reconstitution inflammatory syndromes (IRIS) are a spectrum of inflammatory conditions associated with opportunistic infections and occurring in approximately16% of human immunodeficiency type 1 (HIV-1)-infected patients given antiretroviral therapy. It has been proposed that these conditions are linked by a dysregulated immune system that is prone to exaggerated responses. However, immunologic studies have been limited by the availability of longitudinal samples from patients with IRIS and appropriate matched control subjects. Cytomegalovirus (CMV) immune recovery uveitis (IRU) is an IRIS occurring in up to 38% of patients with CMV retinitis. Although the pathologic immune responses occur in the eye, immune dysregulation that allows for development of pathologic responses is presumably caused by faulty systemic immune cell reconstitution.we examined CMV-specific T cell responses, regulatory T (T(reg)) cell function and polyclonal T cell responses, including IL-17 production, in 25 patients with CMV IRU and 49 immunorestored control subjects with CMV retinitis who did not develop IRU.patients with CMV IRU had poor CMV-specific CD4(+) T cell responses, as compared with control subjects, whereas CD8(+) T cell responses were comparable. Patients with CMV IRU were characterized by smaller numbers of circulating Th17 cells. Deficiency in anti-CMV responses was not associated with differences in T(reg) cell function.the T(reg) cell compartment is intact in patients with CMV IRU, and these patients do not develop exaggerated systemic CMV-specific or polyclonal immune responses. Cases are instead characterized by more profound depletion of Th17 cells and poor antiviral immune responses. CMV IRU may be most likely to develop in persons experiencing the greatest degree of immune dysfunction before initiating highly active antiretroviral therapy.

SUBMITTER: Hartigan-O'Connor DJ

PROVIDER: S-EPMC3060886 | biostudies-other | 2011 Feb

REPOSITORIES: biostudies-other

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Development of cytomegalovirus (CMV) immune recovery uveitis is associated with Th17 cell depletion and poor systemic CMV-specific T cell responses.

Hartigan-O'Connor Dennis J DJ Jacobson Mark A MA Tan Qi Xuan QX Sinclair Elizabeth E

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20101228 3

<h4>Background</h4>the immune reconstitution inflammatory syndromes (IRIS) are a spectrum of inflammatory conditions associated with opportunistic infections and occurring in approximately16% of human immunodeficiency type 1 (HIV-1)-infected patients given antiretroviral therapy. It has been proposed that these conditions are linked by a dysregulated immune system that is prone to exaggerated responses. However, immunologic studies have been limited by the availability of longitudinal samples fr ...[more]

PMID: 21189271

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Project description:BackgroundBased on sequence variation in the UL55 gene that encodes glycoprotein B (gB), human cytomegalovirus (CMV) can be classified into four gB genotypes. Previous studies have suggested an association between CMV gB genotype and clinical outcome in patients who underwent an allogeneic hematopoietic stem cell transplant (HSCT). The goals of this study were identify patients with active infection caused by CMV in recipients of HSCT; determine the prevalence of CMV genotypes in the study group; correlate genotype with CMV disease, acute GVHD and overall survival.MethodsThe diagnosis of active CMV infection after allogeneic HSCT was detected by antigenemia (AGM) and/or nested-PCR (N-PCR). Positive samples from patients with active CMV infection were submitted to genotyping using N-PCR to amplify a region of UL55, followed by restriction analysis based on HinfI and RsaI digestion. Real-time PCR (qPCR) was used to determine the viral load during active CMV infection and antiviral treatment.ResultsSixty-three allogeneic HSCT recipients were prospectively evaluated; 49/63 (78%) patients were infected with CMV genotypes - gB1 19/49 (39%), gB2 17/49 (35%), gB3 3/49 (6%), gB4 7/49 (14%) - and 3 (6%) had mixed CMV genotypes (gB1 + gB3, gB1 + gB4 and gB2 + gB4). Characterized by gastrointestinal disease, CMV disease occurred in 3/49 (6.1%) patients, who had CMV gB3 genotype. These gB3 genotype patients presented an increasing AGM number, mean 125 (± 250) (P = 0.70), and qPCR copies/ml, mean 37938 (SD ± 50542) (P = 0.03), during antiviral treatment, when compared with other CMV genotypes. According to CMV genotypes, stratified overall survival was 55% for gB1, 43% for gB2; 0% for gB3 and 57% for gB4 (P = 0.03).ConclusionsOne of the restrictions of the presented study was the low number of CMV gB sub-cohorts). However, we demonstrated that the frequency of active CMV infection in this HSCT population was high, and the most prevalent genotype in these patients with active CMV infection was gB1 and gB2 genotype (74%). In Brazil, HSCT recipients seem to carry mainly gB1 and gB2 CMV genotype.

Project description:The dynamics of recovery of cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) and its impact on controlling clinically significant CMV infections following hematopoietic stem cell transplant (HSCT) are rarely reported in pediatric HSCT recipients. In this study, dynamics of recovery of CMV-specific CMI and its clinical significance in controlling CMV viremia and clinically significant CMV infections were assessed in pediatric allogeneic HSCT recipients. All subjects underwent CMV pp65- and IE1-specific enzyme-linked immune absorbent spot (ELISPOT) assays just before transplantation and then monthly until the detection of CMV-specific CMI with ≥ 5 spot-forming cells (SFC) / 2.0 × 105 cells. Clinically significant CMV infections were defined as CMV diseases, prolonged CMV infections, recurrent CMV infections or late onset CMV infections. Among 52 recipients, 88.5% of recipients recovered CMV-specific CMI with ≥ 5 SFC/ 2.0 × 105 cells at a median of 34 days (interquartile range [IQR]: 29-95 days) following HSCT, 55.8% at 30 days following HSCT, and 73.1% at 90 days following HSCT. The presence of CMV-specific CMI before HSCT was the significant factors for the reconstitution of CMV specific CMI after HSCT (adjusted odds ratio [aOR] = 13.33; 95% confidence interval [CI] = 1.21-142.86). After HSCT, 30 recipients experienced CMV viremia, of which 20 were clinically significant CMV infections. The full recovery of CMV-specific CMI with ≥ 50 SFC / 2.0 × 105 cells after HSCT was the protective factor for the development of clinically significant CMV infections (aOR = 0.13; 95% CI = 0.22-0.71). In the haploidentical HSCT recipients, 82.1% recovered CMV-specific CMI at a median of 65 days after HSCT (IQR: 34-118 days) with a tendency to recover their CMV-specific CMI later than did those from non-haploidentical donors (65 days vs. 30 days; P = 0.001). Clinically significant CMV infections tended to occur more frequently in the haploidentical HSCT recipients compared to those with matched donor HSCT (46.4% vs. 29.2%; P = 0.205). The full recovery of CMV-specific CMI with ≥ 50 SFC/2.0 × 105 cells after HSCT also lowered the risk of development of clinically significant CMV infections (aOR = 0.08; 95% CI = 0.01-0.90). However, transplantation from haploidentical donors was a significant risk factor hampering recovery of CMV-specific CMI (aOR = 0.08; 95% CI = 0.01-0.86) and full recovery of CMV-specific CMI (aOR = 0.05; 95% CI = 0.01-0.50). Pre-transplant CMV-specific CMI influenced the recovery of CMV-specific CMI, and the full recovery of CMV-specific CMI could be a surrogate marker for preventing clinically significant CMV infections in pediatric HSCT recipients. Immunologic monitoring using ELISPOT assay before and after HSCT helps in identifying patients with a high risk of CMV infection and in controlling CMV infection.

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Development of cytomegalovirus (CMV) immune recovery uveitis is associated with Th17 cell depletion and poor systemic CMV-specific T cell responses.

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Development of cytomegalovirus (CMV) immune recovery uveitis is associated with Th17 cell depletion and poor systemic CMV-specific T cell responses.

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