Decoupling activation and exhaustion of B cells in spontaneous controllers of HIV infection

Sciaranghella, Gaia; Tong, Neath; Mahan, Alison E.; Suscovich, Todd J.; Alter, Galit

doi:10.1097/qad.0b013e32835bd1f0

Cited by 35 publications

(39 citation statements)

References 20 publications

(39 reference statements)

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“…Nevertheless, systemic accumulation of B-cells with CD27+CD21 low phenotype, e.g. during chronic viral infections, is also considered as a sign of aberrant B-cell activation and dysfunction within the memory compartment [21,30]. In this study we observed very similar B-cell changes in LN patients.…”

Section: Discussionsupporting

confidence: 77%

Changes of memory B- and T-cell subsets in lupus nephritis patients

Kosałka

Jakieła

Musiał

2015

Folia Histochem Cytobiol.

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Introduction. Renal involvement in systemic lupus erythematosus (SLE) is associated with production of antibodies to double stranded DNA, deposition of immune complexes and organ damage. These processes have been linked with abnormalities in B-and T-cell memory compartments. The aim of the study was to analyze subsets of peripheral memory B-cells and T-cells in lupus nephritis (LN) patients. Material and methods. We used multicolor flow cytometry to analyze major memory subsets of peripheral blood B-cells (defined by CD27, IgD and CD21) and T-cells (CD45RA, CD45RO, CCR7) in 32 patients with active or inactive LN, and 23 control subjects. Results. Lupus nephritis patients were characterized by increased percentage of immature/early-transitional B-cells (CD27-IgD+CD21-), higher frequency of activated switched memory (SM, CD27+IgD-CD21-) and exhausted memory B-cells (CD27-IgD-), and decrease in non-switched memory (NSM, CD27+IgD+) B-cells. CD21 low subsets (immature and activated B-cells) were particularly expanded in patients with active disease. In both groups of LN patients we observed decline in the absolute count of NSM B-cells. It was paralleled by lymphopenia in naïve CD4+ T-cell compartment and increase in the frequency of effector memory T-cells, and these changes were more pronounced in active LN. Conclusions. B-cell memory compartment in LN is deficient in NSM cells and during active disease it is further skewed towards SM and exhausted memory phenotypes, most likely as a cause of chronic antigenic stimulation. Parallel changes in T-helper cell subsets suggest a similar mechanism of SLE-related lymphopenia for both B-cell and T-cell compartment.

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Section: Discussionsupporting

confidence: 77%

Changes of memory B- and T-cell subsets in lupus nephritis patients

Kosałka

Jakieła

Musiał

2015

Folia Histochem Cytobiol.

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“…On the other hand, CD21 expression on previously CD21 þ B cells might become downregulated or silenced, indicating hyperactivated B cells. This cell type has been referred to as exhausted B cells because of its hypoproliferative behavior [42]. Similar findings were obtained in systemic lupus erythematosus (SLE) patients with abnormally low CD21 expression compared with healthy individuals [43].…”

Section: Discussionmentioning

confidence: 64%

CD19+CD21low B Cells and CD4+CD45RA+CD31+ T Cells Correlate with First Diagnosis of Chronic Graft-versus-Host Disease

Greinix

Kuzmina

Weigl

et al. 2015

Biology of Blood and Marrow Transplantation

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Chronic graft-versus-host disease (cGVHD) is a serious and frequent complication of allogeneic hematopoietic stem cell transplantation (HCT). Currently, no biomarkers for prediction and diagnosis of cGVHD are available. We performed a large prospective study focusing on noninvasive biomarkers for National Institutes of Health-defined cGVHD patients (n = 163) in comparison to time-matched HCT recipients who never experienced cGVHD (n = 64), analyzed from day 100 after HCT. In logistic regression analysis, CD19(+)CD21(low) B cells (P = .002; hazard ratio [HR], 3.31; 95% confidence interval [CI], 1.53 to 7.17) and CD4(+)CD45RA(+)CD31(+) T cells (P < .001; HR, 3.88; 95% CI, 1.88 to 7.99) assessed on day 100 after HCT were significantly associated with subsequent development of cGVHD, independent of clinical parameters. A significant association with diagnosis of cGVHD was only observed for CD19(+)CD21(low) B cells (P = .008; HR, 3.00; 95% CI, 1.33 to 6.75) and CD4(+)CD45RA(+)CD31(+) T cells (P = .017; HR, 2.80; 95% CI, 1.19 to 6.55). CD19(+)CD21(low) B cells were found to have the highest discriminatory value with an area under the receiver operating curve of .77 (95% CI, .64 to .90). Our results demonstrate that CD19(+)CD21(low) B cells and CD4(+)CD45RA(+)CD31(+) T cells are significantly elevated in patients with newly diagnosed cGVHD.

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“…Surprisingly, perturbation of global plasma IgG glycosylation was apparent even during acute infection, indicating that despite the long plasma half-life of IgG, infection rapidly impacts the composition, and therefore activity, of the antibody compartment. Furthermore, although elite controllers durably maintain HIV replication to undetectable levels and exhibit low-level systemic immune activation (23,24), the shift toward agalactosylated glycans was even more pronounced in these individuals compared with that in both treated and untreated chronically infected subjects ( Figure 1D), suggesting that unlike the T cell compartment, the B cell compartment in elite controllers is inflamed (25), resulting in the production of antibodies with altered glycan composition. However, despite this change, the increase in G0 could not explain the difference in ADCVI activity among infected subject groups.…”

Section: Antiviral Effector Activity Of Antibodies From Hiv-infected mentioning

confidence: 99%

Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity

Ackerman

Crispin²,

Yu³

et al. 2013

J. Clin. Invest.

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313

349

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While the induction of a neutralizing antibody response against HIV remains a daunting goal, data from both natural infection and vaccine-induced immune responses suggest that it may be possible to induce antibodies with enhanced Fc effector activity and improved antiviral control via vaccination. However, the specific features of naturally induced HIV-specific antibodies that allow for the potent recruitment of antiviral activity and the means by which these functions are regulated are poorly defined. Because antibody effector functions are critically dependent on antibody Fc domain glycosylation, we aimed to define the natural glycoforms associated with robust Fc-mediated antiviral activity. We demonstrate that spontaneous control of HIV and improved antiviral activity are associated with a dramatic shift in the global antibody-glycosylation profile toward agalactosylated glycoforms. HIV-specific antibodies exhibited an even greater frequency of agalactosylated, afucosylated, and asialylated glycans. These glycoforms were associated with enhanced Fc-mediated reduction of viral replication and enhanced Fc receptor binding and were consistent with transcriptional profiling of glycosyltransferases in peripheral B cells. These data suggest that B cell programs tune antibody glycosylation actively in an antigen-specific manner, potentially contributing to antiviral control during HIV infection.

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Decoupling activation and exhaustion of B cells in spontaneous controllers of HIV infection

Cited by 35 publications

References 20 publications

Changes of memory B- and T-cell subsets in lupus nephritis patients

Changes of memory B- and T-cell subsets in lupus nephritis patients

CD19+CD21low B Cells and CD4+CD45RA+CD31+ T Cells Correlate with First Diagnosis of Chronic Graft-versus-Host Disease

Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity

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