Knocking out of CD38 accelerates development of a lupus-like disease in lpr mice

Viegas, Marta S.; Silva, Teresa; Monteiro, Maria M; Carmo, Anália do; Martins, Teresa

doi:10.1093/rheumatology/ker178

Cited by 16 publications

(15 citation statements)

References 26 publications

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“…Our data showed that CD38 − / − mice presented glomerular thickening, mesangial proliferation and tubular occlusion at 16 months of age (Figure B‐C). These findings correlate with previous reports from CD38 − / − mice backcrossed with a susceptible genetic background that developed a lupus‐like disease, and those Cd38 −/− ‐Fas lpr /Fas lpr presented severe glomerulonephritis and deposition of immune complexes at 6 months of age . Considering these results, we propose that CD38 could play a role in the control of the autoimmune development and autoantibody production.…”

Section: Discussionsupporting

confidence: 91%

“…We evaluated the presence of anti‐dsDNA and ANAs autoantibodies in CD38 − / − mice at 4, 6, 8, 10, 12, 14 and 16 months of age, and no significant differences in the levels of anti‐dsDNA antibodies were observed in CD38 − / − mice from 4 to 10 months old (Figure B). These results correlate with previous reports for CD38 − / − mice in a genetic background susceptible to develop a lupus‐like disease, in which it is reported that there is no increase in anti‐dsDNA antibodies at 6 months of age . Interestingly, after the 12th month, CD38 − / − mice showed an increase in the levels of anti‐dsDNA, which was more evident at 14 and 16 months of age (Figure B‐C).…”

Section: Discussionsupporting

confidence: 91%

“…It has been reported that systemic autoimmune diseases are characterized by kidney damage. Continued stimulation of autoantibodies triggers inflammatory responses by effector cells culminating in tissue destruction and pathological manifestations of disease in the kidneys . We decided to determine whether the autoantibody levels produced by the CD38 −/− correlated with kidney damage.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, in collagen‐induced arthritis (CIA), autoantibodies are increased in CD38 −/− mice . Finally, a CD38 deficiency accelerated the development of a lupus‐like disease in Cd38 −/− ‐Fas lpr /Fas lpr . In all these reports, the development of autoimmunity was exacerbated when CD38 was deficient, suggesting a relationship between CD38 and the disease.…”

Section: Introductionmentioning

confidence: 96%

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CD38 protein deficiency induces autoimmune characteristics and its activation enhances IL‐10 production by regulatory B cells

et al. 2018

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CD38 is a transmembrane protein expressed in B lymphocytes, and is able to induce responses as proliferation, differentiation or apoptosis. Several reports propose that CD38 deficiency accelerates autoimmune processes in murine models of autoimmune diabetes, lymphoproliferation and rheumatoid arthritis. Other reports have shown elevated CD38 expression in B and T cells from patients with autoimmunity; however, the role of CD38 is still unclear in the development of autoimmunity. Recently, it has been characterized as CD1d CD5 regulatory B cell subpopulation able to produce IL-10, and the loss of these cells exacerbates the autoimmunity in murine models. Here, we report that CD38 mice exhibited elevated titres of ANAS, anti-dsDNA autoantibodies from 12 months of age and were higher by 16 months of age and mice presented kidney damage. Interestingly, there is a reduction in the survival of CD38 mice compared to the WT. Furthermore, CD38 is highly expressed by CD1d CD5 regulatory B cells, and the agonistic anti-CD38 stimulus plus LPS was able to increase the percentage of this cell subset and its ability to induce IL-10 production. Together, these results suggest that CD38 could play a role in the control of autoimmune diseases through their expression on regulatory B cells.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

See 2 more Smart Citations

CD38 protein deficiency induces autoimmune characteristics and its activation enhances IL‐10 production by regulatory B cells

et al. 2018

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“…Although CD38 has been used extensively to classify various subpopulations of lymphocytes, in recent years, several publications also have linked CD38 with different pathologies, including autoimmune diseases. Indeed, apoptotic effect mediated by CD38 in immature cells is well described and absence of CD38 in lpr mice has been associated with an accelerated development of a lupus-like disease [17]. Furthermore, an increased acquisition of CD38 expression on memory B cells along with the expansion of plasmablasts observed in active SLE patients further supports the hypothesis of a stronger stimulation on SLE B cells and the subsequent generation of plasmablasts in active disease.…”

Section: Discussionmentioning

confidence: 77%

CD38, CD81 and BAFFR combined expression by transitional B cells distinguishes active from inactive systemic lupus erythematosus

Henriques

Silva²,

Inês

et al. 2015

Clin Exp Med

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In view of its heterogeneous presentation and unpredictable course, clinical management of systemic lupus erythematosus (SLE) is difficult. There is a need for biomarkers and diagnostic aids to monitor SLE disease activity and severity prior to, during and after treatment. We undertook this study to search for unique phenotypic patterns in each peripheral blood (PB) B cell subset, capable of distinguishing SLE patients with inactive disease versus SLE patients with active disease versus controls by using an automated population separator (APS) visualization strategy. PB was collected from 41 SLE patients and 28 age- and gender-matched controls. We analyzed the cell surface markers (in a tube CD20/CD27/CD19/CD45/CD38/CD81/BAFFR combination) expression on PB B cell subsets using principal component analysis, implemented in the APS software tool. Overall, our analysis indicates that active SLE can be distinguished from inactive SLE on the basis of a single tube analysis, focused on the decreased expression of CD38, CD81 and BAFFR in transitional B cells. The cluster analysis of immunophenotypic profiles of B cell subsets highlighted disease-specific abnormalities on transitional B cells that emerge as promising surrogate markers for disease activity. Further validation is needed with larger samples and prospective follow-up of patients.

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The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections

et al. 2020

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Graphical Abstract Highlights d Expanded CD8CD38 high T cells in SLE patients identify patients with infections d CD8CD38 high T cells express decreased amounts of cytotoxic molecules d CD38 decreases NAD + and SIRT1 activity and releases the activity of EZH2 d Inhibition of EZH2 restores the degranulation capacity of CD8CD38 high T cells In Brief Katsuyama et al. find that an expanded CD8CD38 high T cell population in SLE patients is linked to infections. CD8CD38 high T cells display decreased cytotoxic capacity by suppressing the expression of related molecules through an NAD + /Sirtuin1/EZH2 pathway. EZH2 inhibitors increase cytotoxicity offering a means to mitigate infection rates in SLE. SUMMARYPatients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38 high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38 high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38 high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.

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Knocking out of CD38 accelerates development of a lupus-like disease in lpr mice

Abstract: Although the role of CD38 in tolerance is still to be elucidated, we provide evidence that it may play an active role in the control of a murine lupus-like disease.

Cited by 16 publications

References 26 publications

CD38 protein deficiency induces autoimmune characteristics and its activation enhances IL‐10 production by regulatory B cells

CD38 protein deficiency induces autoimmune characteristics and its activation enhances IL‐10 production by regulatory B cells

CD38, CD81 and BAFFR combined expression by transitional B cells distinguishes active from inactive systemic lupus erythematosus

The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections

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