OP0119 The CRL4 Cereblon E3 Ubiquitin Ligase Modulator CC-220 Induces Degradation of the Transcription Factors Aiolos and Ikaros: Immunomodulation in Healthy Volunteers and Relevance to Systemic Lupus Erythematosus

ObjectivesIKZF1 and IKZF3 (encoding transcription factors Ikaros and Aiolos) are susceptibility loci for systemic lupus erythematosus (SLE). The pharmacology of iberdomide (CC-220), a cereblon (CRBN) modulator targeting Ikaros and Aiolos, was studied in SLE patient cells and in a phase 1 healthy volunteer study.MethodsCRBN, IKZF1 and IKZF3 gene expression was measured in peripheral blood mononuclear cells (PBMC) from patients with SLE and healthy volunteers. Ikaros and Aiolos protein levels were measured by Western blot and flow cytometry. Anti-dsDNA and anti-phospholipid autoantibodies were measured in SLE PBMC cultures treated for 7 days with iberdomide. Fifty-six healthy volunteers were randomised to a single dose of iberdomide (0.03–6 mg, n=6 across seven cohorts) or placebo (n=2/cohort). CD19+ B cells, CD3+ T cells and intracellular Aiolos were measured by flow cytometry. Interleukin (IL)-2 and IL-1β production was stimulated with anti-CD3 and lipopolysaccharide, respectively, in an ex vivo whole blood assay.ResultsSLE patient PBMCs expressed significantly higher CRBN (1.5-fold), IKZF1 (2.1-fold) and IKZF3 (4.1-fold) mRNA levels compared with healthy volunteers. Iberdomide significantly reduced Ikaros and Aiolos protein levels in B cells, T cells and monocytes. In SLE PBMC cultures, iberdomide inhibited anti-dsDNA and anti-phospholipid autoantibody production (IC50 ≈10 nM). Single doses of iberdomide (0.3–6 mg) in healthy volunteers decreased intracellular Aiolos (minimum mean per cent of baseline: ≈12%–28% (B cells); ≈0%–33% (T cells)), decreased absolute CD19+ B cells, increased IL-2 and decreased IL-1β production ex vivo.ConclusionsThese findings demonstrate pharmacodynamic activity of iberdomide and support its further clinical development for the treatment of SLE.Trial registration numberNCT01733875; Results.

Download Full-text

Faculty Opinions recommendation of Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733519000.793576798 ◽

2020 ◽

Author(s):

Tak Mao Chan ◽

Susan Yung

Keyword(s):

Systemic Lupus Erythematosus ◽

Transcription Factors ◽

Healthy Volunteers ◽

Lupus Erythematosus ◽

Systemic Lupus

Download Full-text

TNF-related apoptosis-inducing ligand is involved in neutropenia of systemic lupus erythematosus

Blood ◽

10.1182/blood-2003-12-4274 ◽

2004 ◽

Vol 104 (1) ◽

pp. 184-191 ◽

Cited By ~ 53

Author(s):

Wataru Matsuyama ◽

Masuki Yamamoto ◽

Ikkou Higashimoto ◽

Ken-ichi Oonakahara ◽

Masaki Watanabe ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Healthy Volunteers ◽

Lupus Erythematosus ◽

Laboratory Finding ◽

Significant Negative Correlation ◽

Trail Receptor ◽

Death Domain ◽

Systemic Lupus ◽

Inhibitory Protein

Abstract Neutropenia is a common laboratory finding in systemic lupus erythematosus (SLE). However, the molecular mechanism of SLE neutropenia has not been fully explained. In this study, we examined whether TNF-related apoptosis-inducing ligand (TRAIL) is involved in the pathogenesis of SLE neutropenia using samples from SLE patients. Serum TRAIL levels in SLE patients with neutropenia were significantly higher than those of SLE patients without neutropenia and healthy volunteers. Serum TRAIL levels showed a significant negative correlation with neutrophil counts in SLE patients. The expression of TRAIL receptor 3 was significantly lower in SLE patients with neutropenia than in patients without neutropenia or in healthy volunteers. Treatment with glucocorticoids negated the decrease of TRAIL receptor 3 expression on neutrophils of SLE patients. TRAIL may accelerate neutrophil apoptosis of neutrophils from SLE patients, and autologous T cells of SLE patients, which express TRAIL on surface, may kill autologous neutrophils. Interferon gamma and glucocorticoid modulated the expression of TRAIL on T cells of SLE patients and also modulated the expression of cellular Fas-associating protein with death domain–like interleukin-1β–converting enzyme (FLICE)–inhibitory protein (cFLIP), an inhibitor of death receptor signaling, in neutrophils. Thus, our results provide a novel insight into the molecular pathogenesis of SLE neutropenia.

Download Full-text

Discovery of new serum biomarker panels for systemic lupus erythematosus diagnosis

Rheumatology ◽

10.1093/rheumatology/kez634 ◽

2020 ◽

Vol 59 (6) ◽

pp. 1416-1425

Author(s):

Hua-Zhi Ling ◽

Shu-Zhen Xu ◽

Rui-Xue Leng ◽

Jun Wu ◽

Hai-Feng Pan ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Logistic Regression ◽

Differential Diagnosis ◽

Healthy Volunteers ◽

Lupus Erythematosus ◽

Clinical Characteristics ◽

Systemic Lupus ◽

Control Groups ◽

Systematic Screening ◽

Systemic Lupus Erythematosus Diagnosis

Abstract Objective Clinical diagnosis of SLE is currently challenging due to its heterogeneity. Many autoantibodies are associated with SLE and are considered potential diagnostic markers, but systematic screening and validation of such autoantibodies is lacking. This study aimed to systematically discover new autoantibodies that may be good biomarkers for use in SLE diagnosis. Methods Sera from 15 SLE patients and 5 healthy volunteers were analysed using human proteome microarrays to identify candidate SLE-related autoantibodies. The results were validated by screening of sera from 107 SLE patients, 94 healthy volunteers and 60 disease controls using focussed arrays comprised of autoantigens corresponding to the identified candidate antibodies. Logistic regression was used to derive and validate autoantibody panels that can discriminate SLE disease. Extensive ELISA screening of sera from 294 SLE patients and 461 controls was performed to validate one of the newly discovered autoantibodies. Results A total of 31, 11 and 18 autoantibodies were identified to be expressed at significantly higher levels in the SLE group than in the healthy volunteers, disease controls and healthy volunteers plus disease control groups, respectively, with 25, 7 and 13 of these differentially expressed autoantibodies being previously unreported. Diagnostic panels comprising anti-RPLP2, anti-SNRPC and anti-PARP1, and anti-RPLP2, anti-PARP1, anti-MAK16 and anti- RPL7A were selected. Performance of the newly discovered anti-MAK16 autoantibody was confirmed by ELISA. Some associations were seen with clinical characteristics of SLE patients, such as disease activity with the level of anti-PARP1 and rash with the level of anti-RPLP2, anti-MAK16 and anti- RPL7A. Conclusion The combined autoantibody panels identified here show promise for the diagnosis of SLE and for differential diagnosis of other major rheumatic immune diseases.

Download Full-text

AB0179 THE TRANSCRIPTION FACTORS IKZF1 AND IKZF3 CONTROL B CELL ACTIVATION AND DIFFERENTIATION IN SYSTEMIC LUPUS ERYTHEMATOSUS

10.1136/annrheumdis-2019-eular.6343 ◽

2019 ◽

Author(s):

Sotiria Manou-Stathopoulou ◽

Felice Rivellese ◽

Daniele Mauro ◽

Katriona Goldmann ◽

Debasish Pyne ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Transcription Factors ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Activation ◽

B Cell Activation ◽

Systemic Lupus

Download Full-text

Eryptosis as an Underlying Mechanism in Systemic Lupus Erythematosus-Related Anemia

Cellular Physiology and Biochemistry ◽

10.1159/000453191 ◽

2016 ◽

Vol 40 (6) ◽

pp. 1391-1400 ◽

Cited By ~ 8

Author(s):

Peipei Jiang ◽

Maohong Bian ◽

Wenjuan Ma ◽

Chunqiu Liu ◽

Peng Yang ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Healthy Volunteers ◽

Lupus Erythematosus ◽

Calcium Ion ◽

Underlying Mechanism ◽

Cytosolic Calcium ◽

Systemic Lupus ◽

Cell Shrinkage ◽

Experimental Subjects ◽

Underlying Mechanisms

Background: The progression of systemic lupus erythematosus (SLE) leads to anemia in patients, adversely affecting prognosis. The diverse causes of anemia may include excessive eryptosis or premature suicidal erythrocyte death characterized by cell shrinkage and phosphatidylserine (PS) exposure on the cell surface. The present study explored if SLE enhances eryptosis and the underlying mechanisms. Materials and Methods: Eryptosis was assessed using flow cytometry in healthy volunteers (n = 20) and anemic patients hospitalized for SLE (n = 22), for parameters including PS exposure, cell volume, cytosolic calcium ion (Ca2+) levels and reactive oxygen species (ROS) and ceramide abundance. These indicators were measured in erythrocytes of experimental subjects and erythrocytes treated with plasma from healthy volunteers or SLE patients. Results: The hemoglobin and hematocrit levels were significantly lower in anemic SLE patients than in healthy volunteers (***p<0.001, p<0.001, respectively). The percentage of PS-exposing erythrocytes was significantly higher in SLE patients than in healthy volunteers (p<0.001), accompanied by an increase in cytosolic Ca2+ levels, oxidative stress. The measurements of PS and Ca2+ levels were significantly higher in the erythrocytes of healthy volunteers following incubation in plasma of SLE patients than in plasma of healthy volunteers for 24h (***p<0.001, *p<0.05 respectively). Conclusion: Eryptosis is enhanced in SLE and may contribute to anemia. The probable underlying mechanisms may be an excessive formation of ROS in erythrocytes. Also, some plasma components may trigger eryptosis by increasing the cytosolic Ca2+ concentration.

Download Full-text