| 1. |
- Camponeschi, Alessandro, et al.
(författare)
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Human CD38 regulates B cell antigen receptor dynamic organization in normal and malignant B cells.
- 2022
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:9
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Tidskriftsartikel (refereegranskat)abstract
- CD38 is a multifunctional protein expressed on the surface of B cells in healthy individuals but also in B cell malignancies. Previous studies have suggested a connection between CD38 and components of the IgM class B cell antigen receptor (IgM-BCR) and its coreceptor complex. Here, we provide evidence that CD38 is closely associated with CD19 in resting B cells and with the IgM-BCR upon engagement. We show that targeting CD38 with an antibody, or removing this molecule with CRISPR/Cas9, inhibits the association of CD19 with the IgM-BCR, impairing BCR signaling in normal and malignant B cells. Together, our data suggest that CD38 is a new member of the BCR coreceptor complex, where it exerts a modulatory effect on B cell activation upon antigen recognition by regulating CD19. Our study also reveals a new mechanism where α-CD38 antibodies could be a valuable option in therapeutic approaches to B cell malignancies driven by aberrant BCR signaling.
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| 2. |
- Gatto, Mariele, et al.
(författare)
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Early increase of circulating transitional B cells and autoantibodies to joint-related proteins in patients with metastatic melanoma developing checkpoint inhibitor-induced inflammatory arthritis.
- 2023
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 75:5, s. 856-863
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Tidskriftsartikel (refereegranskat)abstract
- To investigate potential associations between B cell-related immunological changes and development of inflammatory arthritis (IA) after treatment with immune checkpoint inhibitors (ICI).Patients who developed IA (ICI-IA) and patients who did not develop immune-related adverse events (non-irAE) after receiving ICI due to metastatic melanoma were consecutively recruited. Blood samples were collected at the time of ICI-IA occurrence and at different timepoints during treatment. Peripheral blood B cell subsets during ICI treatment were analyzed by flow cytometry. Rheumatoid factor, autoantibodies against citrullinated peptides and against joint-related proteins were measured.Proportions of CD19+ B cells were higher in patients with ICI-IA (n=7) vs. non-irAE (n=15; median (interquartile range, IQR), %: 11.7 (9.7-16.2) vs. 8.1 (5.7-11.0), p=0.03). The proportion and absolute numbers of transitional CD19+ CD10+ CD24hi CD38hi B cells were increased in patients with ICI-IA vs. non-irAE (median (IQR); %: 8.1 (4.9-12.1) vs. 3.6 (1.9-4.9); cells/μl: 10.7 (8.9-19.6) vs. 4.4 (2.3-6.6), p<0.01 for both), and higher levels of transitional B cells were associated with development of ICI-IA (OR 95% CI: 2.25 (1.03-4.9), p=0.04). Transitional B cells increased before the onset of overt ICI-IA and decreased from active to quiescent ICI-IA (p=0.02). Autoantibodies to collagen II epitopes were detected in up to 43% of ICI-IA patients compared to none of the non-irAE patients (p=0.02).Development of ICI-IA is accompanied by an increase in transitional B cells and by production of autoantibodies to joint-related proteins. Monitoring of B cell-driven abnormalities upon ICI treatment may help earlier recognition of ICI-IA. This article is protected by copyright. All rights reserved.
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| 3. |
- Parodis, Ioannis, 1981-, et al.
(författare)
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Associations Between Early Changes in Circulating B Cell Subsets and Severe Flare in Systemic Lupus Erythematosus : Results from Three Phase III Trials of Belimumab
- 2021
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 73:Suppl. 9, s. 2699-2700
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background/Purpose: Belimumab is the only approved targeted treatment for systemic lupus erythematosus (SLE). Identification of early predictors of response or non- response to therapy is imperative to optimize surveillance and decision- making. We studied early changes in B cell subsets in relation to flare during standard therapy plus belimumab or placebo given to patients with active SLE within the frame of three phase III clinical trials of belimumab.Methods: We analyzed pooled 52- week data from BLISS- 76 (N=819), BLISS- SC (N=836), and BLISS North- East Asia (N=60). B cell subsets were determined with flow cytometry. Severe flare was evaluated according to the SELENA-SLEDAI Flare Index every fourth week. We investigated B cell changes relative to baseline using proportional hazards regression analysis.Results: Early decreases in CD19+CD20- CD138+ long- lived (HR: 0.7; 95% CI: 0.56– 0.98; P=0.034) and CD19+CD-38brightCD27bright SLE- associated plasma cells (HR: 0.7; 95% CI: 0.50– 0.87; P=0.003) from baseline through week 24 were negatively associated with the development of a severe flare during the study period, i.e. through week 52 from treatment initiation. A similar trend was seen for decreases in naïve CD19+CD20+CD27- B cells (HR: 0.7; 95% CI: 0.56– 1.00; P=0.051). No such association was observed for early changes in the total CD19+CD20+ B cell pool, or in CD19+CD20+CD27+ memory B cells, CD19+CD20+CD69+ activated B cells, CD19+CD20+CD138+ cells or CD19+CD20- CD27bright short- lived plasma cells. The association with CD19+CD38brightCD27bright SLE- associated plasma cells held true for patients treated with belimumab (any dose) (HR: 0.7; 95% CI: 0.47– 0.97; P=0.032) but not placebo, while placebo receivers showing reductions in CD19+CD20- CD138+ long- lived plasma cells displayed a lower probability to flare (HR: 0.6; 95% CI: 0.38– 0.87; P=0.009).Conclusion: Early decreases in long- lived circulating plasma cells were negatively associated with severe flares in patients with active SLE treated with standard immunosuppression with or without add- on belimumab, while reductions in circulating CD19+CD38brightCD27bright SLE- associated plasma cells may prove a useful early biological marker of favorable response to belimumab therapy.
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| 4. |
- Parodis, Ioannis, 1981-, et al.
(författare)
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B Cell Kinetics upon Therapy Commencement for Active Extrarenal Systemic Lupus Erythematosus in Relation to Development of Renal Flares : Results from Three Phase III Clinical Trials of Belimumab
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:22
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Tidskriftsartikel (refereegranskat)abstract
- Renal flares constitute major determinants of poor prognosis in people living with systemic lupus erythematosus (SLE). The aim of the present study was to investigate changes in B cell subsets in relation to renal flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with SLE. Using data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) percentage changes in circulating CD19+ B cell subsets characterised through flow cytometry, anti-dsDNA antibodies, and complement levels with the occurrence of renal flares over one year. Patients who developed renal flares showed more prominent rapid decreases in CD19+CD20+CD138+ short-lived plasma cells (-50.4% vs. -16.7%; p = 0.019) and CD19+CD20-CD27bright plasmablasts (-50.0% vs. -29.9%; p = 0.020) compared to non-flaring patients, followed by a subsequent return. Less prominent rapid reductions in CD19+CD27-CD24brightCD38bright transitional B cells (-42.9% vs. -75.0%; p = 0.038) and CD19+CD20-CD138+ peripheral long-lived plasma cells (-11.3% vs. -29.2%; p = 0.019) were seen in belimumab-treated-but not placebo-treated-patients who developed renal flares compared to belimumab-treated patients who did not. Rapid and early changes in anti-dsDNA or complement levels showed no clear association with renal flares. In summary, a rapid drop followed by a subsequent return in circulating short-lived plasma cells and plasmablasts upon treatment for active extra-renal SLE portended renal flares, indicating a need for therapeutic adjustments in patients showing such B cell patterns. Rapid decreases in transitional B cells and peripheral long-lived plasma cells upon belimumab therapy commencement may signify a greater protection against renal flares. B cell kinetics may prove useful in early drug evaluation.
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| 5. |
- Parodis, Ioannis, 1981-, et al.
(författare)
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B cells in systemic lupus erythematosus : Targets of new therapies and surveillance tools
- 2022
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Ingår i: Frontiers in Medicine. - : Frontiers Media S.A.. - 2296-858X. ; 9
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Forskningsöversikt (refereegranskat)abstract
- B cell hyperactivity is a hallmark of the complex autoimmune disease systemic lupus erythematosus (SLE), which has justified drug development focusing on B cell altering agents during the last decades, as well as the off-label use of B cell targeting biologics. About a decade ago, the anti-B cell activating factor (BAFF) belimumab was the first biological agent to be licensed for the treatment of adult patients with active yet non-renal and non-neuropsychiatric SLE, to later be expanded to include treatment of pediatric SLE and, recently, lupus nephritis. B cell depletion is recommended as an off-label option in refractory cases, with the anti-CD20 rituximab having been the most used B cell depleting agent to date while agents with a slightly different binding specificity to CD20 such as obinutuzumab have also shown promise, forming a part of the current pipeline. In addition, terminally differentiated B cells have also been the targets of experimental therapies, with the proteasome inhibitor bortezomib being one example. Apart from being promising drug targets, B and plasma cells have also shown promise in the surveillance of patients with SLE, especially for monitoring B cell depleting or B cell altering therapies. Inadequate B cell depletion may signify poor expected clinical response to rituximab, for example, while prominent reductions in certain B cell subsets may signify a protection against flare development in patients treated with belimumab. Toward an era with a richer therapeutic armamentarium in SLE, including to a large extent B cell altering treatments, the challenge that emerges is to determine diagnostic means for evidence-based therapeutic decision-making, that uses clinical information, serological markers, and gene expression patterns to guide individualized precision strategies.
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| 6. |
- Parodis, Ioannis, 1981-, et al.
(författare)
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Early B Cell and Plasma Cell Kinetics Upon Treatment Initiation Portend Flares in Systemic Lupus Erythematosus : A Post-Hoc Analysis of Three Phase III Clinical Trials of Belimumab
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate changes in B cell subsets in relation to disease flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with systemic lupus erythematosus (SLE).Patients and Methods: Using data from the BLISS-76, BLISS-SC and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) changes in peripheral B cell subsets, anti-dsDNA and complement levels with the occurrence of disease flares from week 24 through week 52 (Mann-Whitney U tests) or the entire study follow-up (Cox regression analysis), assessed using the SELENA-SLEDAI Flare Index.Results: Patients on ST alone who flared displayed less prominent early decreases in CD19+CD20-CD138+ long-lived plasma cells (-16.1% versus -35.1%; P=0.012). In all arms combined, patients who developed severe flares showed less prominent early decreases in CD19+CD20-CD138+ long-lived plasma cells (-23.5% versus -39.4%; P=0.028) and CD19+CD27brightCD38bright SLE-associated plasma cells (-19.0% versus -27.8%; P=0.045). After adjustment for rapid changes, early increases in overall CD19+CD20+ B cells (HR: 1.81; 95% CI: 1.08-3.05; P=0.024) and early increases or no return after a rapid expansion in CD19+CD20+CD27+ memory B cells (HR: 1.58; 95% CI: 1.18-2.11; P=0.002) portended subsequent severe flares. Patients who developed flares of any severity showed no or less prominent rapid (0.0% versus -12.5%; P<0.001) or early (-1.9% versus -21.7%; P<0.001) decreases in anti-dsDNA levels, and patients who developed severe flares showed no or less prominent early decreases in anti-dsDNA levels (0.0% versus -13.3%; P=0.020). Changes in complement levels exhibited no ability to distinguish flaring from non-flaring patients.Conclusions: Increase or lack of decrease in certain circulating B cell subsets or anti-dsDNA levels upon treatment initiation for active SLE heralded subsequent severe disease flares. A rapid expansion of memory B cells may signify sustained response to therapy when followed by a subsequent drop, while no return or delayed increases in memory B cells may portend flaring. Peripheral B cell and serological marker kinetics may help identify patients in whom therapeutic modifications could protect against flare development, and may hence prove a useful complement to traditional surveillance and early treatment evaluation in SLE.
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| 7. |
- Parodis, Ioannis, 1981-, et al.
(författare)
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Early Changes in B and Plasma Cell Subsets and Traditional Serological Markers as Predictors of SRI-4 Response to Therapy in Systemic Lupus Erythematosus
- 2022
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Ingår i: Frontiers in medicine. - : Frontiers Media S.A.. - 2296-858X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Objective: With the premise of the hypothesis that early biological responses to therapy for active systemic lupus erythematosus (SLE) portend later clinical improvements, we studied changes in B cell subsets and traditional serological markers in relation to clinical response to standard therapy (ST) with or without the addition of belimumab.Patients and Methods: We analyzed data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials (N = 1712). Circulating CD19+ B cell subsets were determined by flow-cytometry. We studied associations of relative to baseline percentage changes in circulating B and plasma cell subsets, anti-dsDNA antibody levels and complement levels with SLE Responder Index (SRI)-4 response after 52 weeks of treatment. Changes occurring through week 8 were deemed "rapid," through week 24 "early," and thereafter "delayed".Results: In the analysis of the entire cohort, SRI-4 responders showed more prominent decreases from baseline through week 52 in CD19+CD20+CD27- naïve B cells (median change: -61.2% versus -50.0%; P = 0.004), CD19+CD20-CD27 bright plasmablasts (-44.9% versus -33.3%; P = 0.011), and CD19+CD20-CD138+ long-lived plasma cells (-48.2% versus -37.1%; P = 0.024), and a more prominent rapid (+92.0% versus +66.7%; P = 0.002) and early (+60.0% versus +49.5%; P = 0.033) expansion of CD19+CD20+CD27+ memory B cells than non-responders. More prominent rapid reductions in anti-dsDNA (-14.8% versus -8.7%; P = 0.043) and increases in C3 (+4.9% versus +2.1%; P = 0.014) and C4 levels (+11.5% versus +8.3%; P = 0.017) were documented in SRI-4 responders compared with non-responders among patients who received add-on belimumab, but not among patients who received non-biological ST alone.Conclusion: SRI-4 responders showed a more prominent rapid expansion of memory B cells and more prominent delayed reductions in naïve B cells, plasmablasts and long-lived plasma cells. Moreover, clinical response to belimumab was associated with preceding more prominent reductions of anti-dsDNA and increases in C3 and C4 levels. Monitoring biological changes may prove useful in SLE patient surveillance and early treatment evaluation.
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| 8. |
- Parodis, Ioannis, 1981-, et al.
(författare)
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Early Increase in Circulating Memory B Cells Portends Clinical Response to Treatment in Pooled Data from Three Phase III Trials of Belimumab
- 2021
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 73:Suppl. 9, s. 2695-2696
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background/Purpose: Belimumab blocks soluble B cell activating factor (BAFF) and is the only to date approved targeted treatment for systemic lupus erythematosus (SLE). Identification of biological predictors of response occurring earlier upon treatment would provide measurable tools to improve patient monitoring and stratification according to likelihood of response. We investigated early changes in B lymphocyte subsets in relation to response to standard therapy plus belimumab or placebo given to patients with active SLE and mainly musculoskeletal and mucocutaneous symptoms.Methods: We analyzed pooled data from belimumab phase III clinical trials including BLISS-76 (N=819) and BLISS-SC (N=836); in addition, 60 patients from the BLISS North- East Asia trial were included in the analysis. B lymphocyte subsets were determined with flow cytometry. Treatment response was assessed using the composite measure SLE Responder Index 4 (SRI- 4), defined as decrease in SLEDAI by ≥4 points, no worsening in the physician’s global assessment by >30% and no new British Lupus Isles Assessment Group (BILAG) index (≥1 A or ≥2 B), at week 52. Additionally, persistence of SRI- 4 through week 52 was evaluated. We investigated B cell changes relative to baseline using logistic or proportional hazards regression analysis, as appropriate.Results: We found an association between an early expansion of CD19+CD20+CD27+ memory B cells from baseline through week 8 and attainment of SRI- 4 response at week 52 (OR: 1.5; 95% CI: 1.18– 1.89; P=0.001), or for relative increases >10% (OR: 1.5; 95% CI: 1.17– 1.83; P=0.001). Expansion above this threshold of 10% was also associated with increased probability or shorter time to achieve SRI- 4 response that was maintained through week 52 (HR: 1.4; 95% CI: 1.15– 1.61; P< 0.001). Notably, belimumab treatment (any dose) yielded an 11.5- fold increased probability of memory B cell expansion through week 8 compared with placebo (95% CI: 8.74– 15.02; P< 0.001). No association with SRI- 4 response was observed for early changes in CD19+CD20+ B cells, CD19+CD20+CD27- naïve B cells, CD19+CD20+CD69+ activated B cells, CD19+CD20- CD27bright short- lived plasma cells, CD19+CD20- CD138+ long- lived plasma cells, or CD19+CD38brightCD27bright SLE- associated plasma cells.Conclusion: Early increases in memory B cells through the first 8 weeks of therapy, mainly driven by belimumab, portended good and sustained clinical response within one year from treatment initiation. Early immunological changes preceding the clinical outcome and may prove useful in early evaluation of belimumab therapy.
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| 9. |
- Parodis, Ioannis, 1981-, et al.
(författare)
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Is per-protocol kidney biopsy required in lupus nephritis?
- 2024
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Ingår i: Autoimmunity Reviews. - : Elsevier. - 1568-9972 .- 1873-0183. ; 23:1
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Forskningsöversikt (refereegranskat)abstract
- Baseline kidney biopsy is recommended in lupus nephritis (LN). Biopsy allows to classify different forms of LN and differentiate other forms of renal involvement, such as tubulo-interstitial nephritis or thrombotic microangiopathy. The indications for repeat biopsy are more controversial. Some authors feel that good clinical monitoring is sufficient to assess prognosis and make therapeutic decisions. Based on the recently demonstrated discordance between clinical and histological response, some physicians recommend per-protocol biopsies either at 6 months in stable patients to verify the response to induction therapy, or after one-to-two years to assess treatment efficacy and tune the duration of maintenance therapy. Others recommend repeating kidney biopsy in case of incomplete response or to discriminate between active and chronic lesions. By definition, a per-protocol kidney biopsy differs from a repeat biopsy in that the former is foreseen at fixed timepoints, regardless of the clinical response. Although any decision should always consider the patient's overall clinical condition, there are no doubts that repeat kidney biopsy represents a useful tool in difficult cases to evaluate treatment response, modulate treatment intensity, and predict long-term renal outcome both in quiescent lupus and during flares. How to harmonize per-protocol biopsies in the LN course remains challenging.
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