To investigate whether bortezomib, a proteasome inhibitor approved for treatment of multiple myeloma, induces clinically relevant plasma cell (PC) depletion in patients with active, refractory ...systemic lupus erythematosus (SLE).
Twelve patients received a median of two (range 1-4) 21-day cycles of intravenous bortezomib (1.3 mg/m(2)) with the coadministration of dexamethasone (20 mg) for active SLE. Disease activity was assessed using the SLEDAI-2K score. Serum concentrations of anti-double-stranded DNA (anti-dsDNA) and vaccine-induced protective antibodies were monitored. Flow cytometry was performed to analyse peripheral blood B-cells, PCs and Siglec-1 expression on monocytes as surrogate marker for type-I interferon (IFN) activity.
Upon proteasome inhibition, disease activity significantly declined and remained stable for 6 months on maintenance therapies. Nineteen treatment-emergent adverse events occurred and, although mostly mild to moderate, resulted in treatment discontinuation in seven patients. Serum antibody levels significantly declined, with greater reductions in anti-dsDNA (∼60%) than vaccine-induced protective antibody titres (∼30%). Bortezomib significantly reduced the numbers of peripheral blood and bone marrow PCs (∼50%), but their numbers increased between cycles. Siglec-1 expression on monocytes significantly declined.
These findings identify proteasome inhibitors as a putative therapeutic option for patients with refractory SLE by targeting PCs and type-I IFN activity, but our results must be confirmed in controlled trials.
In light of the SARS-CoV-2 pandemic, protecting vulnerable groups has become a high priority. Persons at risk of severe disease, for example, those receiving immunosuppressive therapies for chronic ...inflammatory cdiseases (CIDs), are prioritised for vaccination. However, data concerning generation of protective antibody titres in immunosuppressed patients are scarce. Additionally, mRNA vaccines represent a new vaccine technology leading to increased insecurity especially in patients with CID.
Here we present for the first time, data on the efficacy and safety of anti-SARS-CoV-2 mRNA vaccines in a cohort of immunosuppressed patients as compared with healthy controls.
42 healthy controls and 26 patients with CID were included in this study (mean age 37.5 vs 50.5 years). Immunisations were performed according to national guidelines with mRNA vaccines. Antibody titres were assessed by ELISA before initial vaccination and 7 days after secondary vaccination. Disease activity and side effects were assessed prior to and 7 days after both vaccinations.
Anti-SARS-CoV-2 antibodies as well as neutralising activity could be detected in all study participants. IgG titres were significantly lower in patients as compared with controls (2053 binding antibody units (BAU)/mL ±1218 vs 2685±1102). Side effects were comparable in both groups. No severe adverse effects were observed, and no patients experienced a disease flare.
We show that SARS-CoV-2 mRNA vaccines lead to development of antibodies in immunosuppressed patients without considerable side effects or induction of disease flares. Despite the small size of this cohort, we were able to demonstrate the efficiency and safety of mRNA vaccines in our cohort.
NZB/W F1 mice were treated with: 1) anti-CD20, 2) anti-CD20 plus bortezomib, 3) anti-CD20 plus anti-LFA-1/anti-VLA-4 blocking antibodies, 4) anti-CD20 plus bortezomib and anti-LFA-1/anti-VLA4 ...blocking antibodies. Short- and long-lived plasma cells including autoreactive cells in the bone marrow and spleen were enumerated by flow cytometry and ELISPOT seven days after treatment. Based on these data in another experiment, mice received one cycle of anti-CD20 plus bortezomib followed by four cycles of anti-CD20 therapy every 10 days and were monitored for its effect on plasma cells and disease.
Short-lived plasma cells in bone marrow and spleen were efficiently depleted by all regimens targeting plasma cells. Conversely, LLPCs and anti-dsDNA-secreting plasma cells in bone marrow and spleen showed resistance to depletion and were strongly reduced by bortezomib plus anti-CD20. The effective depletion of plasma cells by bortezomib complemented by the continuous depletion of their precursor B cells using anti-CD20 promoted the persistent reduction of IgG anti-dsDNA antibodies, delayed nephritis and prolonged survival in NZB/W F1 mice.
These findings suggest that the effective depletion of LLPCs using bortezomib in combination with a therapy that continuously targeting B cells as their precursors may prevent the regeneration of autoreactive LLPCs and, thus, might represent a promising treatment strategy for SLE and other (auto)antibody-mediated diseases.
Aberrant production of autoantibodies by inappropriately self-reactive plasma cells is an inherent characteristic of autoimmune diseases. Several therapeutic strategies aim to deplete the plasma cell ...pool, or to prevent maturation of B cells into plasma cells. However, accepted views of B-cell biology are changing; recent findings show that long-lived plasma cells refractory to immunosuppressants and B-cell depletion therapies contribute to the maintenance of humoral memory and, in autoimmunity, to autoreactive memory. As a consequence of their longevity and persistence, long-lived plasma cells can support chronic inflammatory processes in autoimmune diseases by continuously secreting pathogenic antibodies, and they can contribute to flares of symptoms. As long-lived plasma cells are not sufficiently eliminated by current therapies, these findings are extremely relevant to the development of novel concepts for the treatment of autoimmune diseases. Thus, long-lived plasma cells appear to be a promising new therapeutic target.
Memory B and memory plasma cells Yoshida, Taketoshi; Mei, Henrik; Dörner, Thomas ...
Immunological reviews,
September 2010, Letnik:
237, Številka:
1
Journal Article
Recenzirano
Vaccination provides a powerful means to control infections. It exploits and exemplifies the ability of the immune system to preserve the information that a specific pathogen has been encountered in ...the past. The cells and molecular mechanisms of immunological memory are still being discussed controversially. Here, we review the current concepts of memory B cells, the signals involved in their maintenance, and their role in enhanced secondary reactions. Memory plasma cells, secreting protective antibodies over lifetime, have been recognized only recently. Their characterization as cells resting in terms of proliferation and migration, and surviving in dedicated stromal niches, in the absence of antigen, has generated new concepts of how memory cells in general are organized by stroma cells, the 'resting memory'. In autoimmunity and chronic inflammation, memory B cells and memory plasma cells can be essential players, and they require special attention, as they do not respond to most conventional therapies. Their selective targeting will depend on a molecular understanding of their lifestyle.
Highlights • Plasma cells can be short-lived plasmablast or long-lived memory plasma cells • Memory plasma cells provide persisting antibody titers for years, even decades • Protective memory plasma ...cells are important for longlasting immunity to infections • Pathogenic autoreactive memory plasma cells exist in autoimmunity • They are refractory to conventional immunosuppression and their depletion constitutes a therapeutic challenge
Objective
The relative risk of SARS–CoV‐2 infection and COVID‐19 disease severity among people with rheumatic and musculoskeletal diseases (RMDs) compared to those without RMDs is unclear. This study ...was undertaken to quantify the risk of SARS–CoV‐2 infection in those with RMDs and describe clinical outcomes of COVID‐19 in these patients.
Methods
We conducted a systematic literature review using 14 databases from January 1, 2019 to February 13, 2021. We included observational studies and experimental trials in RMD patients that described comparative rates of SARS–CoV‐2 infection, hospitalization, oxygen supplementation/intensive care unit (ICU) admission/mechanical ventilation, or death attributed to COVID‐19. Methodologic quality was evaluated using the Joanna Briggs Institute critical appraisal tools or the Newcastle‐Ottawa scale. Risk ratios (RRs) and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated, as applicable for each outcome, using the Mantel‐Haenszel formula with random effects models.
Results
Of the 5,799 s screened, 100 studies met the criteria for inclusion in the systematic review, and 54 of 100 had a low risk of bias. Among the studies included in the meta‐analyses, we identified an increased prevalence of SARS–CoV‐2 infection in patients with an RMD (RR 1.53 95% CI 1.16–2.01) compared to the general population. The odds of hospitalization, ICU admission, and mechanical ventilation were similar in patients with and those without an RMD, whereas the mortality rate was increased in patients with RMDs (OR 1.74 95% CI 1.08–2.80). In a smaller number of studies, the adjusted risk of outcomes related to COVID‐19 was assessed, and the results varied; some studies demonstrated an increased risk while other studies showed no difference in risk in patients with an RMD compared to those without an RMD.
Conclusion
Patients with RMDs have higher rates of SARS–CoV‐2 infection and an increased mortality rate.
Improved understanding of the immunopathogenesis of systemic lupus erythematosus (SLE) has paved the way for new selective treatment strategies for these inflammatory systemic diseases, similarly to ...diseases such as rheumatoid arthritis and the spondylarthritides. New specific biologics were developed or are being developed and open up new treatment options for patients. Belimumab is particularly important in this respect. The monoclonal antibody that blocks the cytokine BAFF/BLyS is the first medicament approved for the treatment of serologically active SLE in the last decade and also the first biologic approved for this disease. A number of other biologics for the treatment of SLE are in clinical development. This article addresses the promising new drugs currently under development for the treatment of SLE.
Objective
The American College of Rheumatology and the European League Against Rheumatism embarked on a project to reevaluate classification criteria for systemic lupus erythematosus (SLE). The first ...phase of the classification project involved generation of a broad set of items potentially useful for classification of SLE and their selection for use in a subsequent forced‐choice decision analysis.
Methods
A large international group of expert lupus clinicians was invited to participate in a 2‐step process to generate, rate, and select items based on their importance in diagnosing early and established SLE, via a web‐based survey.
Results
A total of 135 and 147 experts were invited to participate in the item‐generation and item‐reduction process, respectively. Of 145 items generated, item reduction resulted in 40 candidate items moving forward to the next phase. Key features for classifying both early and established SLE included characteristic autoantibodies, specific renal features, and skin manifestations. A small majority (51%) stated that 1 organ system would be sufficient for classifying SLE, but that additional typical laboratory features (antinuclear antibody, anti–double‐stranded DNA) would be required. Notably, 85% of the expert group would positively classify SLE if renal pathology alone showed lupus nephritis.
Conclusion
The Delphi exercise resulted in a set of 40 candidate criteria for the classification of SLE for subsequent assessment. This study comprised the largest panel ever involved in the development of SLE classification criteria, providing a broadly representative view of the current approach to classification of SLE.
We have previously shown that both short- and long-lived plasma cells (PCs) significantly contribute to autoantibody production in NZB/W mice as a model of lupus nephritis. The aim of this study was ...to determine the role of autoreactive long-lived (memory) PCs refractory to immunosuppression and B cell depletion in the pathogenesis of systemic lupus erythematosus.
Splenic CD138+ antibody-secreting cells (ASCs) from >6-month-old NZB/W mice with high titres of anti-dsDNA autoantibodies or from Balb/c mice 5 days after secondary immunisation with ovalbumin (OVA) were adoptively transferred to immunodeficient Rag1(-/-) mice, in which the development of nephritis was investigated by measuring proteinuria. Total IgG and IgM as well as anti-dsDNA and anti-OVA antibody levels were followed up by ELISA. After 21 weeks the recipient mice were sacrificed so that PCs in spleen and bone marrow could be analysed using ELISPOT and flow cytometry and renal immunohistology performed.
The adoptive transfer of NZB/W and anti-OVA ASCs resulted in the continuous generation of anti-dsDNA antibodies and anti-OVA antibodies, respectively, exclusively by long-lived PCs that had homed to the spleen and bone marrow of recipient Rag1(-/-) mice. Rag1(-/-) mice generating autoantibodies including anti-dsDNA had reduced survival, proteinuria and immune complex nephritis with C1q, C3, IgG and IgM deposits 21 weeks after transfer.
These findings demonstrate that autoantibodies exclusively secreted by long-lived (memory) PCs contribute to autoimmune pathology and should be considered as candidate targets for future therapeutic strategies.
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