scholarly journals A novel proangiogenic B cell subset is increased in cancer and chronic inflammation

2020 ◽  
Vol 6 (20) ◽  
pp. eaaz3559 ◽  
Author(s):  
Willem van de Veen ◽  
Anna Globinska ◽  
Kirstin Jansen ◽  
Alex Straumann ◽  
Terufumi Kubo ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Cytokine Production ◽  
Cell Subset ◽  
Tube Formation ◽  
Surface Markers ◽  
Cell Clones ◽  
B Cell Subsets ◽  
Simultaneous Expression

B cells contribute to immune responses through the production of immunoglobulins, antigen presentation, and cytokine production. Several B cell subsets with distinct functions and polarized cytokine profiles have been reported. In this study, we used transcriptomics analysis of immortalized B cell clones to identify an IgG4+ B cell subset with a unique function. These B cells are characterized by simultaneous expression of proangiogenic cytokines including VEGF, CYR61, ADM, FGF2, PDGFA, and MDK. Consequently, supernatants from these clones efficiently promote endothelial cell tube formation. We identified CD49b and CD73 as surface markers identifying proangiogenic B cells. Circulating CD49b+CD73+ B cells showed significantly increased frequency in patients with melanoma and eosinophilic esophagitis (EoE), two diseases associated with angiogenesis. In addition, tissue-infiltrating IgG4+CD49b+CD73+ B cells expressing proangiogenic cytokines were detected in patients with EoE and melanoma. Our results demonstrate a previously unidentified proangiogenic B cell subset characterized by expression of CD49b, CD73, and proangiogenic cytokines.

Impact of Autologous Dendritic Cell Immunotherapy (Arcelis™) on B Cell Subsets in HIV-1-Infected Subjects Receiving Antiretroviral Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 80-80
Author(s):  
Mohamed-Rachid Boulassel ◽  
Bader Yassine-Diab ◽  
Don Healey ◽  
Charles Nicolette ◽  
Rafick-Pierre Sékaly ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Memory B Cells ◽  
B Cell Subsets ◽  
Hiv 1

Abstract We demonstrated the enhancement of CD8-specific responses following the administration of an immune-based therapy consisting of dendritic cells (DC) electroporated with autologous amplified HIV-1 RNA and CD40 ligand (CD40 L) RNA manufactured by the Arcelis™ process in HIV patients receiving antiretroviral therapy (ART). We conducted a sub study on circulating B cell populations to further assess changes induced by this autologous DC therapy as CD40L is a major B cell co-stimulatory factor. To this end, we assessed B cell subset changes in relation to the proliferative capacity of CD4+ and CD8+ T cells response to DC targets containing the 4 HIV-1 antigens (Gag, Vpr, Rev, Nef). The co-expression of CD19, CD38, IgD, CD10, CD23, CD27, CD5, and CD138 were analyzed by multi-parametric flow cytometry to assess circulating B cell subsets such as naïve resting B-cells (Bm1), activated naïve B cells (Bm2), GC founder cells (Bm2’), centroblasts and centrocytes (Bm3 and Bm4), early memory B cells (eBm5), memory B cells (Bm5), IgD memory cells, plasma cells, and B-1 cells. Changes in B cells subsets were analyzed before and after the four intradermal injections of this immunotherapeutic product containing 1.2 × 107 DC. Ten ART treated subjects with undetectable viral load (< 50 copies/ml), median CD4+ count of 440 cells/μl (range: 316–1102), and with a CD4+ nadir > 200 cells/μl were studied. Throughout the study, no significant changes in CD4+ cell count, CD4/CD8 ratio, and no viral blips were noticed. The percentage of total B cells, Bm1, Bm2, Bm2′, eBm5, IgD memory, plasma cells, and B-1 cell subsets did not significantly change. However, a decrease in the percentage of Bm3 and Bm4 cells was found (0.36 [0.06–0.86] versus 0.11 [0.04–0.36]; P=0.05). Conversely, an important increase in the Bm5 cell subset was evidenced (10.4 [1.6–24.2] versus 18.1 [5.1–27.5]; P=0.005) suggesting a proliferation of B memory cells induced by DC immunization. In addition, the multifunctional and polyvalent CD8+ T cell proliferative responses to the 4 HIV genes used in this immunotherapy were noticed in 8 out of 9 subjects available for analysis and characterized by an effector memory phenotype. No CD4+ T cell immune responses were detected, consistent with the endogenous HLA class I loading of the antigens. Collectively, these results indicate that this immunotherapy induces an increase in the B memory cell population in the absence of inducing any clinically apparent autoimmunity along with strong HIV specific multifunctional CD8+ T cell specific immune responses.

scholarly journals Proinflammatory B-cell profile in the early phases of MS predicts an active disease

2017 ◽  
Vol 5 (2) ◽  
pp. e431 ◽  
Author(s):  
Thomas Guerrier ◽  
Myriam Labalette ◽  
David Launay ◽  
Catalina Lee-Chang ◽  
Olivier Outteryck ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cytokine Production ◽  
Cell Subset ◽  
Cell Ratio ◽  
Relapsing Remitting ◽  
B Cell Subsets ◽  
Production Capacities ◽  
Transitional B Cell ◽  
Early Phases

Objective:To assess whether any alteration of B-cell subset distribution and/or the cytokine production capacities of B cells could be associated with any stage of MS and could be predictive of MS evolution.Methods:We prospectively enrolled radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), naive patients with relapsing remitting MS (RRMS) of any disease modifying drug, and healthy controls (HCs). Peripheral blood B-cell subset distributions and the interleukin (IL)-6/IL-10–producing B-cell ratio were assessed by flow cytometry to evaluate their proinflammatory and anti-inflammatory functional properties.Results:Twelve RIS, 46 CIS, 31 RRMS patients, and 36 HCs were enrolled. We observed that a high IL-6/IL-10–producing B-cell ratio in patients with RIS/CIS was associated with the evolution of the disease in the short term (6 months). This imbalance in cytokine production was mainly explained by an alteration of the production of IL-10 by B cells, especially for the transitional B-cell subset. In addition, a significant increase in IgD−/CD27− B cells was detected in patients with CIS and RRMS compared with HCs (p = 0.01). Apart from this increase in exhausted B cells, no other variation in B-cell subsets was observed.Conclusions:The association between a high IL-6/IL-10–producing B-cell ratio and the evolution of patients with RIS/CIS suggest a skew of B cells toward proinflammatory properties that might be implicated in the early phases of MS disease.

scholarly journals Hyper‐metabolic B cells in the spleens of old mice make antibodies with autoimmune specificities

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Daniela Frasca ◽  
Maria Romero ◽  
Denisse Garcia ◽  
Alain Diaz ◽  
Bonnie B. Blomberg
Keyword(s):  
B Cells ◽  
B Cell ◽  
Inflammatory Markers ◽  
Cell Subset ◽  
Antibody Responses ◽  
Metabolic Phenotype ◽  
Cellular Mechanisms ◽  
Autoimmune Antibodies ◽  
B Cell Subsets ◽  
Old Mice

Abstract Background Aging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses. The effects of aging on the metabolic phenotype of B cells and on the metabolic programs that lead to the secretion of protective versus autoimmune antibodies are not known. Methods Splenic B cells and the major splenic B cell subsets, Follicular (FO) and Age-associated B cells (ABCs), were isolated from the spleens of young and old mice and left unstimulated. The RNA was collected to measure the expression of markers associated with intrinsic inflammation and autoimmune antibody production by qPCR. B cells and B cell subsets were also stimulated with CpG and supernatants collected after 7 days to measure autoimmune IgG secretion by ELISA. Metabolic measures (oxygen consumption rate, extracellular acidification rate and glucose uptake) were performed using a Seahorse XFp extracellular flux analyzer. Results Results have identified the subset of ABCs, whose frequencies and numbers increase with age and represent the most pro-inflammatory B cell subset, as the cell type mainly if not exclusively responsible for the expression of inflammatory markers and for the secretion of autoimmune antibodies in the spleen of old mice. Hyper-inflammatory ABCs from old mice are also hyper-metabolic, as compared to those from young mice and to the subset of FO B cells, a feature needed not only to support their higher expression of RNA for inflammatory markers but also their higher autoimmune antibody secretion. Conclusions These results identify a relationship between intrinsic inflammation, metabolism and autoimmune B cells and suggest possible ways to understand cellular mechanisms that lead to the generation of pathogenic B cells, that are hyper-inflammatory and hyper-metabolic, and secrete IgG antibodies with autoimmune specificities.

scholarly journals Proportions of B-cell subsets are altered in incomplete systemic lupus erythematosus and correlate with interferon score and IgG levels

Rheumatology ◽  
2020 ◽  
Vol 59 (9) ◽  
pp. 2616-2624
Author(s):  
Svenja Henning ◽  
Wietske M Lambers ◽  
Berber Doornbos-van der Meer ◽  
Wayel H Abdulahad ◽  
Frans G M Kroese ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Subset ◽  
Cross Sectional Study ◽  
Type I ◽  
Healthy Controls ◽  
Sectional Study ◽  
Cross Sectional ◽  
B Cell Subsets

Abstract Objectives Incomplete SLE (iSLE) patients display symptoms typical for SLE but have insufficient criteria to fulfil the diagnosis. Biomarkers are needed to identify iSLE patients that will progress to SLE. IFN type I activation, B-cell-activating factor (BAFF) and B-cell subset distortions play an important role in the pathogenesis of SLE. The aim of this cross-sectional study was to investigate whether B-cell subsets are altered in iSLE patients, and whether these alterations correlate with IFN scores and BAFF levels. Methods iSLE patients (n = 34), SLE patients (n = 41) with quiescent disease (SLEDAI ≤4) and healthy controls (n = 22) were included. Proportions of B-cell subsets were measured with flow cytometry, IFN scores with RT-PCR and BAFF levels with ELISA. Results Proportions of age-associated B-cells were elevated in iSLE patients compared with healthy controls and correlated with IgG levels. In iSLE patients, IFN scores and BAFF levels were significantly increased compared with healthy controls. Also, IFN scores correlated with proportions of switched memory B-cells, plasma cells and IgG levels, and correlated negatively with complement levels in iSLE patients. Conclusion In this cross-sectional study, distortions in B-cell subsets were observed in iSLE patients and were correlated with IFN scores and IgG levels. Since these factors play an important role in the pathogenesis of SLE, iSLE patients with these distortions, high IFN scores, and high levels of IgG and BAFF may be at risk for progression to SLE.

scholarly journals Evidence for enhanced Bruton’s tyrosine kinase activity in transitional and naïve B cells of patients with granulomatosis with polyangiitis

Rheumatology ◽  
2019 ◽  
Vol 58 (12) ◽  
pp. 2230-2239
Author(s):  
Anouk von Borstel ◽  
Wayel H Abdulahad ◽  
Jan Stephan Sanders ◽  
Jasper Rip ◽  
Stefan F H Neys ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antibody Production ◽  
Granulomatosis With Polyangiitis ◽  
Cytokine Production ◽  
B Cell Subsets ◽  
Auto Antibody ◽  
Subset Distribution ◽  
Cell Cytokine Production

Abstract Objectives To determine Bruton’s tyrosine kinase (BTK) protein and phosphorylation levels in B cell subsets of granulomatosis with polyangiitis (GPA) patients and to investigate the effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production. Methods BTK protein and phosphorylation levels were determined by flow cytometry in peripheral blood B cells of 29 untreated GPA patients [9 active and 20 remission GPA patients (10 ANCA– and 10 ANCA+)], 9 age- and sex-matched healthy controls (HCs) and 9 untreated active RA patients. The effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production was determined in the same donors in peripheral blood mononuclear cell cultures. Results BTK protein levels were significantly increased in transitional and naïve B cells of active GPA and RA patients compared with remission GPA patients and HCs. Both B cell subsets of active patients were more sensitive to B cell receptor stimulation, as BTK and phospholipase Cγ2 phosphorylation were increased in these patients. In vitro BTK blockade had profound effects on B cell cytokine production, plasma cell formation and (auto)antibody production in both GPA patients and HCs. Interestingly, the effect of BTK blockade was less pronounced in active GPA patients, possibly due to increased activation of B cells. Conclusion We show that BTK protein and phosphorylation levels are most profoundly increased in newly emerging B cells of active GPA patients compared with remission patients. BTK blockade greatly inhibits in vitro B cell effector functions in GPA patients and HCs. These promising data identify BTK as an interesting novel therapeutic target in the treatment of GPA.

scholarly journals Complexity of the human memory B-cell compartment is determined by the versatility of clonal diversification in germinal centers

2015 ◽  
Vol 112 (38) ◽  
pp. E5281-E5289 ◽  
Author(s):  
Bettina Budeus ◽  
Stefanie Schweigle de Reynoso ◽  
Martina Przekopowitz ◽  
Daniel Hoffmann ◽  
Marc Seifert ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Clone ◽  
Human Memory ◽  
Memory B Cells ◽  
Sequencing Analysis ◽  
Cell Compartment ◽  
Memory B Cell ◽  
Cell Clones ◽  
B Cell Subsets

Our knowledge about the clonal composition and intraclonal diversity of the human memory B-cell compartment and the relationship between memory B-cell subsets is still limited, although these are central issues for our understanding of adaptive immunity. We performed a deep sequencing analysis of rearranged immunoglobulin (Ig) heavy chain genes from biological replicates, covering more than 100,000 memory B lymphocytes from two healthy adults. We reveal a highly similar B-cell receptor repertoire among the four main human IgM+ and IgG+ memory B-cell subsets. Strikingly, in both donors, 45% of sequences could be assigned to expanded clones, demonstrating that the human memory B-cell compartment is characterized by many, often very large, B-cell clones. Twenty percent of the clones consisted of class switched and IgM+(IgD+) members, a feature that correlated significantly with clone size. Hence, we provide strong evidence that the vast majority of Ig mutated B cells—including IgM+IgD+CD27+ B cells—are post-germinal center (GC) memory B cells. Clone members showed high intraclonal sequence diversity and high intraclonal versatility in Ig class and IgG subclass composition, with particular patterns of memory B-cell clone generation in GC reactions. In conclusion, GC produce amazingly large, complex, and diverse memory B-cell clones, equipping the human immune system with a versatile and highly diverse compartment of IgM+(IgD+) and class-switched memory B cells.

scholarly journals B Cell Subsets as Severity-Associated Signatures in COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Víctor A. Sosa-Hernández ◽  
Jiram Torres-Ruíz ◽  
Rodrigo Cervantes-Díaz ◽  
Sandra Romero-Ramírez ◽  
José C. Páez-Franco ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Subset ◽  
Hierarchical Cluster ◽  
Specific Subset ◽  
Respiratory Parameters ◽  
Cell Subpopulations ◽  
Severity Of The Disease ◽  
B Cell Subsets ◽  
Relationship Of

BackgroundSARS-CoV-2 infection represents a global health problem that has affected millions of people. The fine host immune response and its association with the disease course have not yet been fully elucidated. Consequently, we analyze circulating B cell subsets and their possible relationship with COVID-19 features and severity.MethodsUsing a multiparametric flow cytometric approach, we determined B cell subsets frequencies from 52 COVID-19 patients, grouped them by hierarchical cluster analysis, and correlated their values with clinical data.ResultsThe frequency of CD19+ B cells is increased in severe COVID-19 compared to mild cases. Specific subset frequencies such as transitional B cell subsets increase in mild/moderate cases but decrease with the severity of the disease. Memory B compartment decreased in severe and critical cases, and antibody-secreting cells are increased according to the severity of the disease. Other non-typical subsets such as double-negative B cells also showed significant changes according to disease severity. Globally, these differences allow us to identify severity-associated patient clusters with specific altered subsets. Finally, respiratory parameters, biomarkers of inflammation, and clinical scores exhibited correlations with some of these subpopulations.ConclusionsThe severity of COVID-19 is accompanied by changes in the B cell subpopulations, either immature or terminally differentiated. Furthermore, the existing relationship of B cell subset frequencies with clinical and laboratory parameters suggest that these lymphocytes could serve as potential biomarkers and even active participants in the adaptive antiviral response mounted against SARS-CoV-2.

scholarly journals Optimisation of ex vivo memory B cell expansion/differentiation for interrogation of rare peripheral memory B cell subset responses

2018 ◽  
Vol 2 ◽  
pp. 97 ◽  
Author(s):  
Luke Muir ◽  
Paul F. McKay ◽  
Velislava N. Petrova ◽  
Oleksiy V. Klymenko ◽  
Sven Kratochvil ◽  
...  
Keyword(s):  
Cell Culture ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
Ex Vivo ◽  
Cell Subset ◽  
Human Memory ◽  
Memory B Cells ◽  
Memory B Cell ◽  
B Cell Subsets

Background:Human memory B cells play a vital role in the long-term protection of the host from pathogenic re-challenge. In recent years the importance of a number of different memory B cell subsets that can be formed in response to vaccination or infection has started to become clear. To study memory B cell responses, cells can be culturedex vivo,allowing for an increase in cell number and activation of these quiescent cells, providing sufficient quantities of each memory subset to enable full investigation of functionality. However, despite numerous papers being published demonstrating bulk memory B cell culture, we could find no literature on optimised conditions for the study of memory B cell subsets, such as IgM+memory B cells.Methods:Following a literature review, we carried out a large screen of memory B cell expansion conditions to identify the combination that induced the highest levels of memory B cell expansion. We subsequently used a novel Design of Experiments approach to finely tune the optimal memory B cell expansion and differentiation conditions for human memory B cell subsets. Finally, we characterised the resultant memory B cell subpopulations by IgH sequencing and flow cytometry.Results:The application of specific optimised conditions induce multiple rounds of memory B cell proliferation equally across Ig isotypes, differentiation of memory B cells to antibody secreting cells, and importantly do not alter the Ig genotype of the stimulated cells. Conclusions:Overall, our data identify a memory B cell culture system that offers a robust platform for investigating the functionality of rare memory B cell subsets to infection and/or vaccination.

scholarly journals Vaccination boosts protective responses and counters SARS-CoV-2-induced pathogenic memory B cells

2021 ◽  
Author(s):  
Pankaj Kumar Mishra ◽  
Natalie Bruiners ◽  
Rahul Ukey ◽  
Pratik Datta ◽  
Alberta Onyuka ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Cell Subset ◽  
Mechanistic Explanation ◽  
Memory B Cells ◽  
Immune Priming ◽  
Neutralizing Activity ◽  
Specific Memory ◽  
Rapid Spread

AbstractGiven the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the recent implementation of SARS-CoV-2 vaccination, we have much to learn about the duration of immune protection and the interface between the immune responses to infection and to vaccination. To address these questions, we monitored immune responses to SARS-CoV-2 infection in convalescent individuals over seven months and following mRNA vaccination. Spike Receptor-Binding-Domain (RBD)-specific circulating antibodies and plasma neutralizing activity generally decreased over time, whereas RBD-specific memory B cells persisted. Additionally, using antibody depletion techniques, we showed that the neutralizing activity of plasma specifically resides in the anti-RBD antibodies. More vigorous antibody and B cell responses to vaccination were observed in previously infected subjects relative to uninfected comparators, presumably due to immune priming by infection. SARS-CoV-2 infection also led to increased numbers of double negative B memory cells, which are described as a dysfunctional B cell subset. This effect was reversed by SARS-CoV-2 vaccination, providing a potential mechanistic explanation for the vaccination-induced reduction in symptoms in patients with “Long-COVID”.

scholarly journals Defining Fundamental B Cell-Subset Dysfunction in Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2085-2085
Author(s):  
Rao H Prabhala ◽  
Srikanth Talluri ◽  
Megan Stekla ◽  
Andreea Negroiu ◽  
Michael Buonopane ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Memory T Cells ◽  
Cell Subset ◽  
Cell Dysfunction ◽  
B Cell Function ◽  
Ifn Γ ◽  
B Cell Subsets

Abstract One of the most prominent features of multiple myeloma (MM) has been immune deficiency which predisposes patients to infectious complications and suppresses development of anti-MM immune responses. We and others have previously described the T cell dysfunction in Th1, Treg and Th17 cells, plasmacytoid dendritic cells and myeloid-derived suppressor cells (MDSC). However, the most fundamental and long identified deficiency is in the humoral immune response. Suppression of uninvolved immunoglobulins (UIgs) have been well described (i.e. suppression of serum IgA and IgM in IgG myeloma); and antibody responses to vaccination have been inadequate. However, very limited information is available regarding B cell function and how UIgs are suppressed in myeloma. We have now evaluated six different B cell subsets (B1a, B1b, B2, Breg, IRA-B, and MZ) in peripheral blood (PBMC) and bone marrow (BM) to understand alterations in B cell immune function in MM. We have observed significantly lower ratio of B2 (normal B cell-subset) and B1a (natural antibody-producing cells) subsets (10±4 vs 57±17; p < 0.05) and B2 and Breg (regulatory B cell-subset) subsets (14±4 vs 45±13; p< 0.05) in PBMC from MM patients (N=19) compared with healthy donor (N=33) respectively. Similar results were observed in BM samples from MM patients (N=18) compared with healthy donors (N=12); B2/B1a subset (2.4±0.6 vs 8±1.3; p < 0.05) and B2/Breg subset (8±1.4 vs 43.7±8.4; p< 0.05) respectively. To understand whether MM cells directly or indirectly alter B cell-subsets, we incubated myeloma cells (N=4) with healthy donor PBMCs, and analyzed B cell subsets after 3 days. We observed significant elevation in B1 subset (2.5 fold of control) and reduced B2 subset (89±3% of control). When we incubated PBMCs with IL-17A over-expressing MM cells (N=3), we observed further significant reduction in B2 subset (74% of control). When normal PBMCs are cultured in IL-17A (N=4) we observed significantly increased IL-10-producing Breg subset (28% of control). Similarly, co-culture of healthy B cells with MDSC led to significant increase (3.8 times) in Breg cell- population (N=3) compared with control group. To study the impact of B cell dysfunction on T cell function in MM, we activated normal PBMC via anti-CD3 antibody, in the presence or absence of B cells, and measured intra-cellular IFN-γ levels in CD69+ cells. We observed that the absence of B cells significantly inhibited interferon-producing T cells compared to control (by 43%; p<0.05). Importantly, following removal of CD25+ cells (Tregs and activated memory T cells), with or without B cells, we did not observe any difference in the inhibition of IFN-γ, indicating that B cells influence memory T cells rather than naïve T cells for the production of IFN-γ. To evaluate impact of lenalidomide on this interaction, we stimulated purified normal donor CD45RO memory T cells with Th1 polarizing cocktail in the presence or absence of purified normal B cells or B cells from MM patient (MM-B) in presence of lenalidomide and observed thatlenalidomide significantly improved MM-B cell-mediated IFN-γ-producing Th1 responses (by 32%, p<0.05) compared to normal B cell-mediated Th1 responses. In an effort to evaluate whether any therapy may improve the B cell function, we cultured normal PBMCs in the presence of lenalidomide (N=9) and observed reduction in Breg subset by 40% of control. To evaluate the effect of therapy on B cell-subsets in MM, we analyzed B cell subsets in PBMC from newly-diagnosed and lenalidomide-treated MM patients and observed that lenalidomide-treated group showed significant (p<0.05) improvement in B cell subsets (increased B2 and lower B1 cells) even before clinical response. These results suggest that immunomodulatory agents may be able to re-program humoral immunity in these patients. In summary, we report that the myeloma cell driven skewed B cell subset distribution with consequent B cell dysfunction drives the observed abnormalities in humoral/cell mediated immunity. The current therapeutic interventions, besides providing deep clinical responses, may also improve B cell function with impact on long term outcome. Disclosures No relevant conflicts of interest to declare.

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