MicroRNA Expression Differences in Blood-Derived CD19+ B Cells of Methotrexate Treated Rheumatoid Arthritis Patients

Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as STAT3, PRDM1 and PTEN. Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response.

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POS1223 RAS GUANYL RELEASING PROTEIN 1 (RASGRP1) IN PERIPHERAL B CELLS LINKS RA TO COVID-19

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2809 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 895.2-895

Author(s):

S. Hannawi ◽

F. Alqutami ◽

M. Y. Hachim

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Plasma Cells ◽

Immune Cell ◽

In Silico Analysis ◽

Differentially Expressed ◽

Transcriptional Enhancer ◽

Activated T Cells

Background:Changes in the B cell subpopulations is a hallmark of the antiviral response against SARS-CoV-2 and is associated with COVID-19 severity (1). Recently our group showed common derangement observed in rheumatoid arthritis (RA) and COVID-19 (2). In RA, synovium attracts potentially autoreactive—B cells and plasma cells that play a central role in RA pathogenesis (3). We were interested to know the similarity in B cell’s transcriptomic changes specific to RA and COVID-19.Objectives:Identify similar upregulated genes in synovium and B cells in RA and at the same time are differentially expressed in B cells infected with SARS-CoV-2 or from COVID-19 patients.Methods:RNAseq dataset (GSE89408) of (218) samples isolated from joint synovial biopsies from subjects with and without rheumatoid arthritis were retrieved from GEO online database. Differentially expressed genes (DRGs) specific to RA were identified after exclusion of those upregulated in Osteoarthritis or other joint condition samples in the same dataset. The RA specific genes were intersected with DEGs between B cells from healthy versus RA as extracted from (GSE110999) dataset. The shortlisted genes specifically upregulated in B cells of RA were identified and were explored in B cells COVID-19 transcriptome datasets using (https://metascape.org/COVID).Results:60 genes were found to be specifically upregulated in RA synovium and B cells and are changed in B cells infected with SARS-CoV-2 or from COVID-19 patients, Figure (1-A). Those genes were involved in interferon signaling, antiviral and immune cell activation. RASGRP1 was common between B cells of RA and COVID-19 and might play a role in the pathogenesis of both, Figure (1-B). RASGRP1 controls ERK/MAPK kinase cascade needed in B-/T-cell differentiation and development. It is vital to protect against viral infection and the autoimmune associated proliferation of activated T-cells like RA (4). We checked its level in another dataset (GSE152641) of the whole blood RNASeq of 62 COVID-19 patients and 24 healthy controls. RASGRP1 was significantly down in COVID-19 compared to healthy control, Figure (1-C).Conclusion:SARS-CoV-2 impair B and T’s cells’ immune response through its action on RASGRP1 and that can be a novel mechanistic explanation of how the virus decreases immune cells and impair the B cell’s humoral immunity.References:[1]Sosa-Hernández VA, Torres-Ruíz J, Cervantes-Díaz R, Romero-Ramírez S, Páez-Franco JC, Meza-Sánchez DE, et al. B Cell Subsets as Severity-Associated Signatures in COVID-19 Patients. Frontiers in Immunology. 2020;11(3244).[2]Hachim MY, Hachim IY, Naeem KB, Hannawi H, Al Salmi I, Hannawi S. C-C chemokine receptor type 5 links COVID-19, rheumatoid arthritis, and Hydroxychloroquine: in silico analysis. Translational Medicine Communications. 2020;5(1):14.[3]Doorenspleet ME, Klarenbeek PL, de Hair MJ, van Schaik BD, Esveldt RE, van Kampen AH, et al. Rheumatoid arthritis synovial tissue harbours dominant B-cell and plasma-cell clones associated with autoreactivity. Ann Rheum Dis. 2014;73(4):756-62.[4]Molineros JE, Singh B, Terao C, Okada Y, Kaplan J, McDaniel B, et al. Mechanistic Characterization of RASGRP1 Variants Identifies an hnRNP-K-Regulated Transcriptional Enhancer Contributing to SLE Susceptibility. Frontiers in Immunology. 2019;10(1066).Disclosure of Interests:None declared

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Specific hypomethylation programs underpin B cell activation in early multiple sclerosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2111920118 ◽

2021 ◽

Vol 118 (51) ◽

pp. e2111920118

Author(s):

Qin Ma ◽

Stacy J. Caillier ◽

Shaun Muzic ◽

Michael R. Wilson ◽

Roland G. Henry ◽

...

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Cell Function ◽

Immune Cell ◽

Disease Onset ◽

Cell Types ◽

B Cell Differentiation ◽

Dna Hypomethylation

Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). However, their contribution to MS pathogenesis remains poorly understood partly because of sample heterogeneity and limited coverage of array-based methods. To fill this gap, we conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation. Integration of the methylome to changes in gene expression and susceptibility-associated regions further indicates that hypomethylated regions are significantly associated with the up-regulation of cell activation transcriptional programs. Altogether, these findings implicate aberrant B cell function in MS etiology.

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A Single-Cell Transcriptome Profiling of Anterior Kidney Leukocytes From Nile Tilapia (Oreochromis niloticus)

Frontiers in Immunology ◽

10.3389/fimmu.2021.783196 ◽

2021 ◽

Vol 12 ◽

Author(s):

Liting Wu ◽

Along Gao ◽

Lan Li ◽

Jianlin Chen ◽

Jun Li ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Single Cell ◽

Nile Tilapia ◽

Immune Cell ◽

Cell Types ◽

Cell Transcriptome ◽

B Cell Subsets ◽

Single Cell Transcriptome

Teleost fish anterior kidney (AK) is an important hematopoietic organ with multifarious immune cells, which have immune functions comparable to mammalian bone marrow. Myeloid and lymphoid cells locate in the AK, but the lack of useful specific gene markers and antibody-based reagents for the cell subsets makes the identification of the different cell types difficult. Single-cell transcriptome sequencing enables single-cell capture and individual library construction, making the study on the immune cell heterogeneity of teleost fish AK possible. In this study, we examined the transcriptional patterns of 11,388 AK leukocytes using 10× Genomics single-cell RNA sequencing (scRNA-seq). A total of 22 clusters corresponding to five distinct immune cell subsets were identified, which included B cells, T cells, granulocytes, macrophages, and dendritic cells (DCs). However, the subsets of myeloid cells (granulocytes, macrophages, and DCs) were not identified in more detail according to the known specific markers, even though significant differences existed among the clusters. Thereafter, we highlighted the B-cell subsets and identified them as pro/pre B cells, immature/mature B cells, activated B/plasmablasts, or plasma cells based on the different expressions of the transcription factors (TFs) and cytokines. Clustering of the differentially modulated genes by pseudo-temporal trajectory analysis of the B-cell subsets showed the distinct kinetics of the responses of TFs to cell conversion. Moreover, we classified the T cells and discovered that CD3+CD4−CD8−, CD3+CD4+CD8+, CD4+CD8−, and CD4−CD8+ T cells existed in AK, but neither CD4+CD8− nor CD4−CD8+ T cells can be further classified into subsets based on the known TFs and cytokines. Pseudotemporal analysis demonstrated that CD4+CD8− and CD4−CD8+ T cells belonged to different states with various TFs that might control their differentiation. The data obtained above provide a valuable and detailed resource for uncovering the leukocyte subsets in Nile tilapia AK, as well as more potential markers for identifying the myeloid and lymphoid cell types.

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Mirna Profiling Reveals Specific Patterns for Normal B Cell Subsets and B Cell Lymphomas with a Unique Burkitt Lymphoma Profile

Blood ◽

10.1182/blood.v112.11.3763.3763 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3763-3763

Author(s):

Jan-Lukas Robertus ◽

Geert Harms ◽

Rogier Reijmers ◽

Steven Pals ◽

Yolanthe Swart ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Hierarchical Clustering ◽

Burkitt Lymphoma ◽

Plasma Cells ◽

Memory B Cells ◽

Fold Change ◽

Differentially Expressed ◽

Differentially Expressed Mirnas ◽

B Cell Subsets

Abstract Abstract: MicroRNAs (miRNAs) are small (22–23nt) noncoding RNAs, which negatively regulate gene expression by inhibiting protein translation. MiRNAs play an important role in various cellular processes such as hematopoiesis. Deregulated expression is associated with development of B-cell lymphomas. The aim of this study was to define miRNA expression profiles to identify differentially expressed miRNAs in normal B cell subsets and malignancies derived from these subsets. Using Agilent Human miRNA microarrays the expression levels of 556 miRNAs were determined in 7 Mantle cell lymphoma (MCL), 7 Follicular lymphoma (FL), 7 paediatric Burkitt lymphoma (BL) and 13 Chronic lymphocytic lymphoma (CLL; 8 ZAP70 pos and 5 ZAP70 neg) cases, as well as in naïve, germinal center (GC), memory B cells and plasma cells obtained from 3 paediatric tonsils. Median normalisation was performed on all array data using GeneSpring GX 9.0.5. Differentially expressed miRNAs were defined by at least a four fold difference using ANOVA (p<0.05). Quantitive (q)RT-PCR was used for validation of the arrays. In the normal B-cell subsets 23 differentially expressed miRNAs were found with a four fold difference. Hierarchical clustering revealed a distinct pattern of these subsets. Specifically in GC B cells miR-15b, miR-17-5p and its seed family member miR- 106a were upregulated in comparison to the naïve, memory B cells and plasma cells. MiR-150, miR-221 and miR-222 were downregulated. Only miR-146a was significantly differentially expressed between naïve and memory B cell subsets. In the lymphoma cases a total of 59 miRNAs were differentially expressed. Hierarchical clustering of these miRNAs grouped all four lymphoma entities separately. ZAP70 positive and negative CLL cases did not cluster separately and none of the miRNAs were differentially expressed. Interestingly, 35 miRNAs were specifically deregulated in the Burkitt lymphomas as compared to MCL, FL and CLL, including miR-18a (up), miR-29a, miR-150, miR-155 and miR-222 (down). Almost all of these miRNAs were found not to be differentially expressed within the normal B cell subsets suggesting that these miRNAs might play a specific role in the biologic behaviour of BL. Comparison of BL to normal GC B cells revealed 15 miRNAs upregulated, including miR-126 and miR-145 (fold change >40), and 79 miRNAs downregulated, including miR-150, miR-155, miR-15, miR-16, miR- 17-5p, miR-21 and miR-222. In comparison with GC B cells FL showed 11 upregulated miRNAs, e.g. miR-143 and miR-145 (fold change >40) and 49 downregulated miRNAs. In comparison with memory B cells 21 miRNAs in the CLL group were upregulated, including miR-143 and miR-145 (fold change > 40) and 83 miRNAs were downregulated. Finally MCL was compared to the naïve B cells and showed 23 upregulated miRNAs with miR-126 showing the highest fold change (>40) and 70 downregulated miRNAs. In conclusion, we have identified specific miRNA profiles for MCL, BL, FL and CLL and also for normal B cell subsets. The differentially expressed miRNA profiles contain several miRNAs that have been shown to be directly or indirectly involved in B cell malignancies but also contain new potentially interesting miRNAs. We also have found several miRNAs that may play a tumor specific role in BL and it can be speculated that miRNAs contained in this profile may target genes related to the more aggressive clinical phenotype of BL.

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Synovial Infiltration with CD79a-positive B Cells, But Not Other B Cell Lineage Markers, Correlates with Joint Destruction in Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.110615 ◽

2011 ◽

Vol 38 (11) ◽

pp. 2301-2308 ◽

Cited By ~ 16

Author(s):

YING-QIAN MO ◽

LIE DAI ◽

DONG-HUI ZHENG ◽

LANG-JING ZHU ◽

XIU-NING WEI ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

Disease Activity ◽

B Cell ◽

Cell Density ◽

Joint Destruction ◽

Chinese Patients ◽

Positive Staining ◽

Synovitis Score ◽

Sharp Score

Objective.The efficacy of B cell depletion in the treatment of patients with rheumatoid arthritis (RA) has revitalized interest in the pathogenic role(s) of B cells in RA. We evaluated the distribution of synovial B lineage cells and their correlation with histologic disease activity and joint destruction in RA.Methods.Synovial tissue samples were obtained by closed-needle biopsy from 69 Chinese patients with active RA, from 14 patients with osteoarthritis (OA), and from 15 with orthopedic arthropathies (OrthA) as disease controls. Serial tissue sections were stained immunohistochemically for CD79a (pro-B cell to plasma cell), CD20 (B cells), CD38 (plasma cells), CD21 (follicular dendritic cells), CD68 (macrophages), CD3 (T cells), and CD34 (endothelial cells). Densities of positive-staining cells were determined and correlated with histologic disease activity (Krenn 3-component synovitis score) and radiographic joint destruction (Sharp score).Results.Mean sublining CD79a-positive cell density was significantly higher in RA than in OA (p <0.001) or OrthA (p = 0.003). Receiver operating characteristic curve analysis showed that CD79a-positive cell density differentiated RA well from OA [area under the curve (AUC) = 0.79] or OrthA (AUC = 0.75). Spearman’s rank order correlation showed significant correlations between sublining CD79a-positive cell density and the synovitis score (r = 0.714, p < 0.001), total Sharp score (r = 0.490, p < 0.001), and the erosion subscore (r = 0.545, p < 0.001), as well as the joint space narrowing subscore (r = 0.468, p = 0.001) in RA.Conclusion.Synovial CD79a-positive B cells may be a helpful biomarker for histologic disease activity in RA and may be involved in the pathogenesis of joint destruction in RA.

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Phenotype of recovering lymphoid cell populations after marrow transplantation.

Journal of Experimental Medicine ◽

10.1084/jem.161.6.1483 ◽

1985 ◽

Vol 161 (6) ◽

pp. 1483-1502 ◽

Cited By ~ 139

Author(s):

K A Ault ◽

J H Antin ◽

D Ginsburg ◽

S H Orkin ◽

J M Rappeport ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Nk Cells ◽

Cell Types ◽

Lymphoid Cells ◽

The Other ◽

Hla Dr ◽

T Cell Antigens ◽

Leu 7

Four patients who received bone marrow transplants were studied sequentially during the posttransplant period to define the pattern of recovering lymphoid cell types. Three patients received T cell-depleted, HLA-matched marrow, and one received untreated marrow from an identical twin. Blood lymphoid cells were labeled with 25 different pairs of monoclonal antibodies. In each sample, one antibody was conjugated to fluorescein and one to phycoerythrin, thus allowing simultaneous assessment of the expression of the two markers using the fluorescence activated cell sorter. A total of 14 antibodies were used, routinely including HLE, Leu-M3, Leu-4, Leu-1, Leu-5, Leu-9, Leu-6, Leu-2, Leu-3, HLA-DR, Leu-7, Leu-11, Leu-15, and Leu-12. Other antibodies were used to further define some populations. This study has allowed us to define six distinct cell types that have appeared in all four patients by day 90 posttransplantation, and which account for 90-100% of all circulating lymphoid cells. These cell types are (a) T helper cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-3, and variable amounts of HLA-DR; (b) T suppressor cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-2, and variable amounts of HLA-DR; (c) B cells expressing Leu-12, B1, HLA-DR, IgD, and IgM, but none of the T cell antigens; (d) an unusual B cell phenotype (Leu-1 B) expressing all of the B cell markers, and also having low amounts of Leu-1, but none of the other T cell antigens; (e) natural killer (NK) cells expressing Leu-11, Leu-15, Leu-5 but none of the other T cell or B cell markers; (f) NK cells expressing Leu-11, Leu-15, Leu-5, and low levels of Leu-2. Both NK types also express Leu-7 on some, but not all cells. The relative frequencies of these cell types varied among the patients and with time, but the striking findings were the presence of relatively few mature T cells, large numbers of NK cells, and the preponderance of the unusual Leu-1 B cell over conventional B cells in all three patients who developed B cells. Sorting experiments confirmed the NK activity of the major NK cell phenotypes, and DNA analysis confirmed that all of the cells studied were of donor origin. In addition, analysis of Ig genes in one patient showed that the Leu-1 B cells were not clonally rearranged.(ABSTRACT TRUNCATED AT 400 WORDS)

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TP53INP1 deficiency maintains murine B lymphopoiesis in aged bone marrow through redox-controlled IL-7R/STAT5 signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1809980116 ◽

2018 ◽

Vol 116 (1) ◽

pp. 211-216 ◽

Cited By ~ 2

Author(s):

Bochra Zidi ◽

Christelle Vincent-Fabert ◽

Laurent Pouyet ◽

Marion Seillier ◽

Amelle Vandevelde ◽

...

Keyword(s):

Oxidative Stress ◽

Bone Marrow ◽

B Cells ◽

B Cell ◽

Immune Cell ◽

B Lymphopoiesis ◽

Hematopoietic Stem ◽

Chronic Oxidative Stress ◽

The Impact ◽

Deficient Mice

Bone marrow (BM) produces all blood and immune cells deriving from hematopoietic stem cells (HSCs). The decrease of immune cell production during aging is one of the features of immunosenescence. The impact of redox dysregulation in BM aging is still poorly understood. Here we use TP53INP1-deficient (KO) mice endowed with chronic oxidative stress to assess the influence of aging-associated redox alterations in BM homeostasis. We show that TP53INP1 deletion has no impact on aging-related accumulation of HSCs. In contrast, the aging-related contraction of the lymphoid compartment is mitigated in TP53INP1 KO mice. B cells that accumulate in old KO BM are differentiating cells that can mature into functional B cells. Importantly, this phenotype results from B cell-intrinsic events associated with defective redox control. Finally, we show that oxidative stress in aged TP53INP1-deficient mice maintains STAT5 expression and activation in early B cells, driving high Pax5 expression, which provides a molecular mechanism for maintenance of B cell development upon aging.

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TAPP2 links phosphoinositide 3-kinase signaling to B-cell adhesion through interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting complex in B-cell leukemia

Blood ◽

10.1182/blood-2009-03-213058 ◽

2009 ◽

Vol 114 (21) ◽

pp. 4703-4712 ◽

Cited By ~ 20

Author(s):

Jennifer L. Costantini ◽

Samuel M. S. Cheung ◽

Sen Hou ◽

Hongzhao Li ◽

Sam K. Kung ◽

...

Keyword(s):

Cell Adhesion ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Cell Types ◽

Potential Interaction ◽

Cytoskeletal Proteins ◽

Lymphocytic Leukemia ◽

Pleckstrin Homology Domain ◽

Ph Domain

Abstract Tandem pleckstrin homology domain proteins (TAPPs) are recruited to the plasma membrane via binding to phosphoinositides produced by phosphoinositide 3-kinases (PI3Ks). Whereas PI3Ks are critical for B-cell activation, the functions of TAPP proteins in B cells are unknown. We have identified 40 potential interaction partners of TAPP2 in B cells, including proteins involved in cytoskeletal rearrangement, signal transduction and endocytic trafficking. The association of TAPP2 with the cytoskeletal proteins utrophin and syntrophin was confirmed by Western blotting. We found that TAPP2, syntrophin, and utrophin are coexpressed in normal human B cells and B-chronic lymphocytic leukemia (B-CLL) cells. TAPP2 and syntrophin expression in B-CLL was variable from patient to patient, with significantly higher expression in the more aggressive disease subset identified by zeta-chain–associated protein kinase of 70 kDa (ZAP70) expression and unmutated immunoglobulin heavy chain (IgH) genes. We examined whether TAPP can regulate cell adhesion, a known function of utrophin/syntrophin in other cell types. Expression of membrane-targeted TAPP2 enhanced B-cell adhesion to fibronectin and laminin, whereas PH domain–mutant TAPP2 inhibited adhesion. siRNA knockdown of TAPP2 or utrophin, or treatment with PI3K inhibitors, significantly inhibited adhesion. These findings identify TAPP2 as a novel link between PI3K signaling and the cytoskeleton with potential relevance for leukemia progression.

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Mast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213418 ◽

2018 ◽

Vol 77 (12) ◽

pp. 1773-1781 ◽

Cited By ~ 20

Author(s):

Felice Rivellese ◽

Daniele Mauro ◽

Alessandra Nerviani ◽

Sara Pagani ◽

Liliane Fossati-Jimack ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

Mast Cells ◽

Disease Activity ◽

B Cell ◽

Synovial Tissue ◽

Autoantibody Production ◽

Early Ra ◽

Treatment Naïve

ObjectivesMast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). However, their contribution remains controversial. To establish their role in RA, we analysed their presence in the synovium of treatment-naïve patients with early RA and their association and functional relationship with histological features of synovitis.MethodsSynovial tissue was obtained by ultrasound-guided biopsy from treatment-naïve patients with early RA (n=99). Immune cells (CD3/CD20/CD138/CD68) and their relationship with CD117+MCs in synovial tissue were analysed by immunohistochemistry (IHC) and immunofluorescence (IF). The functional involvement of MCs in ectopic lymphoid structures (ELS) was investigated in vitro, by coculturing MCs with naïve B cells and anticitrullinated protein antibodies (ACPA)-producing B cell clones, and in vivo in interleukin-27 receptor alpha (IL27ra)-deficient and control mice during antigen-induced arthritis (AIA).ResultsHigh synovial MC counts are associated with local and systemic inflammation, autoantibody positivity and high disease activity. IHC/IF showed that MCs reside at the outer border of lymphoid aggregates. Furthermore, human MCs promote the activation and differentiation of naïve B cells and induce the production of ACPA, mainly via contact-dependent interactions. In AIA, synovial MC numbers increase in IL27ra deficient mice, in association with ELS and worse disease activity.ConclusionsSynovial MCs identify early RA patients with a severe clinical form of synovitis characterised by the presence of ELS.

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Abstract 464: Chemokine Receptor CCR6 Expression on B Cells Augments Local IgM Production and Atheroprotection

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.464 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Cited By ~ 1

Author(s):

Prasad Srikakulapu ◽

Chantel McSkimming ◽

Coleen McNamara

Keyword(s):

B Cells ◽

B Cell ◽

Adoptive Transfer ◽

Chemokine Receptors ◽

Immune Cell ◽

Dependent Manner ◽

Perivascular Adipose Tissue ◽

Cell Recruitment ◽

Cell Numbers ◽

Atherosclerosis Development

Background: CCR6 mediates immune cell recruitment to inflammatory sites and has cell type-specific effects on diet-induced atherosclerosis in mice. Recent studies implicate the local immune responses in the adventitia/perivascular adipose tissue (PVAT) in atherosclerosis development. We have previously demonstrated that adoptive transfer of CD43 - splenocytes (B cells) into B cell deficient μMT -/- ApoE -/- mice results in reduced diet-induced atherosclerosis in a CCR6-dependent manner. Notably, there were significantly greater numbers of B cells in the aorta including PVAT of μMT -/- ApoE -/- mice which received splenic B cells from CCR6 +/+ mice compared to CCR6 -/- mice, despite no difference in B cell numbers in blood, spleen and peritoneal cavity, suggesting that CCR6 expression on B cells is important in B cell aortic homing. Production of IgM antibodies is thought to be a major mechanism whereby B cells limit atherosclerosis development. Yet whether B cells produce IgM locally in the PVAT and whether this is regulated by chemokine receptors such as CCR6 is unknown. Methods and Results: FACS experiments demonstrated high numbers of B cells available in the PVAT than aorta of young ApoE -/- (49121±11190 and 80±11; p<0.001, n=7) mice. ELISPOT experiments demonstrated significantly fewer IgM secreting cells were in the PVAT of ApoE -/- CCR6 -/- mice compared to ApoE -/- CCR6 +/+ mice (100±25 vs 850±150, p<0.05, n=5), despite no differences in IgM secreting cell numbers in spleen and bone marrow. Adoptive transfer of CD43 - splenic B cells from ApoE -/- CCR6 -/- and ApoE -/- CCR6 +/+ mice into secretory IgM deficient ApoE -/- sIgM -/- mice demonstrated significantly reduced atherosclerosis in mice that received B cells from ApoE -/- CCR6 +/+ mice compared to those that received B cells from ApoE -/- CCR6 -/- mice. Moreover, the B cells from ApoE -/- CCR6 +/+ mice attenuated atherosclerosis only when they were capable of secreting IgM. FACS data from human blood demonstrated that circulating B and T cells but not monocytes express CCR6, suggesting potential human relevance to our murine findings. Conclusion: Results provide evidence that CCR6 expression on B cells mediates B cell recruitment into aorta and/or PVAT to provide atheroprotection via IgM secretion.

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