Neutrophil-Mediated IFN Activation in the Bone Marrow Alters B Cell Development in Human and Murine Systemic Lupus Erythematosus

Background:B cell differentiation and dysfunction play a key role in the pathogenesis of Systemic lupus erythematosus (SLE). Bone marrow (BM) is the development organ of B cells, and also the home and residence place of plasma cells and memory B cells. However, there is a lack of studies on B cells in BM with lupus.Objectives:To map the development of BM and peripheral B cells and investigate the mechanism of abnormal early B cell development in SLE.Methods:A total of 11 SLE patients and 5 age- and sex-matched controls were recruited.BM and peripheral B cell subsets were measured by flow cytometry. sorting-purified B cell subsets were subject toSingle-cell RNA sequencing (scRNA-seq) and functional studies. Plasma cytokines and secreted immunoglobulins were detected by Luminex or ELISA. Disease activity of SLE patients was measured using the SLE Disease Activity Index (SLEDAI).Results:In the present study, we find out that the percentage of monocytes in MNC (p=0.070) and plasma cells(p=0.001)in CD19+ were significantly decreased in BM of SLE, compared to healthy controls. While, SLE patients had increased T%MNC(p=0.008) and B%CD19+(p=0.002) in BM that controls. In detail, the B cell subsets of bone marrow in patients with active lupus (SLEDAI≥8 score) were seriously disordered, showing the increasing T%MNC(p=0.049), propre-B%CD19+ (p=0.006)and immature B cell%CD19+ (p=0.010) than healthy donors. propre-B%CD19+ exhibited good relationship with SLEDAI. By integrating single B cell expression profiling and repertoire analysis, we map the development of B cells in BM and peripheral and pathogenic characteristics of early B cells, especially propre-B.Conclusion:These findings demonstrated that early B cells in BM, especially propre-B are abnormally differentiated with dysregulations. BM is an important organ targeted by SLE. This studyis not only to clarify the internal mechanism of the disorder of differentiation of B cells, but also to provide new clues for the targeted diagnosis and treatment of SLE.References:[1]Palanichamy, A., et al.,Neutrophil-mediated IFN activation in the bone marrow alters B cell development in human and murine systemic lupus erythematosus.J Immunol, 2014.192(3): p. 906-18.[2]Papadaki, H.A., J.C. Marsh, and G.D. Eliopoulos,Bone marrow stem cells and stromal cells in autoimmune cytopenias.Leuk Lymphoma, 2002.43(4): p. 753-60.[3]Karrar, S. and D.S. Cunninghame Graham,Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us.Arthritis Rheumatol, 2018.70(4): p. 496-507.[4]Woods, M., Y.R. Zou, and A. Davidson,Defects in Germinal Center Selection in SLE.Front Immunol, 2015.6: p. 425.[5]Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients.Cell Signal, 2012.24(12): p. 2307-14.Disclosure of Interests:None declared

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Review: Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us

Arthritis & Rheumatology ◽

10.1002/art.40396 ◽

2018 ◽

Vol 70 (4) ◽

pp. 496-507 ◽

Cited By ~ 13

Author(s):

Sarah Karrar ◽

Deborah S. Cunninghame Graham

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Development ◽

B Cell Development ◽

Systemic Lupus

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Impact of genetic variants on B-cell development and function in systemic lupus erythematosus

Arthritis Research & Therapy ◽

10.1186/ar4624 ◽

2014 ◽

Vol 16 (Suppl 1) ◽

pp. A8

Author(s):

Karen Cerosaletti ◽

Tania Habib ◽

Richard James ◽

Janice Chen ◽

Melissa Pickett ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cell ◽

Lupus Erythematosus ◽

Genetic Variants ◽

Cell Development ◽

B Cell Development ◽

Systemic Lupus ◽

And Function

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OP0073 SINGLE-CELL TRANSCRIPTOMICS UNCOVERS DEFECTIVE BONE MARROW EARLY B CELL DEVELOPMENT IN A SUBSET OF LUPUS PATIENTS ASSOCIATED WITH AGGRAVATED INFLAMMATION

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3061 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 39.2-39

Author(s):

C. Dong ◽

X. Gu ◽

J. Ji ◽

X. Zhang ◽

Z. Gu

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Development ◽

B Cell Development ◽

Cell Tolerance ◽

Systemic Lupus ◽

B Cell Tolerance ◽

Healthy Donors

Background:Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that occurs when the body’s immune system attacks own tissues and organs. B cells play a central role in SLE pathogenesis by producing autoantibodies as well as antibody-independent functions. Peripheral B cell abnormality is well known in lupus patients such as expansions of plasmablasts and atypical memory B cells, which are associated with active diseases. However, little is known about the B cell development in the bone marrow of lupus patients.Objectives:We conduct this survey to explore the disorder of the B cell development in the bone marrow of lupus patients.Methods:In this study, we have performed the scRNASeq to profile the bone marrow B cell compartment in lupus patients and healthy donors.Results:We identified that in a subset of lupus patients, the early B cells (proB and preB cells) were strongly decreased, which were confirmed by flow cytometry in an expanded cohort. Furthermore, bone marrow B cells from these patients showed a strong proinflammatory signature revealed by pathway analysis. Interestingly, BCR repertoire analysis showed that the IGHV-4-34 was highly enriched in these patients, indicating an enhanced B cell tolerance defect. Finally, a panel of proinflammatory cytokines (TNF-a, IL-1a, IL-12p70, IFN-g, et al.) were strongly increased in the bone marrow plasma of these patients compared with early B normal patients and healthy donors, confirming a localized proinflammatory microenvironment.Conclusion:Altogether, the current study has revealed that a defective early B cell development in lupus patients is associated with a more severe B cell tolerance defect and aggravated inflammation, which may shed new light on developing novel therapies by targeting relevant pathways.References:[1]Min Wang, Hua Chen, Jia Qiu, et al. Antagonizing miR-7 suppresses B cell hyperresponsiveness and inhibits lupus development. J Autoimmun 2020.[2]A M Jacobi, D M Goldenberg, F Hiepe, et al. Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls. Ann Rheum Dis, 2008.Acknowledgements:This work was funded by Special project of clinical medicine of Nantong University (Grant/Award number: 2019LQ001), National Natural Science Foundation of China (Grant/Award number: 81671616, 81871278 and 82071838).Disclosure of Interests:None declared

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Immunomodulatory effects of H.P. Acthar Gel on B cell development in the NZB/W F1 mouse model of systemic lupus erythematosus

Lupus ◽

10.1177/0961203314531840 ◽

2014 ◽

Vol 23 (8) ◽

pp. 802-812 ◽

Cited By ~ 14

Author(s):

DA Decker ◽

C Grant ◽

L Oh ◽

PM Becker ◽

D Young ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Mouse Model ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Development ◽

B Cell Development ◽

Immunomodulatory Effects ◽

Systemic Lupus

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The Yaa Locus and IFN-α Fine-Tune Germinal Center B Cell Selection in Murine Systemic Lupus Erythematosus

The Journal of Immunology ◽

10.4049/jimmunol.1200745 ◽

2012 ◽

Vol 189 (9) ◽

pp. 4305-4312 ◽

Cited By ~ 22

Author(s):

Ioana Moisini ◽

Weiqing Huang ◽

Ramalingam Bethunaickan ◽

Ranjit Sahu ◽

Peta-Gay Ricketts ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cell ◽

Lupus Erythematosus ◽

Germinal Center ◽

Cell Selection ◽

Systemic Lupus ◽

Germinal Center B Cell ◽

Murine Systemic Lupus Erythematosus ◽

Fine Tune

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CTLA4Ig inhibits T cell–dependent B-cell maturation in murine systemic lupus erythematosus

Journal of Clinical Investigation ◽

10.1172/jci9244 ◽

2000 ◽

Vol 106 (1) ◽

pp. 91-101 ◽

Cited By ~ 118

Author(s):

Masahiko Mihara ◽

Irene Tan ◽

Yelena Chuzhin ◽

Bhoompally Reddy ◽

Lalbachan Budhai ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cell ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Maturation ◽

Systemic Lupus ◽

B Cell Maturation ◽

Murine Systemic Lupus Erythematosus

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Hidden autoantibodies against common serum proteins in murine systemic lupus erythematosus. Detection by in vitro plaque-forming cell assay.

Journal of Experimental Medicine ◽

10.1084/jem.161.6.1587 ◽

1985 ◽

Vol 161 (6) ◽

pp. 1587-1592 ◽

Cited By ~ 3

Author(s):

P L Cohen ◽

R G Rapoport ◽

R A Eisenberg

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Activation ◽

Serum Proteins ◽

B Cell Activation ◽

Systemic Lupus ◽

Autoantibody Production ◽

Murine Systemic Lupus Erythematosus

The autoantibodies found in human and murine systemic lupus erythematosus (SLE) are generally directed against cells or components of cells such as nuclear antigens. This predilection may be due to the unusual immunogenicity of certain autoantigens, or to unusual patterns of antibody crossreactivity. Alternatively, the observed spectrum of reactivities may reflect the in vivo absorption of those autoantibodies directed against soluble antigens. To test whether hitherto undetected autoantibodies against serum proteins might exist in murine SLE, we developed assays that were independent of the possibility of absorption of autoantibodies by serum autoantigens; large numbers of plaque-forming cells (PFC) directed against mouse albumin and mouse transferrin were easily detected in the spleens of MRL/Mp-lpr/lpr, BXSB, and NZB mice. The secreted antibodies were relatively specific for the mouse proteins, since only limited cross-reactivity was seen with albumin and transferrins of other species in inhibition experiments. The production of these hidden antibodies could not be the result of diffuse polyclonal B cell activation, since the PFC to mouse transferrins and albumin were not always accompanied by comparable numbers of PFC against related albumins and transferrins. The results indicate that autoantibody production in murine lupus is a generalized phenomenon, not limited to the production of autoantibodies to nuclear or other cell-bound antibodies. However, the relative specificity of the autoantibodies for self-antigens indicates that diffuse polyclonal B cell activation cannot be the mechanism responsible, and argues that a selective mechanism, probably driven by antigen, accounts for production of autoantibodies in SLE.

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Intrinsic B cell defects in NZB and NZW mice contribute to systemic lupus erythematosus in (NZB x NZW)F1 mice.

Journal of Experimental Medicine ◽

10.1084/jem.184.3.853 ◽

1996 ◽

Vol 184 (3) ◽

pp. 853-861 ◽

Cited By ~ 93

Author(s):

L Reininger ◽

T H Winkler ◽

C P Kalberer ◽

M Jourdan ◽

F Melchers ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cells ◽

B Cell ◽

Cell Lines ◽

Lupus Erythematosus ◽

Fetal Liver ◽

Systemic Lupus ◽

Murine Systemic Lupus Erythematosus ◽

B Lineage

We have previously shown that long-term in vitro proliferating fetal liver pre-B cell lines derived from autoimmune-prone (NZB x NZW)F1 (BW) mice, but not normal (B6 x DBA2)F1 mice, can differentiate in severe combined immunodeficient (SCID) mice to produce elevated levels of serum immunoglobulin (Ig) M and IgG, and high titers of antinuclear antibodies The contribution of parental NZB and NZW strains to B cell abnormalities of BW hybrid mice was investigated here by preparing pre-B cells and transferring them into immunodeficient SCID- and RAG-2-targeted mice. We show that transfer of NZB pre-B cells led to a marked IgM hypergammaglobulinemia and to the production of limited amounts of IgG2a. On the other hand, the transfer of NZW pre-B cell lines led to moderately elevated IgM levels and marked hypergammaglobulinemia of IgG2a. High IgM and low IgG anti-DNA titers are found in the recipients of NZB pre-B cells, whereas those receiving NZW pre-B cells contained lower levels of IgM and high titers of IgG anti-DNA. In marked contrast, essentially identical titers of antibodies directed against a non-self-antigen, DNP, are found in all group of pre-B cell recipients. Thus, B-lineage cells of both NZB and NZW parental strains manifest abnormalities associated with the development of this lupus-like disease. Therefore, the present study strongly suggests a complex inheritance of B cell abnormalities in autoimmune-prone (NZB x NZW)F1 mice and emphasizes the critical importance of intrinsic B cell defects in the development of murine systemic lupus erythematosus.

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