Cellular Mechanism of Immunology in Systemic Lupus Erythematosus

T Cells ◽

Lupus Erythematosus ◽

Plasma Cells ◽

Suppressor Cells ◽

T Helper 1 ◽

Systemic Lupus ◽

Autoantibody Production ◽

Autoreactive T Cells ◽

Cytokine Levels

To date, the mechanism of systemic lupus erythematosus (SLE) has not been thoroughly deciphered. Recent research demonstrated that CD138+ T cells accumulate in an SLE murine model, indicating that they are autoreactive T cells that significantly promote autoantibody production. Double negative (DN) T cells have been demonstrated to participate in the progression of SLE, but their detailed mechanism and the role in SLE remain unclear. Importantly, the expression of CD138 in CD3+ T cells plays a key role in the progression of lupus; it causes the accumulation of autoreactive T cells, including DN T cells, by significantly preventing their apoptosis. T helper 1 cells and interferon gamma both prevail in SLE; they may play essential roles in building the inflammatory condition of SLE. Defects occur in regulatory B (Breg) cells during their expansion in SLE, resulting in more differentiation of activated B cells into plasma cells; this subsequently increases antibody production. Myeloid-derived suppressor cells (MDSCs) enhance the expansion of Breg cells. However, the sustained increase of cytokine levels in SLE promotes the differentiation of more MDSCs into macrophage and dendritic cells, resulting in the defective expansion of MDSCs. The defective expansion of Breg cells and MDSCs breaks the immune-tolerance milieu in SLE, resulting in increased autoantibody secretion from those abnormal plasma cells. This review discusses recent advances regarding the detailed roles and mechanisms of these immunocytes in SLE.

Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1607101113 ◽

2016 ◽

Vol 113 (38) ◽

pp. 10637-10642 ◽

Cited By ~ 45

Author(s):

Elaine V. Lourenço ◽

Aijing Liu ◽

Giuseppe Matarese ◽

Antonio La Cava

Keyword(s):

T Cells ◽

New Zealand ◽

Renal Disease ◽

Lupus Erythematosus ◽

Cellular Level ◽

Presentation Of Self ◽

Systemic Lupus ◽

Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptin-sufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

Scientific Reports ◽

10.1038/s41598-020-62480-3 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

R. Lande ◽

R. Palazzo ◽

N. Gestermann ◽

C. Jandus ◽

M. Falchi ◽

...

Keyword(s):

T Cells ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

The Pathology of T Cells in Systemic Lupus Erythematosus

Journal of Immunology Research ◽

10.1155/2014/419029 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 75

Author(s):

Anselm Mak ◽

Nien Yee Kow

Keyword(s):

Clinical Trials ◽

T Cells ◽

B Cells ◽

Lupus Erythematosus ◽

Calcineurin Inhibitors ◽

Cell Receptor ◽

Systemic Lupus ◽

Autoantibody Production ◽

Lupus Glomerulonephritis

Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoantibodies. Thus, the condition was traditionally classified as a “B-cell disease”. Compelling evidence has however shown that without the assistance of the helper T lymphocytes, it is indeed difficult for the “helpless” B cells to become functional enough to trigger SLE-related inflammation. T cells have been recognized to be crucial in the pathogenicity of SLE through their capabilities to communicate with and offer enormous help to B cells for driving autoantibody production. Recently, a number of phenotypic and functional alterations which increase the propensity to trigger lupus-related inflammation have been identified in lupus T cells. Here, potential mechanisms involving alterations in T-cell receptor expressions, postreceptor downstream signalling, epigenetics, and oxidative stress which favour activation of lupus T cells will be discussed. Additionally, how regulatory CD4+, CD8+, andγδT cells tune down lupus-related inflammation will be highlighted. Lastly, while currently available outcomes of clinical trials evaluating therapeutic agents which manipulate the T cells such as calcineurin inhibitors indicate that they are at least as efficacious and safe as conventional immunosuppressants in treating lupus glomerulonephritis, larger clinical trials are undoubtedly required to validate these as-yet favourable findings.

Fyn and CD70 Expression in CD4+ T Cells from Patients with Systemic Lupus Erythematosus

The Journal of Rheumatology ◽

10.3899/jrheum.090424 ◽

2009 ◽

Vol 37 (1) ◽

pp. 53-59 ◽

Cited By ~ 3

Author(s):

ANNA KOZLOWSKA ◽

PAWEL HRYCAJ ◽

JAN K. LACKI ◽

PAWEL P. JAGODZINSKI

Keyword(s):

T Cells ◽

Disease Activity ◽

Protein Content ◽

Lupus Erythematosus ◽

Cd4 T Cells ◽

Healthy Individuals ◽

Systemic Lupus ◽

Autoantibody Production ◽

Protein Levels

Objective.CD4+ T cells from patients with systemic lupus erythematosus (SLE) display defective function that contributes to abnormal activation of B cells and autoantibody production.Methods.We compared the transcript and protein levels of Fyn and CD70 in CD4+ T cells from patients with SLE (n = 41) and healthy individuals (n = 34). The CD4+ T cells were isolated by positive biomagnetic separation technique. The quantitative analysis of messenger RNA was performed by reverse transcription and real-time quantitative PCR. The protein contents in the CD4+ T cells were determined by Western blotting analysis.Results.We observed significantly higher levels of Fyn (p = 0.03) and CD70 (p = 0.029) transcripts in SLE CD4+ T cells than in controls. There was a significant increase in CD70 protein levels (p < 0.0001), but not Fyn protein levels (p = 0.081) in CD4+ T cells from patients with SLE compared to healthy individuals. In the group with high disease activity [SLE Disease Activity Index (SLEDAI) ≥ 9], we observed a significantly higher Fyn protein content than in controls (p = 0.030). There was no correlation between Fyn and CD70 protein levels in SLE CD4+ T cells and disease activity as expressed in the SLEDAI scale.Conclusion.We confirmed previous observations of higher expression of CD70 in CD4+ T cells from patients with SLE. Our findings suggest that increased Fyn protein content in CD4+ T cells can be associated with high SLE disease activity.

AB0138 INCREASED CD38 EXPRESSION LEVELS ON IMMUNE CELL SUBSETS IN SYSTEMIC LUPUS ERYTHEMATOSUS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6531 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1369.2-1370

Author(s):

L. Ostendorf ◽

P. Enghard ◽

P. Durek ◽

F. Heinrich ◽

M. F. Mashreghi ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Lupus Erythematosus ◽

Plasma Cells ◽

Immune Cell ◽

Systemic Lupus ◽

Cd38 Expression ◽

Cd8 T Lymphocytes ◽

Immune Cell Subsets

Background:Plasma Cells (PCs) are implicated in the pathogenesis of Systemic Lupus erythematosus (SLE) and their targeting proved a promising treatment modality. As there is a monoclonal therapeutic antibody targeting CD38 licensed for clinical use in multiple myeloma, plasma cell depletion via CD38 seems to represent a promising path in SLE treatment. While CD38 Is highly expressed on plasmacells, it is present on the surface of subsets of T and B lymphocytes as well as myeloid cells.Objectives:Here we aim to identify the differential expression of CD38 on peripheral blood leukocytes in SLE compared to healthy controls (HC) investigate the function of CD38+ T lymphocytesMethods:We performed flow cytometry to investigate the expression of CD38 on peripheral blood mononuclear cells of SLE patients (n=36) and HCs (n=20). We additionally analyzed the expression of T lymphocytes within the urine of patients with lupus nephritis as well as the skin of SLE patients. We investigated the inflammatory potential of CD38 positive memory T lymphocytes after stimulation and performed single-cell RNA sequencing analyses.Results:CD38 Expression is increased on certain immune cell subsets: Plasmablasts and unswitched Memory B cells, as well as plasmacytoid dendritic cells and CD16+ non-classical monocytes. We observed a drastic increase CD38 in both memory CD4 and CD8 T lymphocytes in SLE patients. These cells were mostly effector T cells (and not regulatory T cells) and expressed other markers of T cell activation and proliferation. We found an enrichment of CD38+ memory T cells in the urine of patients with lupus nephritis. After polyclonal stimulation of T cells, CD38+ produced less inflammatory cytokines. Preliminary single-cell sequencing results indicate that CD38+ CD8+ T-lymphocytes have decreased clonal diversity and that these cells express genes associated with exhaustion and type 1 interferon response.Conclusion:Increased CD38 expression on various lymphocyte subsets provides an additional rationale for investigating CD38-directed therapies in SLE. Targeting CD38 could not only deplete plasma cells but also has the potential to target interferon alpha producing plasmacytoid dendritic cells and modulate inflammatory T cell functions.Disclosure of Interests:Lennard Ostendorf: None declared, Philipp Enghard: None declared, Pawel Durek: None declared, Frederik Heinrich: None declared, Mir-Farzin Mashreghi: None declared, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Andreas Radbruch: None declared, Falk Hiepe: None declared, Tobias Alexander: None declared

AB0385 TARGETING CD38 IN SYSTEMIC LUPUS ERYTHEMATOSUS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5052 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1493.3-1493

Author(s):

L. Ostendorf ◽

U. Schneider ◽

M. Urbicht ◽

P. Enghard ◽

F. Heinrich ◽

...

Keyword(s):

T Cells ◽

Single Cell ◽

Lupus Erythematosus ◽

Peripheral Blood ◽

Immune Thrombocytopenia ◽

Plasma Cells ◽

Memory T Cells ◽

Systemic Lupus

Background:Depletion of long-lived plasma cells (PC) resembles a novel concept for the treatment of antibody-mediated autoimmune diseases, such as systemic lupus erythematosus (SLE). Therapeutic approaches such as autologuos stem-stem cell transplantation and proteasome inhibition are limited by significant treatment-related toxicity. A novel target for PC depletion is CD38, a surface protein that is highly expressed on plasma cells (PCs) but also activated T-cells and most myeloid cells. Daratumumab is a monoclonal antibody targeting CD38 that is licensed for the treatment of multiple myeloma.Objectives:Here, we aimed to ascertain clinical safety and efficacy of Daratumumab for the treatment of refractory SLE, as well as to gain insights into effects of Daratumumab on the immune system.Methods:We treated two SLE patients with life- and organ-threatening SLE with four weekly dosis of 16 mg/kg Daratumumab. We performed integrative analyses of clinical, serological and immunological effects over a follow-up period of 6 months. Using flow cytometry and single-cell RNA and T-cell receptor sequencing we followed CD38 expression and composition of peripheral blood leukocytes with a special focus on memory T cells.Results:Patient 1, a 50-year old woman, suffered from active biopsy-proven class III lupus nephritis (LN) with nephrotic syndrome, pericarditis, arthritis and skin rash. Upon Daratumumab treatment, her glomerular filtration rate normalized within 3 months and proteinuria gradually declined from 6.4 to 1.9g/g Creatinine during the 180-day follow-up period. Pericarditis, arthritis and skin rash completely resolved. Patient 2, a 32-year-old woman, presented with autoimmune hemolytic anemia requiring blood transfusions, immune thrombocytopenia and cutaneous vasculitis. Her direct antiglobulin test normalized within 3 months and remained negative throughout follow-up with consecutive recovery of the hemolytic anemia. Immune thrombocytopenia stabilized and vasculitic skin lesions completely resolved. Infusions were well tolerated without severe adverse drug reactions. NK cells and Dendritic Cells were transiently depleted, while numbers of T cells, B cells and Monocytes in the peripheral blood remained stable. CD38+ memory T cells that were expanded prior to treatment were virtually undetectable early after treatment. Their single cell transcriptomics demonstrated an upregulation of genes associated with activation, cytotoxicity and type 1 interferon response. CD38+ CD8+ memory T-cells showed marked oligoclonality. These prominent clones persisted upon treatment but their transcription profile gradually normalized.Conclusion:Daratumumab appears to be a safe and effective treatment for refractory SLE. Further investigations are warranted to establish the efficacy in a clinical trial and to gain further insights into the pathophysiologic mechanism of action.Disclosure of Interests:Lennard Ostendorf: None declared, Udo Schneider: None declared, Marie Urbicht: None declared, Philipp Enghard: None declared, Frederik Heinrich: None declared, Pawel Durek: None declared, Gitta Heinz: None declared, Henrik Mei: None declared, Mir-Farzin Mashreghi: None declared, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Andreas Radbruch: None declared, Falk Hiepe: None declared, Tobias Alexander: None declared

T-bet+ CD11c+ B cells are critical for anti-chromatin IgG production in the development of lupus

10.1101/116145 ◽

2017 ◽

Author(s):

Ya Liu ◽

Shiyu Zhou ◽

Jie Qian ◽

Yan Wang ◽

Xiang Yu ◽

...

Keyword(s):

B Cells ◽

Lupus Erythematosus ◽

Plasma Cells ◽

Cell Subset ◽

Absolute Number ◽

Systemic Lupus ◽

Autoantibody Production ◽

Graft Versus Host

AbstractA hallmark of systemic lupus erythematosus is high titers of circulating autoantibody. A novel CD11c+ B cell subset has been identified that is critical for the development of autoimmunity. However, the role of CD11c+ B cells in the development of lupus is unclear. Chronic graft-versus-host disease (cGVHD) is a lupus-like syndrome with great autoantibody production. In the present study we investigated the role of CD11c+ B cells in the pathogenesis of lupus in the cGVHD model. Here, we found the percentage and absolute number of CD11c+ B cells and titer of sera anti-chromatin IgG and IgG2a antibody were increased in cGVHD mice. CD11c+ plasma cells from cGVHD mice produced large amounts of anti-chromatin IgG2a upon stimulation. Depletion of CD11c+ B cells reduced anti-chromatin IgG and IgG2a production. T-bet expression was further shown to be upregulated in CD11c+ B cells. Knockout of T-bet in B cells alleviated cGVHD. The percentage of T-bet+ CD11c+ B cells was elevated in lupus patients and positively correlated with serum anti-chromatin levels. Our findings suggest T-bet+ CD11c+ B cells contribute to the pathogenesis of lupus and provides potential target for therapeutic intervention.

Evidence for a pathogenic role of extrafollicular, IL-10–producing CCR6+B helper T cells in systemic lupus erythematosus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1917834117 ◽

2020 ◽

Vol 117 (13) ◽

pp. 7305-7316 ◽

Cited By ~ 2

Author(s):

F. Facciotti ◽

P. Larghi ◽

R. Bosotti ◽

C. Vasco ◽

N. Gagliani ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Lupus Erythematosus ◽

Ex Vivo ◽

Helper T Cells ◽

Systemic Lupus ◽

Pathogenic Role ◽

Interleukin 10 (IL-10) is an antiinflammatory cytokine, but also promotes B cell responses and plays a pathogenic role in systemic lupus erythematosus (SLE). CD4+CCR6+IL-7R+T cells from human tonsils produced IL-10 following stimulation by naïve B cells, which promoted B cell immunoglobulin G (IgG) production. These tonsillar CCR6+B helper T cells were phenotypically distinct from follicular helper T (TFH) cells and lacked BCL6 expression. In peripheral blood, a CCR6+T cell population with similar characteristics was identified, which lacked Th17- and TFH-associated gene signatures and differentiation-associated surface markers. CD4+CCR6+T cells expressing IL-10, but not IL-17, were also detectable in the spleens of cytokine reporter mice. They provided help for IgG production in vivo, and expanded systemically in pristane-induced lupus-like disease. In SLE patients, CD4+CCR6+IL-7R+T cells were associated with the presence of pathogenic anti-dsDNA (double-stranded DNA) antibodies, and provided spontaneous help for autoantibody production ex vivo. Strikingly, IL-10–producing CCR6+T cells were highly abundant in lymph nodes of SLE patients, and colocalized with B cells at the margins of follicles. In conclusion, we identified a previously uncharacterized population of extrafollicular B helper T cells, which produced IL-10 and could play a prominent pathogenic role in SLE.

The Progress of Investigating the CD137-CD137L Axis as a Potential Target for Systemic Lupus Erythematosus

Cells ◽

10.3390/cells8091044 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1044 ◽

Cited By ~ 1

Author(s):

Anselm Mak ◽

Herbert Schwarz

Keyword(s):

T Cells ◽

Lupus Erythematosus ◽

Critical Role ◽

Costimulatory Molecules ◽

Tumour Necrosis Factor Receptor ◽

Systemic Lupus ◽

Activated T Cells ◽

Autoantibody Production ◽

Proinflammatory Responses

Costimulatory molecules facilitate cross-talks among leukocytes via mutual stimulatory and inhibitory signalling, contributing to diverse immunological outcomes in normal physiological responses and pathological conditions. Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune condition in which cellular communication through the involvement of costimulatory molecules is crucial in driving proinflammatory responses from the stage of autoantigen presentation to the subsequent process of pathogenic autoantibody production. While the physiology of the costimulatory systems including OX40-OX40L, CD28/CTLA-4-CD80/86, ICOS-B7RP1 and CD70-CD27 has been relatively well studied in SLE, recent data on the immunopathology of the CD137-CD137 ligand (CD137L) system in murine lupus models and patients with SLE highlight the critical role of this costimulatory system in initiating and perpetuating the diverse clinical and serological phenotypes of SLE. CD137, a membrane-bound receptor which belongs to the tumour necrosis factor receptor superfamily, is mainly expressed on activated T cells. Activation of the CD137 receptor via its interaction with CD137L which is expressed on antigen present cells (APC) including B cells, triggers bi-directional signalling; that is, signalling through CD137 as well as signalling through CD137L (reverse signalling), which further activates T cells and polarizes them to the Th1/Tc1 pathway. Further, via reverse CD137L signalling it enhances differentiation and maturation of the APC, particularly of dendritic cells, which subsequently drive proinflammatory cytokine production. In this review, recent data including our experience in the manipulation of CD137L signalling pertaining to the pathophysiology of SLE will be critically reviewed. More in-depth understanding of the biology of the CD137-CD137L co-stimulation system opens an opportunity to identify new prognostic biomarkers and the design of novel therapeutic approaches for advancing the management of SLE.

TLR4+CXCR4+ plasma cells drive nephritis development in systemic lupus erythematosus

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213615 ◽

2018 ◽

Vol 77 (10) ◽

pp. 1498-1506 ◽

Cited By ~ 9

Author(s):

Kongyang Ma ◽

Jingyi Li ◽

Xiaohui Wang ◽

Xiang Lin ◽

Wenhan Du ◽

...

Keyword(s):

Lupus Nephritis ◽

Immune Complex ◽

Lupus Erythematosus ◽

Peripheral Blood ◽

Plasma Cells ◽

Renal Tissue ◽

Systemic Lupus ◽

ObjectivesIn patients with systemic lupus erythematosus (SLE), immune tolerance breakdown leads to autoantibody production and immune-complex glomerulonephritis. This study aimed to identify pathogenic plasma cells (PC) in the development of lupus nephritis.MethodsPC subsets in peripheral blood and renal tissue of patients with SLE and lupus mice were examined by flow cytometry and confocal microscopy, respectively. Sorting-purified PCs from lupus mice were adoptively transferred into Rag2-deficient recipients, in which immune-complex deposition and renal pathology were investigated. In culture, PCs from lupus mice and patients with SLE were treated with a TLR4 inhibitor and examined for autoantibody secretion by enzyme-linked immunospot assay (ELISPOT). Moreover, lupus mice were treated with a TLR4 inhibitor, followed by the assessment of serum autoantibody levels and glomerulonephritis activity.ResultsThe frequencies of TLR4+CXCR4+ PCs in peripheral blood and renal tissue were found significantly increased with the potent production of anti-dsDNA IgG, which were associated with severe renal damages in patients with SLE and mice with experimental lupus. Adoptive transfer of TLR4+CXCR4+ PCs from lupus mice led to autoantibody production and glomerulonephritis development in Rag2-deficient recipients. In culture, TLR4+CXCR4+ PCs from both lupus mice and patients with SLE showed markedly reduced anti-dsDNA IgG secretion on TLR4 blockade. Moreover, in vivo treatment with TLR4 inhibitor significantly attenuated autoantibody production and renal damages in lupus mice.ConclusionsThese findings demonstrate a pathogenic role of TLR4+CXCR4+ PCs in the development of lupus nephritis and may provide new therapeutic strategies for the treatment of SLE.