Immune Tolerance Defects in Lupus

Singh, Ram Raj; Dubey, Shweta; Pinkhasov, Julia

doi:10.1016/b978-1-4377-1893-5.00019-4

Cited by 4 publications

(5 citation statements)

References 189 publications

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“…Thus, patients present with a wide variety of clinical manifestations. Dysregulation of immune cells, such as dendritic cells (DCs), and B and T cells, has been implicated in the systemic autoimmunity best reflected by the presence of autoAbs against systemic autoantigens, such as dsDNA (1). However, since specific organ involvement varies from patient to patient, organ-specific tolerance may also play a role in regulating tissue-specific injury.…”

Section: Introductionmentioning

confidence: 99%

Langerhans Cells Maintain Local Tissue Tolerance in a Model of Systemic Autoimmune Disease

King

Philips

Eriksson

et al. 2015

The Journal of Immunology

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Systemic autoimmune diseases such as lupus affect multiple organs, usually in a diverse fashion where only certain organs are affected in individual patients. It is unclear whether the ‘local’ immune cells play a role in regulating tissue specificity in relation to disease heterogeneity in systemic autoimmune diseases. Here, we used skin as a model to determine the role of tissue-resident dendritic cells in local and systemic involvement within a systemic lupus disease model. Skin-resident dendritic cells, namely Langerhans cells (LC), have been implicated in regulating tolerance or autoimmunity using elegant transgenic models, however, their role in local versus systemic immune regulation is unknown. We demonstrate that while lymphocytes from skin-draining lymph nodes of autoimmune-prone MRL/MpJ-Faslpr/lpr mice react spontaneously to a physiological skin self-Ag desmoglein-3, epicutaneous applications of desmoglein-3 induced tolerance that is dependent on LCs. Inducible ablation of LCs in adult, preclinical MRL/MpJ-Faslpr/lpr and MRL/MpJ-Fas+/+ mice resulted in increased autoantibodies against skin Ags and markedly accelerated lupus dermatitis with increased local macrophage infiltration, but had no effect on systemic autoantibodies such as anti-dsDNA Abs or disease in other organs such as kidneys, lung, and liver. Furthermore, skin-draining lymph nodes of LC-ablated MRL/MpJ-Faslpr/lpr mice had significantly fewer CD4+ T-cells producing anti-inflammatory cytokine IL-10 than LC-intact controls. These results indicate that a skin-resident dendritic cell population regulates local tolerance in systemic lupus and emphasize the importance of the local immune milieu in preventing tissue-specific autoimmunity yet have no effect on systemic autoimmunity.

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Section: Introductionmentioning

confidence: 99%

Langerhans Cells Maintain Local Tissue Tolerance in a Model of Systemic Autoimmune Disease

King

Philips

Eriksson

et al. 2015

The Journal of Immunology

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“…These observations suggest that immune cells in SLO in humans and animals with lupus are in an active state. Although the exact pathogenic contributions of these abnormalities are not fully understood, SLO abnormalities may contribute to autoimmune pathogenesis in multiple ways including initial breakdown of tolerance and activation of autoreactive T and B cells (10,11,36). For example, tissue-resident dendritic cells that carry local antigens to tissue-draining lymph nodes to induce tolerance do not migrate well to lymph nodes in lupus-prone mice, thus contributing to loss of tolerance and inflammation (37,38).…”

Section: Secondary Lymphoid Organsmentioning

confidence: 99%

“…Impaired tolerance to self-antigens via various mechanisms marks the early step in the pathogenesis of autoimmune diseases (10,11), resulting in the initial activation of autoreactive cells. These activated autoimmune cells may then infiltrate the target organs, where the persistent exposure to antigens in chronically inflamed environments keeps them activated.…”

Section: Introductionmentioning

confidence: 99%

Tertiary lymphoid structures as local perpetuators of organ-specific immune injury: implication for lupus nephritis

Wang,

Rajkumar,

Lai

et al. 2023

Front. Immunol.

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In response to inflammatory stimuli in conditions such as autoimmune disorders, infections and cancers, immune cells organize in nonlymphoid tissues, which resemble secondary lymphoid organs. Such immune cell clusters are called tertiary lymphoid structures (TLS). Here, we describe the potential role of TLS in the pathogenesis of autoimmune disease, focusing on lupus nephritis, a condition that incurs major morbidity and mortality. In the kidneys of patients and animals with lupus nephritis, the presence of immune cell aggregates with similar cell composition, structure, and gene signature as lymph nodes and of lymphoid tissue-inducer and -organizer cells, along with evidence of communication between stromal and immune cells are indicative of the formation of TLS. TLS formation in kidneys affected by lupus may be instigated by local increases in lymphorganogenic chemokines such as CXCL13, and in molecules associated with leukocyte migration and vascularization. Importantly, the presence of TLS in kidneys is associated with severe tubulointerstitial inflammation, higher disease activity and chronicity indices, and poor response to treatment in patients with lupus nephritis. TLS may contribute to the pathogenesis of lupus nephritis by increasing local IFN-I production, facilitating the recruitment and supporting survival of autoreactive B cells, maintaining local production of systemic autoantibodies such as anti-dsDNA and anti-Sm/RNP autoantibodies, and initiating epitope spreading to local autoantigens. Resolution of TLS, along with improvement in lupus, by treating animals with soluble BAFF receptor, docosahexaenoic acid, complement inhibitor C4BP(β-), S1P1 receptor modulator Cenerimod, dexamethasone, and anti-CXCL13 further emphasizes a role of TLS in the pathogenesis of lupus. However, the mechanisms underlying TLS formation and their roles in the pathogenesis of lupus nephritis are not fully comprehended. Furthermore, the lack of non-invasive methods to visualize/quantify TLS in kidneys is also a major hurdle; however, recent success in visualizing TLS in lupus-prone mice by photon emission computed tomography provides hope for early detection and manipulation of TLS.

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Section: Introductionmentioning

confidence: 99%

“…Compromised tolerance to self-antigens is an early step in the development of systemic lupus erythematosus (SLE) ( 1 , 2 ). Among the diverse mechanisms that can mediate this process ( 1 ), NETosis is believed to play a major role. NETosis was first reported as a specialized form of cell death that occurs in neutrophils with neutrophil extracellular traps (NETs) released.…”

Section: Introductionmentioning

confidence: 99%

Diverse Roles of NETosis in the Pathogenesis of Lupus

et al. 2022

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NETosis is a form of neutrophil cell death during which extracellular fibrillary structures composed of cytosolic and granule proteins assembled on scaffolds of decondensed chromatin, called neutrophil extracellular traps (NETs), are released. NETs normally contribute to host immune defense. Accumulating evidence implicates aberrant NET production and/or reduced NET clearance, along with alterations of molecules involved in NETosis pathway, in humans and animals with lupus. The extruded nuclear antigens released by NET are a source of autoantigens, which can contribute to the breakdown of self-tolerance in lupus. Excessive NET can also promote the production of pro-inflammatory cytokine interferon-α, elicit direct cytotoxic effect on various renal cells, and cause capillary necrosis and podocyte loss. Additionally, NET can induce endothelial-to-mesenchymal transdifferentiation, which can promote activated myofibroblasts leading to extracellular matrix production. Thus, aberrant NETosis can play diverse roles, including autoantibody production, inflammation, and tissue damage, at different stages of lupus pathogenesis. Evidence suggests that treatments currently used in lupus may reduce NETosis, suggesting a potential utility of targeting NETosis to treat lupus. In fact, several approaches are being experimented to therapeutically target pathways of NETosis. Future studies should precisely delineate distinct roles of NETosis at different stages of lupus pathogenesis in humans, which would offer a rational basis for NETosis-targeting treatments in the clinic.

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Immune Tolerance Defects in Lupus

Cited by 4 publications

References 189 publications

Langerhans Cells Maintain Local Tissue Tolerance in a Model of Systemic Autoimmune Disease

Langerhans Cells Maintain Local Tissue Tolerance in a Model of Systemic Autoimmune Disease

Tertiary lymphoid structures as local perpetuators of organ-specific immune injury: implication for lupus nephritis

Diverse Roles of NETosis in the Pathogenesis of Lupus

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