Anti-Carbamylated LL37 Antibodies Promote Pathogenic Bone Resorption in Rheumatoid Arthritis

O’Neil, Liam J.; Oliveira, Christopher B; Sandoval-Heglund, Donavon; Barrera‐Vargas, Ana; Merayo-Chalico, Javier; Aguirre-Aguilar, Eduardo; Kaplan, Mariana J.; Carmona‐Rivera, Carmelo

doi:10.3389/fimmu.2021.715997

Cited by 14 publications

(14 citation statements)

References 31 publications

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“…NET-induced OCs are functionally active, responding to RANKL in vitro to degrade bone. Of interest, NET-mediated osteoclastogenesis is enhanced by the presence of carbamylated proteins in the NETs, a PTM that is associated with aberrant adaptive immune responses that is linked to bone erosions in patients with RA 4 15 36…”

Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular trap-associated carbamylation and histones trigger osteoclast formation in rheumatoid arthritis

O’Neil

Oliveira

Wang

et al. 2023

Annals of the Rheumatic Diseases

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ObjectiveNeutrophil infiltration into the synovial joint is a hallmark of rheumatoid arthritis (RA), a disease characterised by progressive bone erosion. However, the mechanisms by which neutrophils participate in bone destruction remain unclear. Carbamylation is a posttranslational modification linked to increased bone erosion in RA and we previously showed that carbamylation is present in RA neutrophil extracellular traps (NETs). However, it remains unclear whether NETs and their carbamylated protein cargo directly promote bone destruction and alter osteoclast biology.MethodsNETs and carbamylated NETs (cNETs) were assessed for their capacity to induce osteoclast formation in CD14+ monocytes. Chemical inhibitors and neutralising antibodies were used to elucidate the pathway by which NETs induce osteoclastogenesis. HLA-DRB1*04:01 mice received intra-articular injection of cNETs for 4 weeks. Joints were isolated and assessed for osteoclast formation. Plasma and synovial fluid samples from patients with RA (n=32) were assessed for the presence of carbamylated histone, and correlations to disease specific outcomes were performed.ResultsWe found that NETs, when cNETs, instruct monocytes to undergo rapid osteoclast formation. NET-mediated osteoclastogenesis appears to depend on Toll-like receptor 4 signalling and NET-associated proteins including histones and neutrophil elastase. In vivo, we identified that the number of osteoclasts increased following immunisation with cNETs in HLA-DRB1*04:01 transgenic mice. Furthermore, carbamylated histones are increased in plasma and synovial fluid from patients with RA and correlate with active bone resorption and inflammatory markers.ConclusionsOur results suggest that NETs have a direct role in RA-associated bone erosion by promoting osteoclast formation.

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Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular trap-associated carbamylation and histones trigger osteoclast formation in rheumatoid arthritis

O’Neil

Oliveira

Wang

et al. 2023

Annals of the Rheumatic Diseases

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“…However, autoimmune patients have impaired tolerance and are at higher risk for developing cardiovascular disease (44) suggesting potentially shared pathophysiology. Among the self-antigens of interest, we focused our work on LL-37, a T cell autoantigen in psoriasis and SLE (11)(12)(13)(14), that plays a role in innate immune responses as damage-associated molecular pattern (DAMP) (45) as well as its participation in thrombus formation (19), both key elements of ACS. Increased LL-37 expression by intermediate monocytes in single-cell RNA sequencing assay of PBMCs was recently demonstrated in acute MI (2).…”

Section: Discussionmentioning

confidence: 99%

“…However, the nature of the persistent presence of Memory T cells reactive to the self-antigen LL-37 in ACS patients compared to Controls and stable ASCVD patients remains unclear (6). LL-37 immune response is correlated with disease flare up and activity in autoimmune diseases (11)(12)(13)(14). Thus, we evaluated T cell response to LL-37 in the context of healthy Controls and ACS patients using T cell immune activation, function, and memory markers.…”

Section: Introductionmentioning

confidence: 99%

“…LL-37 is the only known human cathelicidin type antimicrobial peptide ( 6 , 10 ). It is an autoantigen in psoriasis and other autoimmune diseases ( 11 – 15 ) that are known to increase the risk of cardiovascular events. It is a component of neutrophil extracellular traps (NETs) that are implicated in atherogenesis ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

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Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome

et al. 2023

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BackgroundLL-37 is the only member of the cathelicidin family of antimicrobial peptides in humans and is an autoantigen in several autoimmune diseases and in acute coronary syndrome (ACS). In this report, we profiled the specific T cell response to the autoimmune self-antigen LL-37 and investigated the factors modulating the response in peripheral blood mononuclear cells (PBMCs) of healthy subjects and ACS patients.Methods and resultsThe activation induced marker (AIM) assay demonstrated differential T cell profiles characterized by the persistence of CD134 and CD137, markers that impair tolerance and promote immune effector and memory response, in ACS compared to Controls. Specifically, CD8+CD69+CD137+ T cells were significantly increased by LL-37 stimulation in ACS PBMCs. T effector cell response to LL-37 were either HLA dependent or independent as determined by blocking with monoclonal antibody to either Class-I HLA or Class-II HLA. Blocking of immune checkpoints PD-1 and CTLA-4 demonstrated the control of self-reactive T cell response to LL-37 was modulated predominantly by CTLA-4. Platelets from healthy controls down-modulated CD8+CD69+CD137+ T cell response to LL-37 in autologous PBMCs. CD8+CD69+CD137+ T cell AIM profile negatively correlated with platelet count in ACS patients.ConclusionsOur report demonstrates that the immune response to the autoantigen LL-37 in ACS patients is characterized specifically by CD8+CD69+CD137+ T cell AIM profile with persistent T cell activation and the generation of immunologic memory. The results provide potentially novel insight into mechanistic pathways of antigen-specific immune signaling in ACS.

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“…Auto-immunity and periodontitis are connected in many ways. Patients with auto-immune conditions such as Lupus or RA are known to be more prone to developing periodontitis ( 55 , 108 ). Bone destruction in periodontitis shares similarities with tissue damage observed during RA and presents a TH17 cytokines overexpression that can be also found in RA, Lupus psoriasis, and many other auto-immune conditions ( 109 , 110 ).…”

Section: Can Antimicrobial Peptides Affect the Function Of B-cells In...mentioning

confidence: 99%

Could AMPs and B-cells be the missing link in understanding periodontitis?

Lobognon¹,

Alard²

2022

Front. Immunol.

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Periodontal diseases are common inflammatory conditions characterized by bone loss in response to simultaneous bacterial aggression and host defenses. The etiology of such diseases is still not completely understood, however. It has been shown that specific pathogens involved in the build-up of dysbiotic biofilms participate actively in the establishment of periodontitis. This multifactorial pathology also depends on environmental factors and host characteristics, especially defenses. The immune response to the pathogens seems to be critical in preventing the disease from starting but also contributes to tissue damage. It is known that small molecules known as antimicrobial peptides (AMPs) are key actors in the innate immune response. They not only target microbes, but also act as immuno-modulators. They can help to recruit or activate cells such as neutrophils, monocytes, dendritic cells, or lymphocytes. AMPs have already been described in the periodontium, and their expression seems to be connected to disease activity. Alpha and beta defensins and LL37 are the AMPs most frequently linked to periodontitis. Additionally, leukocyte infiltrates, especially B-cells, have also been linked to the severity of periodontitis. Indeed, the particular subpopulations of B-cells in these infiltrates have been linked to inflammation and bone resorption. A link between B-cells and AMP could be relevant to understanding B-cells’ action. Some AMP receptors, such as chemokines receptors, toll-like receptors, or purinergic receptors, have been shown to be expressed by B-cells. Consequently, the action of AMPs on B—cell subpopulations could participate to B-cell recruitment, their differentiation, and their implication in both periodontal defense and destruction.

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Anti-Carbamylated LL37 Antibodies Promote Pathogenic Bone Resorption in Rheumatoid Arthritis

Cited by 14 publications

References 31 publications

Neutrophil extracellular trap-associated carbamylation and histones trigger osteoclast formation in rheumatoid arthritis

Neutrophil extracellular trap-associated carbamylation and histones trigger osteoclast formation in rheumatoid arthritis

Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome

Could AMPs and B-cells be the missing link in understanding periodontitis?

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