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1.
Int J Mol Sci ; 24(1)2022 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-36614095

RESUMO

CXCL4 is an important biomarker of systemic sclerosis (SSc), an incurable autoimmune disease characterized by vasculopathy and skin/internal organs fibrosis. CXCL4 contributes to the type I interferon (IFN-I) signature, typical of at least half of SSc patients, and its presence is linked to an unfavorable prognosis. The mechanism implicated is CXCL4 binding to self-DNA, with the formation of complexes amplifying TLR9 stimulation in plasmacytoid dendritic cells (pDCs). Here, we demonstrate that, upon binding to self-RNA, CXCL4 protects the RNA from enzymatic degradation. As a consequence, CXCL4-RNA complexes persist in vivo. Indeed, we show for the first time that CXCL4-RNA complexes circulate in SSc plasma and correlate with both IFN-I and TNF-α. By using monocyte-derived DCs (MDDCs) pretreated with IFN-α as a model system (to mimic the SSc milieu of the IFN-I signature), we demonstrate that CXCL4-RNA complexes induce MDDC maturation and increase, in particular, pro-inflammatory TNF-α as well as IL-12, IL-23, IL-8, and pro-collagen, mainly in a TLR7/8-dependent but CXCR3-independent manner. In contrast, MDDCs produced IL-6 and fibronectin independently in their CXCL4 RNA-binding ability. These findings support a role for CXCL4-RNA complexes, besides CXCL4-DNA complexes, in immune amplification via the modulation of myeloid DC effector functions in SSc and also during normal immune responses.


Assuntos
Fator Plaquetário 4 , RNA , Escleroderma Sistêmico , Humanos , Inibidores da Angiogênese/metabolismo , Células Dendríticas , Fibrose , Fatores Imunológicos/metabolismo , Interferon-alfa/metabolismo , Fator Plaquetário 4/metabolismo , RNA/metabolismo , Escleroderma Sistêmico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
Int J Mol Sci ; 22(4)2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33562078

RESUMO

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to "self" nucleic acids, LL37 acts as "danger signal," leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while "fully-citrullinated" LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated "adjuvant-like" properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to "fully citrullinated-LL37," "fully carbamylated-LL37" maintains both innate and adaptive immune-cells' stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers.


Assuntos
Adjuvantes Imunológicos/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Autoantígenos/química , Lúpus Eritematoso Sistêmico/imunologia , Processamento de Proteína Pós-Traducional/genética , Autoanticorpos/imunologia , Autoantígenos/imunologia , Autoimunidade/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Citrulinação/imunologia , Células Dendríticas/imunologia , Epitopos de Linfócito T/imunologia , Cadeias HLA-DRB1/imunologia , Cadeias HLA-DRB5/imunologia , Humanos , Interferon Tipo I/imunologia , Ativação Linfocitária/imunologia , Carbamilação de Proteínas/imunologia , Catelicidinas
3.
Int J Mol Sci ; 21(14)2020 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-32707718

RESUMO

Systemic sclerosis (SSc) is characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an SSc biomarker, predicting unfavorable prognosis and lung fibrosis. CXCL4 binds DNA/RNA and favors interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs), contributing to the type I IFN (IFN-I) signature in SSc patients. However, whether CXCL4 is an autoantigen in SSc is unknown. Here, we show that at least half of SSc patients show consistent antibody reactivity to CXCL4. T-cell proliferation to CXCL4, tested in a limited number of patients, correlates with anti-CXCL4 antibody reactivity. Antibodies to CXCL4 mostly correlate with circulating IFN-α levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4-DNA complex's effect on IFN-α production by pDCs; CXCL4-DNA/RNA complexes stimulate purified human B-cells to become antibody-secreting plasma cells in vitro. These data indicate that CXCL4 is indeed an autoantigen in SSc and suggest that CXCL4, and CXCL4-specific autoantibodies, can fuel a harmful loop: CXCL4-DNA/RNA complexes induce IFN-α in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-α release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation.


Assuntos
Autoanticorpos/sangue , Interferon Tipo I/sangue , Fator Plaquetário 4/imunologia , Escleroderma Sistêmico/imunologia , Imunidade Adaptativa , Adulto , Idoso , Especificidade de Anticorpos , Autoantígenos/imunologia , Linfócitos B/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Proliferação de Células , Colite Ulcerativa/imunologia , DNA/imunologia , Células Dendríticas/imunologia , Feminino , Voluntários Saudáveis , Humanos , Imunidade Inata , Memória Imunológica , Técnicas In Vitro , Interferon-alfa/sangue , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia
4.
Antibodies (Basel) ; 13(1)2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38534212

RESUMO

Autoantibodies represent a primary characteristic of many systemic autoimmune diseases [...].

5.
Antibodies (Basel) ; 10(2)2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800661

RESUMO

Chemokine (C-X-C motif) ligand 4 (CXCL4) is a biomarker of unfavorable prognosis in Systemic Sclerosis (SSc), a potentially severe autoimmune condition, characterized by vasculitis, fibrosis and interferon (IFN)-I-signature. We recently reported that autoantibodies to CXCL4 circulate in SSc patients and correlate with IFN-α. Here, we used shorter versions of CXCL4 and CXCL4-L1, the CXCL4 non-allelic variant, to search for autoantibodies exclusively reacting to one or the other CXCL4 form. Moreover, to address whether anti-CXCL4/CXCL4-L1 antibodies were present before SSc onset and predicted SSc-progression, we longitudinally studied two VEDOSS (Very Early Diagnosis of Systemic Sclerosis) patient cohorts, separating SSc-progressors from SSc-non-progressors. We found that anti-CXCL4-specific autoantibodies were present in both SSc and VEDOSS patients (both SSc-progressors and SSc-non-progressors). Anti-CXCL4-L1-specific autoantibodies were especially detected in long-standing SSc (lsSSc). Anti-CXCL4/CXCL4-L1 antibodies correlated with IFN-α and with specific SSc-skin features but only in lsSSc and not in early SSc (eaSSc) or VEDOSS. Thus, a broader antibody response, with reactivity spreading to CXCL4-L1, is characteristic of lsSSc. The early anti-CXCL4 autoantibody response seems qualitatively different from, and likely less pathogenic than, that observed in advanced SSc. Lastly, we confirm that anti-CXCL4 autoantibodies are SSc-biomarkers and uncover that also CXCL4-L1 becomes an autoantigen in lsSSc.

6.
JAMA Dermatol ; 153(4): 304-308, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28122069

RESUMO

IMPORTANCE: Treatment of pityriasis rubra pilaris (PRP) is solely based on its resemblance to psoriasis rather than any knowledge of its pathomechanism. Insight into pathogenic mediators of inflammation is essential for targeted and valid treatment options that could replace previous serendipitous therapeutic approaches in refractory PRP. OBJECTIVE: To determine whether blockade of the interleukin 23-helper T cell 17 (IL-23-TH17) pathway with ustekinumab represents an efficacious and, based on its proinflammatory cytokine profile, targeted treatment option in PRP. DESIGN, SETTING, AND PARTICIPANTS: In this case report, a patient with PRP received outpatient treatment at a university hospital department of dermatology with ustekinumab according to the dosing regimen approved for psoriasis. Lesional skin biopsy samples were taken from this patient and 2 others with refractory PRP. Messenger RNA (mRNA) expression of proinflammatory innate and T-cell-derived cytokines were measured and compared with skin samples from patients with psoriasis and healthy donors. From 1 patient, lesional skin samples were taken before ustekinumab treatment and 4 and 28 weeks after treatment initiation. Follow-up was completed after 6 months. INTERVENTION: Subcutaneous ustekinumab, 45 mg, at weeks 0 and 4 and quarterly thereafter. MAIN OUTCOMES AND MEASURES: The primary outcome was to determine the changes in expression of proinflammatory innate and T-cell-derived cytokines during ustekinumab therapy. The secondary objective was to evaluate the clinical and histopathologic phenotype in relation to the mRNA expression profile of proinflammatory cytokines. RESULTS: In lesional PRP skin samples from a single patient, upregulated expression levels were found for most proinflammatory innate cytokines, including tumor necrosis factor (TNF), IL-6, IL-12, IL-23, and IL-1ß. Among adaptive T-cell cytokines, an increase of TH1 cytokines and, in particular, TH17 cytokines IL-17A, IL-17F, and IL-22 was seen in PRP. The patient with PRP who received ustekinumab showed regression of skin lesions after 2 weeks and almost complete resolution after 1 month. Clinical and histopathologic improvement paralleled the expression levels of TH17 cytokines but not of interferon-γ and TNF, which lagged behind the amelioration. CONCLUSIONS AND RELEVANCE: In this case report, a role of the IL-23-TH17-axis in PRP was identified, suggesting a shared pathogenic inflammatory pathway with psoriasis, despite evident clinical and histopathologic differences. In addition, this report provides a rationale for targeting the IL-23-TH17-pathway as a treatment option for refractory PRP.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Interleucina-23/genética , Pitiríase Rubra Pilar/tratamento farmacológico , Células Th17/metabolismo , Ustekinumab/uso terapêutico , Adulto , Biópsia , Citocinas/genética , Fármacos Dermatológicos/farmacologia , Seguimentos , Humanos , Masculino , Pitiríase Rubra Pilar/genética , Pitiríase Rubra Pilar/patologia , Psoríase/patologia , RNA Mensageiro/metabolismo , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Ustekinumab/farmacologia
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