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1.
Eur Heart J ; 44(47): 4935-4949, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-37941454

RESUMO

BACKGROUND AND AIMS: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. METHODS: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. RESULTS: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. CONCLUSIONS: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.


Assuntos
Autoanticorpos , Doenças Cardiovasculares , Receptores CXCR3 , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Apolipoproteínas E , Aterosclerose , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doenças Autoimunes , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Espessura Intima-Media Carotídea , Fatores de Risco de Doenças Cardíacas , Insuficiência Cardíaca , Receptores de Quimiocinas , Fatores de Risco , Receptores CXCR3/imunologia
2.
Curr Opin Rheumatol ; 35(2): 98-106, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36563007

RESUMO

PURPOSE OF REVIEW: Low-dose interleukin-2 (IL-2) therapy is increasingly recognized as a promising novel therapeutic concept in inflammatory and autoimmune diseases, in particular in systemic lupus erythematosus (SLE). As IL-2 is indispensable for the growth and survival of regulatory T cells (Treg), deficiency of this regulatory cytokine plays a significant role in immune dysregulation and breach of tolerance in SLE. Recovery of Treg activity by low-dose IL-2 therapy directly interferes with the immune pathology in SLE and thus can be considered a targeted treatment approach with a unique and physiological mode of action. RECENT FINDINGS: In this review, the pathophysiological rationales behind the concept of low-dose IL-2 therapy in SLE will be explained and major advances in translational research and the clinical development of low-dose IL-2 therapy focusing on the results from two recent, randomized and placebo-controlled phase 2 trials will be highlighted. SUMMARY: Several clinical studies including two recent randomized trials have proven the very good safety profile of low-dose IL-2 therapy and its capability to selectively recover and expand the Treg population in patients with active SLE. Given the emerging evidence for the clinical potential of low-dose IL-2 therapy in SLE, these studies strongly confirm the pathophysiological concept behind this targeted therapeutic approach in SLE and provide a robust basis for establishing further in-depth and confirmatory clinical trials testing the application of low-dose IL-2 in SLE and other autoimmune diseases.


Assuntos
Interleucina-2 , Lúpus Eritematoso Sistêmico , Humanos , Interleucina-2/uso terapêutico , Linfócitos T Reguladores , Citocinas , Imunoterapia/métodos
3.
Ann Rheum Dis ; 81(12): 1685-1694, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35973803

RESUMO

OBJECTIVES: A regulatory T cell (Treg) insufficiency due to shortage of interleukin-2 (IL-2) is central to the pathophysiology of systemic lupus erythematosus (SLE). We performed a multicentre, double-blinded, randomised, placebo-controlled phase II proof-of-concept trial to evaluate the efficacy of low-dose IL-2 therapy in patients with SLE having moderate-to-severe disease activity while receiving standard treatment. METHODS: We randomly assigned 100 patients in a 1:1 ratio to receive either 1.5 million IU/day of subcutaneous IL-2 (ILT-101) or placebo for 5 days followed by weekly injections for 12 weeks. Clinical efficacy was assessed at week 12 in a predefined hierarchical analysis of (1) the SLE responder index-4 (SRI-4) response as a primary end point, and of (2) relative and (3) absolute changes in the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index scores as key secondary end points. RESULTS: The primary end point was not met in the intention-to-treat population (ILT-101: 68%, placebo: 58%; p=0.3439), due to a 100% SRI-4 response rate in the placebo group from the two sites from Bulgaria. A post hoc per-protocol analysis on a prespecified population that excluded patients from these two sites (n=53) showed a statistically significant difference for the SRI-4 response rate (ILT-101: 83.3%; placebo: 51.7%; p=0.0168), and for the two key secondary end points, accompanied by differences in several secondary exploratory end points. ILT-101 was well tolerated and there was no generation of antidrug antibodies. CONCLUSIONS: The post hoc hierarchical analysis of the primary and key secondary end points in a per-protocol population, complemented by the exploratory analyses of multiple other secondary end points, support that low-dose IL-2 is beneficial in active SLE. TRIAL REGISTRATION NUMBER: NCT02955615.


Assuntos
Interleucina-2 , Lúpus Eritematoso Sistêmico , Humanos , Interleucina-2/uso terapêutico , Índice de Gravidade de Doença , Fatores Imunológicos/uso terapêutico , Método Duplo-Cego , Resultado do Tratamento
4.
Kidney Int ; 99(1): 238-246, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32592813

RESUMO

Systemic lupus erythematosus is a systemic and chronic autoimmune disease characterized by loss of tolerance towards nuclear antigens with autoreactive CD4+ T cells implicated in disease pathogenesis. However, very little is known about their receptor specificity since the detection of human autoantigen specific CD4+ T cells has been extremely challenging. Here we present an analysis of CD4+ T cells reactive to nuclear antigens using two complementary methods: T cell libraries and antigen-reactive T cell enrichment. The frequencies of nuclear antigen specific CD4+ T cells correlated with disease severity. These autoreactive T cells produce effector cytokines such as interferon-γ, interleukin-17, and interleukin-10. Compared to blood, these cells were enriched in the urine of patients with active lupus nephritis, suggesting an infiltration of the inflamed kidneys. Thus, these previously unrecognized characteristics support a role for nuclear antigen-specific CD4+ T cells in systemic lupus erythematosus.


Assuntos
Citocinas , Lúpus Eritematoso Sistêmico , Antígenos Nucleares , Linfócitos T CD4-Positivos , Humanos , Rim
5.
Curr Opin Rheumatol ; 31(2): 208-212, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30562181

RESUMO

PURPOSE OF REVIEW: To provide an overview behind the concept and recent advances of low-dose interleukin-2 (IL-2) therapy in systemic lupus erythematosus (SLE). RECENT FINDINGS: A disruption of regulatory T cell homeostasis caused by an acquired deficiency of IL-2 is a crucial event in the pathogenesis of SLE. Here, we highlight the key rationales for the clinical translation of low-dose IL-2 therapy in SLE and summarize the main findings from two independent, early phase uncontrolled clinical studies that investigated the immunological and clinical responses to low-dose IL-2 therapy in patients with active SLE. Important commonalities and differences between these studies with regard to study design and results are discussed. SUMMARY: Low-dose IL-2 therapy is capable to promote the selective expansion of a functionally competent regulatory T cell population in a well-tolerated way and may have the potential to influence the clinical course in patients with active SLE. Although a clearer proof for the clinical efficacy of low-dose IL-2 therapy in SLE is still outstanding, these early studies provide important rationales and the scientific basis for more comprehensive and placebo-controlled trials in the future.


Assuntos
Imunoterapia/métodos , Interleucina-2/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Animais , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Resultado do Tratamento
6.
Eur J Immunol ; 47(1): 180-192, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27753073

RESUMO

Renal infiltration of inflammatory cells contributes to the pathogenesis of lupus nephritis (LN). Current knowledge on the recruitment mechanisms relies mainly on findings in rodent models. Here, we assess various chemokine pathways in human LN by comparing urinary chemokine concentrations (in 25 patients with acute LN and in 78 lupus patients without active LN) with the expression of corresponding chemokine receptors on urinary leukocytes (in ten acute LN patients). Nine urinary chemokines were significantly elevated in LN patients and correlated with renal disease activity and urinary cell counts; however, their concentrations displayed considerable interindividual heterogeneity. Analysis of the corresponding receptors revealed abundance of urinary CD8+ T cells for CCR5 and CXCR3, while CD4+ T cells were additionally enriched for CCR1, CCR6 and CXCR6. Urinary Treg showed similar CCR expression, and urinary CD14+ macrophages were enriched for CCR5 expressing cells. In conclusion, cell specific recruitment patterns seem to involve CCR5 and CXCR3 in all cells studied, while CD4+ T-cell subset recruitment is probably much more varied. However, urinary chemokine abundance in active LN is individually variable in our cohort and does not offer a singular chemokine usable as universal biomarker or potential future treatment target.


Assuntos
Quimiocinas/urina , Nefrite Lúpica/imunologia , Nefrite Lúpica/urina , Adulto , Idoso , Biomarcadores , Biópsia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Quimiocinas/sangue , Quimiotaxia/imunologia , Análise por Conglomerados , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Contagem de Leucócitos , Nefrite Lúpica/sangue , Nefrite Lúpica/diagnóstico , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Curva ROC , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Urinálise , Adulto Jovem
7.
Ann Rheum Dis ; 75(7): 1407-15, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26324847

RESUMO

OBJECTIVES: Defects in regulatory T cell (Treg) biology have been associated with human systemic autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the origin of such Treg defects and their significance in the pathogenesis and treatment of SLE are still poorly understood. METHODS: Peripheral blood mononuclear cells (PBMC) from 61 patients with SLE and 52 healthy donors and in vitro IL-2 stimulated PBMC were characterised by multicolour flow cytometry. Five patients with refractory SLE were treated daily with subcutaneous injections of 1.5 million IU of human IL-2 (aldesleukin) for five consecutive days, and PBMC were analysed by flow cytometry. RESULTS: Patients with SLE develop a progressive homeostatic dysbalance between Treg and conventional CD4+ T cells in correlation with disease activity and in parallel display a substantial reduction of CD25 expression on Treg. These Treg defects resemble hallmarks of IL-2 deficiency and lead to a markedly reduced availability of functionally and metabolically active Treg. In vitro experiments revealed that lack of IL-2 production by CD4+ T cells accounts for the loss of CD25 expression in SLE Treg, which could be selectively reversed by stimulation with low doses of IL-2. Accordingly, treatment of patients with SLE with a low-dose IL-2 regimen selectively corrected Treg defects also in vivo and strongly expanded the Treg population. CONCLUSIONS: Treg defects in patients with SLE are associated with IL-2 deficiency, and can be corrected with low doses of IL-2. The restoration of endogenous mechanisms of immune tolerance by low-dose IL-2 therapy, thus, proposes a selective biological treatment strategy, which directly addresses the pathophysiology in SLE.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Interleucina-2/análogos & derivados , Interleucina-2/administração & dosagem , Leucócitos Mononucleares/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Tolerância Imunológica/efeitos dos fármacos , Interleucina-2/sangue , Interleucina-2/deficiência , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento , Adulto Jovem
9.
Ann Rheum Dis ; 73(1): 277-83, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23475982

RESUMO

OBJECTIVES: Proliferative lupus nephritis (LN) is one of the major concerns in the treatment of systemic lupus erythematosus (SLE). Here we evaluate urinary CD4 T cells as a biomarker of active LN and indicator of treatment response. METHODS: Urinary CD3CD4 T cells were quantified using flow cytometry in 186 urine samples from 147 patients with SLE. Fourteen patients were monitored as follow-up. Thirty-one patients with other nephropathies and 20 healthy volunteers were included as controls. RESULTS: In SLE, urinary CD4 T cell counts ≥800/100 ml were observed exclusively in patients with active LN. Receiver operator characteristic analysis documented clear separation of SLE patients with active and non-active LN (area under the curve 0.9969). All patients with up-to-date kidney biopsy results showing proliferative LN had high urinary CD4 T cell numbers. In patients monitored under therapy, normalisation of urinary CD4 T cell counts indicated lower disease activity and better renal function. In contrast, patients with persistence of, or increase in, urinary T cells displayed worse outcomes. CONCLUSIONS: Urinary CD4 T cells are a highly sensitive and specific marker for detecting proliferative LN in patients with SLE. Furthermore, monitoring urinary CD4 T cells may help to identify treatment responders and treatment failure and enable patient-tailored therapy in the future.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Monitoramento de Medicamentos/métodos , Imunossupressores/uso terapêutico , Nefrite Lúpica , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/urina , Estudos Transversais , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/imunologia , Nefrite Lúpica/urina , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Resultado do Tratamento , Urina/citologia , Adulto Jovem
12.
Arthritis Rheum ; 64(4): 1237-46, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22006377

RESUMO

OBJECTIVE: Autoantibody immune complexes and cellular infiltrates drive nephritis in patients with systemic lupus erythematosus (SLE) and in murine lupus. The chemokine receptor CXCR3 is assumed to promote cellular infiltration of inflamed tissues. Moreover, CXCR3 deficiency ameliorates lupus nephritis in the MRL/MpJ-Fas(lpr) (MRL/lpr) mouse model of SLE. Hence, CXCR3 blockade has been suggested as a novel therapeutic strategy for the treatment of lupus nephritis. We undertook this study to test the effect of CXCR3 in the (NZB × NZW)F(1) (NZB/NZW) mouse model of SLE. METHODS: CXCR3(-/-) NZB/NZW mice were generated and monitored for survival, proteinuria, and kidney infiltration. Anti-double-stranded DNA (anti-dsDNA) and total IgG1, IgG2a, and IgG2b antibody levels were determined by enzyme-linked immunosorbent assay. T cell and plasma cell infiltrates in the kidneys and interferon-γ production were determined by flow cytometry. Plasma cell infiltrates were measured using enzyme-linked immunospot assay. Kidney tissue was evaluated for pathologic changes. RESULTS: CXCR3(-/-) NZB/NZW mice exhibited reduced production of total and anti-dsDNA antibodies of the IgG1 subclass, but had normal titers of IgG2a and IgG2b antibodies compared to CXCR3(+/+) NZB/NZW mice. Cellular infiltrates and glomerulonephritis were not reduced in CXCR3(-/-) mice. CONCLUSION: CXCR3 has an effect on (auto)antibody production but is not essential for lupus pathogenesis in NZB/NZW mice, indicating that the effect of CXCR3 on the development of kidney disease varies between MRL/lpr and NZB/NZW mice. These results suggest that CXCR3-dependent and -independent mechanisms can mediate lupus nephritis. Hence, therapeutic CXCR3 blockade could be beneficial for only a subgroup of patients with SLE.


Assuntos
Autoanticorpos/imunologia , Imunoglobulina G/imunologia , Nefrite Lúpica/metabolismo , Receptores CXCR3/metabolismo , Animais , Complexo Antígeno-Anticorpo/imunologia , Nefrite Lúpica/imunologia , Camundongos , Camundongos Endogâmicos NZB , Proteinúria/imunologia , Proteinúria/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
13.
Proc Natl Acad Sci U S A ; 107(1): 204-9, 2010 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-20018660

RESUMO

The origins and consequences of a regulatory T cell (Treg) disorder in systemic lupus erythematosus (SLE) are poorly understood. In the (NZBxNZW) F(1) mouse model of lupus, we found that CD4(+)Foxp3(+) Treg failed to maintain a competitive pool size in the peripheral lymphoid organs resulting in a progressive homeostatic imbalance of CD4(+)Foxp3(+) Treg and CD4(+)Foxp3(-) conventional T cells (Tcon). In addition, Treg acquired phenotypic changes that are reminiscent of IL-2 deficiency concomitantly to a progressive decline in IL-2-producing Tcon and an increase in activated, IFN-gamma-producing effector Tcon. Nonetheless, Treg from lupus-prone mice were functionally intact and capable to influence the course of disease. Systemic reduction of IL-2 levels early in disease promoted Tcon hyperactivity, induced the imbalance of Treg and effector Tcon, and strongly accelerated disease progression. In contrast, administration of IL-2 partially restored the balance of Treg and effector Tcon by promoting the homeostatic proliferation of endogenous Treg and impeded the progression of established disease. Thus, an acquired and self-amplifying disruption of the Treg-IL-2 axis contributed essentially to Tcon hyperactivity and the development of murine lupus. The reversibility of this homeostatic Treg disorder provides promising approaches for the treatment of SLE.


Assuntos
Homeostase , Interleucina-2/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Envelhecimento/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Lúpus Eritematoso Sistêmico/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Fenótipo
14.
Front Immunol ; 14: 1213804, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37359516

RESUMO

Systemic sclerosis (SSc) is a chronic, multisystem connective tissue, and autoimmune disease with the highest case-specific mortality and complications among rheumatic diseases. It is characterized by complex and variable features such as autoimmunity and inflammation, vasculopathy, and fibrosis, which pose challenges in understanding the pathogenesis of the disease. Among the large variety of autoantibodies (Abs) present in the sera of patients suffering from SSc, functionally active Abs against G protein-coupled receptors (GPCRs), the most abundant integral membrane proteins, have drawn much attention over the last decades. These Abs play an essential role in regulating the immune system, and their functions are dysregulated in diverse pathological conditions. Emerging evidence indicates that functional Abs targeting GPCRs, such as angiotensin II type 1 receptor (AT1R) and the endothelin-1 type A receptor (ETAR), are altered in SSc. These Abs are part of a network with several GPCR Abs, such as those directed to the chemokine receptors or coagulative thrombin receptors. In this review, we summarize the effects of Abs against GPCRs in SSc pathologies. Extending the knowledge on pathophysiological roles of Abs against GPCRs could provide insights into a better understanding of GPCR contribution to SSc pathogenesis and therefore help in developing potential therapeutic strategies that intervene with pathological functions of these receptors.


Assuntos
Autoanticorpos , Escleroderma Sistêmico , Humanos , Autoimunidade , Fibrose , Receptor de Endotelina A
15.
Front Immunol ; 14: 1254176, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38022661

RESUMO

Introduction: Progressive loss of regulatory T cell (Treg)-mediated control over autoreactive effector T cells contributes to the development of systemic lupus erythematosus (SLE). Accordingly, we hypothesized that Treg may also have the capacity to suppress the activation of autoreactive CD4+ T cells that are considered to drive autoimmunity. Methods: To investigate whether Treg are involved in the control of autoreactive CD4+ T cells, we depleted CD25+ Treg cells either in vivo or in vitro, or combined both approaches before antigen-specific stimulation with the SLE-associated autoantigen SmD1(83-119) in the NZB/W F1 mouse model either after immunization against SmD1(83-119) or during spontaneous disease development. Frequencies of autoantigen-specific CD4+ T cells were determined by flow cytometry using the activation marker CD154. Results: Both in vitro and in vivo depletion of CD25+ Treg, respectively, increased the frequencies of detectable autoantigen-specific CD4+ T cells by approximately 50%. Notably, the combined in vivo and in vitro depletion of CD25+ Treg led almost to a doubling in their frequencies. Frequencies of autoantigen-specific CD4+ T cells were found to be lower in immunized haploidentical non-autoimmune strains and increased frequencies were detectable in unmanipulated NZB/W F1 mice with active disease. In vitro re-addition of CD25+ Treg after Treg depletion restored suppression of autoantigen-specific CD4+ T cell activation. Discussion: These results suggest that the activation and expansion of autoantigen-specific CD4+ T cells are partly controlled by Treg in murine lupus. Depletion of Treg therefore can be a useful approach to increase the detectability of autoantigen-specific CD4+ T cells allowing their detailed characterization including lineage determination and epitope mapping and their sufficient ex vivo isolation for cell culture.


Assuntos
Lúpus Eritematoso Sistêmico , Linfócitos T Reguladores , Animais , Camundongos , Autoantígenos , Camundongos Endogâmicos NZB , Autoimunidade
16.
Autoimmun Rev ; 22(2): 103236, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36436750

RESUMO

Approximately 5% of the world-wide population is affected by autoimmune diseases. Overall, autoimmune diseases are still difficult to treat, impose a high burden on patients, and have a significant economic impact. Like other complex diseases, e.g., cancer, autoimmune diseases develop over several years. Decisive steps in the development of autoimmune diseases are (i) the development of autoantigen-specific lymphocytes and (often) autoantibodies and (ii) potentially clinical disease manifestation at a later stage. However, not all healthy individuals with autoantibodies develop disease manifestations. Identifying autoantibody-positive healthy individuals and monitoring and inhibiting their switch to inflammatory autoimmune disease conditions are currently in their infancy. The switch from harmless to inflammatory autoantigen-specific T and B-cell and autoantibody responses seems to be the hallmark for the decisive factor in inflammatory autoimmune disease conditions. Accordingly, biomarkers allowing us to predict this progression would have a significant impact. Several factors, such as genetics and the environment, especially diet, smoking, exposure to pollutants, infections, stress, and shift work, might influence the progression from harmless to inflammatory autoimmune conditions. To inspire research directed at defining and ultimately targeting autoimmune predisease, here, we review published evidence underlying the progression from health to autoimmune predisease and ultimately to clinically manifest inflammatory autoimmune disease, addressing the following 3 questions: (i) what is the current status, (ii) what is missing, (iii) and what are the future perspectives for defining and modulating autoimmune predisease.


Assuntos
Doenças Autoimunes , Autoimunidade , Humanos , Doenças Autoimunes/etiologia , Autoanticorpos , Autoantígenos , Linfócitos
17.
Front Immunol ; 13: 1007078, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389689

RESUMO

In the normal immune system, T cell activation is tightly regulated and controlled at several levels to ensure that activation occurs in the right context to prevent the development of pathologic conditions such as autoimmunity or other harmful immune responses. CD4+FoxP3+ regulatory T cells (Treg) are crucial for the regulation of T cell responses in the peripheral lymphatic organs and thus for the prevention and control of autoimmunity. In systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease with complex etiology, a disbalance between Treg and pathogenic effector/memory CD4+ T cells develops during disease progression indicating that gradual loss of control over T cell activation is an important event in the immune pathogenesis. This progressive failure to adequately regulate the activation of autoreactive T cells facilitates chronic activation and effector/memory differentiation of pathogenic T cells, which are considered to contribute significantly to the induction and perpetuation of autoimmune processes and tissue inflammation in SLE. However, in particular in humans, little is known about the factors which drive the escape from immune regulation and the chronicity of pathogenic T cell responses in an early stage of autoimmune disease when clinical symptoms are still unapparent. Here we briefly summarize important findings and discuss current views and models on the mechanisms related to the dysregulation of T cell responses which promotes chronicity and pathogenic memory differentiation with a focus on the early stage of disease in lupus-prone individuals.


Assuntos
Autoimunidade , Lúpus Eritematoso Sistêmico , Humanos , Linfócitos T Reguladores , Ativação Linfocitária , Diferenciação Celular
18.
Nat Commun ; 13(1): 1220, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35264564

RESUMO

COVID-19 shares the feature of autoantibody production with systemic autoimmune diseases. In order to understand the role of these immune globulins in the pathogenesis of the disease, it is important to explore the autoantibody spectra. Here we show, by a cross-sectional study of 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate with the clinical severity of COVID-19. Patients with moderate and severe disease are characterized by higher autoantibody levels than healthy controls and those with mild COVID-19 disease. Among the anti-GPCR autoantibodies, machine learning classification identifies the chemokine receptor CXCR3 and the RAS-related molecule AGTR1 as targets for antibodies with the strongest association to disease severity. Besides antibody levels, autoantibody network signatures are also changing in patients with intermediate or high disease severity. Although our current and previous studies identify anti-GPCR antibodies as natural components of human biology, their production is deregulated in COVID-19 and their level and pattern alterations might predict COVID-19 disease severity.


Assuntos
Autoanticorpos/imunologia , COVID-19/imunologia , Receptores Acoplados a Proteínas G/imunologia , Sistema Renina-Angiotensina/imunologia , Autoanticorpos/sangue , Autoimunidade , Biomarcadores/sangue , COVID-19/sangue , COVID-19/classificação , Estudos Transversais , Feminino , Humanos , Aprendizado de Máquina , Masculino , Análise Multivariada , Receptor Tipo 1 de Angiotensina/imunologia , Receptores CXCR3/imunologia , SARS-CoV-2 , Índice de Gravidade de Doença
19.
20.
Eur J Immunol ; 40(6): 1809-18, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20333624

RESUMO

B1a B cells have been implicated in the pathogenesis of systemic lupus erythematosus; however, their precise contribution to the disease remains unclear. Here we analysed isotype expression, organ accumulation and autoreactivity of B1a cells in the NZB/W F1 murine model for systemic lupus erythematosus using flow cytometry, ELISPOT and adoptive cell transfer. In the course of lupus, the B1a compartment is expanded and B1a cells class switch to IgG. Class-switched B1a B cells were excluded from the peritoneal cavity but accumulated in the spleen and target organs such as kidneys and thymus. Autoreactive B1a B cells preferentially class switch, which leads to a subsequent loss of autoreactive B1a cells from the peritoneal cavity. We propose a model whereby autoreactive B1a B cells become activated early in the course of lupus and class switch to IgG. These autoreactive B1a B cells accumulate in the spleen and affected organs where they presumably secrete autoantibodies and contribute to the local and systemic pathogenesis.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Switching de Imunoglobulina/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Cavidade Peritoneal/citologia , Transferência Adotiva , Animais , Anticorpos Antinucleares/imunologia , Autoantígenos/imunologia , Subpopulações de Linfócitos B/patologia , Linfócitos B/patologia , Separação Celular , DNA/imunologia , Progressão da Doença , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos NZB , Cavidade Peritoneal/patologia
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