Cellular and humoral immunity in Lyme arthritis

莱姆关节炎的细胞和体液免疫

• 批准号: 10541106
• 负责人: ALLEN C STEERE
• 金额: $ 58.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-08 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541106
• 关键词: Affinity; Annexins; Anti-Inflammatory Agents; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Response; Arthritis; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; B-Lymphocytes; Binding; Biological Assay; Blood Vessels; Borrelia burgdorferi; CD8-Positive T-Lymphocytes; Cell secretion; Cells; Cellular Immunity; Chronic; Data Correlations; Diagnosis; Disease; Endothelial Growth Factors; Fc Receptor; Fibroblasts; Fibronectins; Fibrosis; Flow Cytometry; Frequencies; Grant; Granzyme; Humoral Immunities; Hyperplasia; IL17 gene; IgG1; IgG2; IgG3; IgG4; Immune response; Immunity; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Arthritis; Inflammatory Response; Innate Immune Response; Interferons; Interleukin-10; Laminin; Lesion; Lyme Arthritis; Lyme Disease; Lymphocyte; Malignant Neoplasms; Measures; Mononuclear; Natural Killer Cells; Order Spirochaetales; Pathogenesis; Pathogenicity; Pathology; Patients; Peripheral Blood Mononuclear Cell; Phagocytosis; Phenotype; Play; Polysaccharides; Population; Proliferating; Property; Proteins; Refractory; Regulatory T-Lymphocyte; Research; Resolution; Rheumatoid Arthritis; Role; Serology; Serum; Synovial Fluid; Synovitis; System; T-Lymphocyte; Th1 Cells; Tissues; Vascular Proliferation; antibody-dependent cell cytotoxicity; apolipoprotein B-100; cytokine; cytotoxic; cytotoxicity; extracellular; genetic signature; human model; in vivo; insight; joint infection; neoplastic cell; neutrophil; novel; perforin; peripheral blood; receptor binding; repaired; response; single-cell RNA sequencing; stromelysin 2; tissue repair; transcriptomics

In most patients, antibiotic treatment of Lyme arthritis (LA) combined with host immunity results in spirochetal elimination, tissue repair and resolution of arthritis, called antibiotic-responsive LA. However, despite spirochetal killing, some patients develop an inflammatory, proliferative synovitis lasting months to several years after antibiotic therapy, called post-infectious (antibiotic- refractory) LA. The synovial lesion in these patients is similar with that in other forms of chronic inflammatory arthritis, including rheumatoid arthritis. The central feature in setting the stage for post-infectious LA seems to be a sustained, excessive pro-inflammatory response, with exceptionally high levels of IFN-, which overwhelms regulatory control mechanisms. In these patients, persistent inflammation leads to further vascular damage, fibrosis, and autoimmune phenomena in synovia, as seen in other forms of chronic inflammatory arthritis. We have shown that this response may be accompanied by Lyme disease (LD)-associated autoantibodies, a response that becomes T cell dependent and potentially pathogenic. In these patients, IgG4 autoantibodies in synovial fluid, but not antibodies of other subclasses, correlate with specific synovial pathology – obliterative microvascular lesions and fibrosis. Moreover, obliteration of blood vessels suggests cytotoxic immune responses, and our recent transcriptomic studies of post-infectious LA synovial tissue show a strong cytotoxic gene signature, similar with that in RA. In this grant, we will use a “systems serology” approach to understand functions of Borrelia burgdorferi (Bb) antibodies and LD autoantibodies by delineating Fc receptor binding, binding affinity, Fc glycans, antibody-dependent phagocytosis and antibody-dependent cytotoxicity in antibiotic-responsive vs. post-infectious LA patients. In addition, we will define the types and frequencies of lymphocytes with cytotoxic and inflammatory potential in peripheral blood and synovial fluid in these two patient groups using flow cytometry, and will further delineate the complete phenotype of implicated cytotoxic cells by single-cell RNA-sequencing. We will correlate these data with determinations of cytokine, granzyme, and perforin levels in vivo in serum and synovial fluid of these patients, as measured by Luminex. Finally, we will examine the cytotoxic potential of implicated T cells in directly killing target cells, and indirectly by asessing the effects of extracellular cytotoxic effector molecules on cells. This research has significant implications for understanding pathogenesis and aiding in diagnosis and treatment of LA, and more generally, as a human model of infection-induced chronic inflammatory arthritis.

在大多数患者中，抗生素治疗莱姆病（LA）结合宿主免疫效果

项目成果

Lyme Arthritis.

• DOI: 10.1016/j.idc.2022.03.006
• 发表时间: 2022-09
• 期刊: INFECTIOUS DISEASE CLINICS OF NORTH AMERICA
• 影响因子: 4.4
• 作者: Arvikar, Sheila L.;Steere, Allen C.
• 通讯作者: Steere, Allen C.

Heightened Proinflammatory Glycosylation of Borrelia burgdorferi IgG Antibodies in Synovial Fluid in Patients With Antibiotic-Refractory Lyme Arthritis.

抗生素难治性莱姆关节炎患者滑液中伯氏疏螺旋体 IgG 抗体的促炎糖基化增强。

• DOI: 10.1002/art.42465
• 发表时间: 2023
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Sanes,JurgenT;Costello,CatherineE;Steere,AllenC
• 通讯作者: Steere,AllenC

Lyme arthritis: linking infection, inflammation and autoimmunity.

• DOI: 10.1038/s41584-021-00648-5
• 发表时间: 2021-08
• 期刊: Nature reviews. Rheumatology

Cell-Mediated Cytotoxicity in Lyme Arthritis.

莱姆关节炎中细胞介导的细胞毒性。

• DOI: 10.1002/art.42408
• 发表时间: 2023
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Ordóñez,David;Lochhead,RobertB;Strle,Klemen;Pianta,Annalisa;Arvikar,Sheila;VanRhijn,Ildiko;Stemmer-Rachamimov,Anat;Steere,AllenC
• 通讯作者: Steere,AllenC

Identification of Novel, Immunogenic HLA-DR-Presented Prevotella copri Peptides in Patients With Rheumatoid Arthritis.

• DOI: 10.1002/art.41807
• 发表时间: 2021-12
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Pianta A;Chiumento G;Ramsden K;Wang Q;Strle K;Arvikar S;Costello CE;Steere AC
• 通讯作者: Steere AC