Streptococcal infection and autoimmune diseases.

Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases. Streptococcus species are gram-positive bacteria that colonize the nasopharynx, respiratory tract, gastrointestinal tract, genitourinary tract, and skin. Group A Streptococcus (GAS) species cause various symptoms, ranging from mild infections, such as tonsillitis and pharyngitis, to serious infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The contribution of GAS infections to several autoimmune diseases, including acute rheumatic fever, vasculitis, and neuropsychiatric disorders, has been studied. In this review, we focus on the association between streptococcal infections and autoimmune diseases, and discuss current research on the mechanisms underlying the initiation and progression of autoimmune diseases.

Alteration of microbial composition in the skin and blood in vasculitis.

Vasculitis is a systemic autoimmune disease characterized by leukocyte infiltration into blood vessels. Various microorganisms have been associated with the pathogenesis of vasculitis; however, the causal microbial agents and underlying mechanisms are not fully understood, possibly because of the technical limitations of pathogen detection. In the present study, we characterized the microbiome profile of patients with cutaneous vasculitis using comprehensive metagenome shotgun sequencing. We found that the abundance of the SEN virus was increased in the affected skin and serum of patients with vasculitis compared to healthy donors. In particular, the abundance of SEN virus reads was increased in the sera of patients with cutaneous arteritis. Among the bacteria identified, Corynebacteriales was the most differentially associated with vasculitis. Linear discriminant analysis effect size also indicated differences in the microbial taxa between patients with vasculitis and healthy donors. These findings demonstrate that vasculitis is associated with considerable alteration of the microbiome in the blood and skin and suggest a role for the infectious trigger in vasculitis.

Chemokines and chemokine receptors as promising targets in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease that commonly causes inflammation and bone destruction in multiple joints. Inflammatory cytokines, such as IL-6 and TNF-α, play important roles in RA development and pathogenesis. Biological therapies targeting these cytokines have revolutionized RA therapy. However, approximately 50% of the patients are non-responders to these therapies. Therefore, there is an ongoing need to identify new therapeutic targets and therapies for patients with RA. In this review, we focus on the pathogenic roles of chemokines and their G-protein-coupled receptors (GPCRs) in RA. Inflamed tissues in RA, such as the synovium, highly express various chemokines to promote leukocyte migration, tightly controlled by chemokine ligand-receptor interactions. Because the inhibition of these signaling pathways results in inflammatory response regulation, chemokines and their receptors could be promising targets for RA therapy. The blockade of various chemokines and/or their receptors has yielded prospective results in preclinical trials using animal models of inflammatory arthritis. However, some of these strategies have failed in clinical trials. Nonetheless, some blockades showed promising results in early-phase clinical trials, suggesting that chemokine ligand-receptor interactions remain a promising therapeutic target for RA and other autoimmune diseases.

Immune checkpoint molecule expression is altered in the skin and peripheral blood in vasculitis.

Dysfunction of immunoinhibitory signals and persistent T cell activation reportedly play important roles in the development of vasculitis. The skin is one of the most accessible organs, and it is suitable for the characterization of immune cell signatures. However, the inhibitory checkpoint molecules in the skin and their relevance to vasculitis have not been studied. Here, we investigated the profile of immune checkpoint molecules in the skin and peripheral blood of patients with vasculitis and healthy donors. We found that some of the inhibitory checkpoint molecules, including programmed cell death 1 receptor (PD-1), were elevated in T-cells in the blood of patients with systemic and cutaneous vasculitis. In addition, programmed death-ligand 1 (PD-L1) expression was elevated in the skin of patients with cutaneous vasculitis. Histologically, PD-L1 was highly expressed in the vessels in the skin along with CD4+ and CD8+ T-cell infiltration in patients with cutaneous vasculitis. Notably, plasma soluble PD-L1 levels were increased, and these correlated with C-reactive protein in patients with systemic vasculitis. Our findings suggest that inhibitory checkpoint molecules might be differentially modulated in the skin and peripheral blood of patients with vasculitis, and that the alteration of the PD-L1/PD-1 axis may be associated with the regulation of T-cell activation in vasculitis.

Pathogens in Vasculitis: Is It Really Idiopathic?

Vasculitis is an autoimmune disease characterized by the infiltration of leukocytes in blood vessels. An increasing number of studies on human and animal models have implicated various microorganisms in the pathogenesis of vasculitis. Previous studies have shown the presence of infectious agents, including viruses, bacteria, and fungi, in diseased vessels. However, despite continued research, the link between infection and vasculitis is not fully understood, possibly owing to the lack of appropriate animal models that mirror human disease and the technical limitations of pathogen detection in blood vessels. Among the pathogen-induced animal models, Candida albicans water-soluble fraction (CAWS)-induced coronary arteritis is currently considered one of the representative models of Kawasaki (KD) disease. Advances in metagenomic next-generation sequencing have enabled the detection of all nucleic acids in tissue, which can help identify candidate pathogens, including previously unidentified viruses. In this review, we discuss the findings from reports on pathogen-associated vasculitis in animal models and humans, with a specific focus on the investigation of the pathogenesis of vasculitis. Further studies on animal models and microbes in diseased vessels may provide important insights into the pathogenesis of vasculitis, which is often considered an idiopathic disease.

Targeting the Chemokine System in Rheumatoid Arthritis and Vasculitis.

Arrest of circulating leukocytes and subsequent diapedesis is a fundamental component of inflammation. In general, the leukocyte migration cascade is tightly regulated by chemoattractants, such as chemokines. Chemokines, small secreted chemotactic cytokines, as well as their G-protein-coupled seven transmembrane spanning receptors, control the migratory patterns, positioning and cellular interactions of immune cells. Increased levels of chemokines and their receptors are found in the blood and within inflamed tissue in patients with rheumatoid arthritis (RA) and vasculitis. Chemokine ligand-receptor interactions regulate the recruitment of leukocytes into tissue, thus contributing in important ways to the pathogenesis of RA and vasculitis. Despite the fact that blockade of chemokines and chemokine receptors in animal models have yielded promising results, human clinical trials in RA using inhibitors of chemokines and their receptors have generally failed to show clinical benefits. However, recent early phase clinical trials suggest that strategies blocking specific chemokines may have clinical benefits in RA, demonstrating that the chemokine system remains a promising therapeutic target for rheumatic diseases, such as RA and vasuculitis and requires further study.

Relationship between lysosomal-associated membrane protein-2 and anti-phosphatidylserine/prothrombin complex antibody in the pathogenesis of cutaneous vasculitis.

OBJECTIVES: We investigated the relationship between lysosomal-associated membrane protein-2 (LAMP-2) and anti-phosphatidylserine/prothrombin (PS/PT) antibody in the pathogenesis of cutaneous vasculitis. METHODS: Cell surface LAMP-2 expression of human neutrophils was measured using flow cytometry. Twenty inbred wild-type Wistar-King-Aptekman-Hokudai (WKAH) rats were divided into four groups: Group 1, rabbit IgG injection only as negative control (n=5); Group 2, both histone and rabbit IgG injection (n=5); Group 3, anti-LAMP-2 antibody injection only (n=5); and Group 4, both histone and anti-LAMP-2 antibody injection (n=5). Ten WKAH rats were divided into two groups: Group A, histone, anti-PS/PT antibody, and anti-LAMP-2 antibody injection (n=5), and Group B, histone, anti-PS/PT antibody, and rabbit IgG injection as control (n=5). RESULTS: LAMP-2 expression on human neutrophils was induced by cell-free histone exposure in a dose- and time-dependent manner. Histopathological examination revealed the recruitment of neutrophils in cutaneous small vessels in all Group 4 rats. These observations were not evident in systemic organs other than the skin. LAMP-2 expression on the surface of vascular endothelial cells was evident in Group 2, exclusively in the skin, but not in Group 1. Thrombi were detected in various organs in all Groups A and B rats. However, no apparent thrombi were observed in the skin. CONCLUSIONS: Anti-PS/PT and anti-LAMP-2 antibodies are responsible for independent effector mechanisms in the rats given intravenous injection of cell-free histones. We considered that undetermined factors other than cell-free histones could be required for the induction of cutaneous vasculitis by anti-PS/PT and anti-LAMP-2 antibodies.

Chemokines in rheumatic diseases: pathogenic role and therapeutic implications.

Chemokines, a family of small secreted chemotactic cytokines, and their G protein-coupled seven transmembrane spanning receptors control the migratory patterns, positioning and cellular interactions of immune cells. The levels of chemokines and their receptors are increased in the blood and within inflamed tissue of patients with rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis or idiopathic inflammatory myopathies. Chemokine ligand-receptor interactions control the recruitment of leukocytes into tissue, which are central to the pathogenesis of these rheumatic diseases. Although the blockade of various chemokines and chemokine receptors has yielded promising results in preclinical animal models of rheumatic diseases, human clinical trials have, in general, been disappointing. However, there have been glimmers of hope from several early-phase clinical trials that suggest that sufficiently blocking the relevant chemokine pathway might in fact have clinical benefits in rheumatic diseases. Hence, the chemokine system remains a promising therapeutic target for rheumatic diseases and requires further study.

Abrogation of lysophosphatidic acid receptor 1 ameliorates murine vasculitis.

BACKGROUND: Lysophosphatidic acid (LPA), generated by autotaxin (ATX), is a bioactive lipid mediator that binds to the receptors (LPA1-6), and serves as an important mediator in inflammation. Previous studies have demonstrated that LPA-LPA1 cascade contributes to arthritis and skin sclerosis. In this study, we examined the role of LPA signals in murine Candida albicans water-soluble fraction (CAWS)-induced vasculitis. METHODS: ATX and LPA receptor expressions were analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. Effects of LPA1 inhibition on CAWS-induced vasculitis were evaluated in LPA1-deficient mice or using an LPA1 antagonist, LA-01. Migration activity was assessed using a chemotaxis chamber. The number of migrated fluorescently labeled neutrophils, which were transferred into the vasculitis mice, was counted in the aortic wall. CXCL1 and IL-8 concentrations were determined by enzyme-linked immunosorbent assay. RESULTS: ATX and LPA1 were highly expressed in the inflamed region of CAWS-induced vasculitis. Severity of the vasculitis in LPA1-deficient mice was suppressed. The LPA1 antagonist, LA-01, also ameliorated the CAWS-induced vasculitis. LPA induced neutrophil migration, which was inhibited by LA-01 in vitro. Infiltration of transferred neutrophils from LPA1-deficient mice into the coronary arteries was suppressed. LA-01 also inhibited the infiltration of wild-type neutrophils. Expression of CXCL1 and IL-8 in human endothelial cells was enhanced by LPA, but was inhibited by LA-01. ATX and LPA1 expression levels were higher in the affected skin region of vasculitis patients than in healthy controls. CONCLUSIONS: These results suggest that LPA-LPA1 signaling contributes to the development of vasculitis via chemoattractant production from endothelial cells followed by neutrophil recruitment. Thus, LPA1 has potential as a novel target for vasculitis therapies.

Dectin-2-induced CCL2 production in tissue-resident macrophages ignites cardiac arteritis.

Environmental triggers, including those from pathogens, are thought to play an important role in triggering autoimmune diseases, such as vasculitis, in genetically susceptible individuals. The mechanism by which activation of the innate immune system contributes to vessel-specific autoimmunity in vasculitis is not known. Systemic administration of Candida albicans water-soluble extract (CAWS) induces vasculitis in the aortic root and coronary arteries of mice that mimics human Kawasaki disease. We found that Dectin-2 signaling in macrophages resident in the aortic root of the heart induced early CCL2 production and the initial recruitment of CCR2+ inflammatory monocytes (iMo) into the aortic root and coronary arteries. iMo differentiated into monocyte-derived dendritic cells (Mo-DC) in the vessel wall and were induced to release IL-1ß in a Dectin-2-Syk-NLRP3 inflammasome dependent pathway. IL-1ß then activated cardiac endothelial cells to express CXCL1 and CCL2 and adhesion molecules that induced neutrophil and further iMo recruitment and accumulation in the aortic root and coronary arteries. Our findings demonstrate that Dectin-2-mediated induction of CCL2 production by macrophages resident in the aortic root and coronary arteries initiates vascular inflammation in a model of Kawasaki disease, suggesting an important role for the innate immune system in initiating vasculitis.

Atypical complement receptor C5aR2 transports C5a to initiate neutrophil adhesion and inflammation.

Chemoattractant-induced arrest of circulating leukocytes and their subsequent diapedesis is a fundamental component of inflammation. However, how tissue-derived chemoattractants are transported into the blood vessel lumen to induce leukocyte entry into tissue is not well understood. Here, intravital microscopy in live mice has shown that the "atypical" complement C5a receptor 2 (C5aR2) and the atypical chemokine receptor 1 (ACKR1) expressed on endothelial cells were required for the transport of C5a and CXCR2 chemokine ligands, respectively, into the vessel lumen in a murine model of immune complex-induced arthritis. Transported C5a was required to initiate C5aR1-mediated neutrophil arrest, whereas transported chemokines were required to initiate CXCR2-dependent neutrophil transdendothelial migration. These findings provide new insights into how atypical chemoattractant receptors collaborate with "classical" signaling chemoattractant receptors to control distinct steps in the recruitment of neutrophils into tissue sites of inflammation.

Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis.

Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammatory ELR+ CXC chemokines. The engineered molecules recognize functional epitopes of ELR+ CXC chemokines and inhibit neutrophil activation ex vivo. Furthermore, an albumin fusion of the most crossreactive single-chain antibody prevents and reverses inflammation in the K/BxN mouse model of arthritis. Thus, we report an approach for the molecular evolution and selection of broadly crossreactive antibodies towards a family of structurally related, yet sequence-diverse protein targets, with general implications for the development of novel therapeutics.