Potential role of decoy B7-H4 in the pathogenesis of rheumatoid arthritis: a mouse model informed by clinical data
| Autor: | Takeshi Azuma, Eric L. Matteson, Charles G. Drake, Gefeng Zhu, Haiying Xu, Cecilia Rietz, Lieping Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
Immunology Immunology/Innate Immunity Immunology/Immunomodulation Immunology/Autoimmunity Arthritis lcsh:Medicine Arthritis Rheumatoid Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine Immune system Rheumatology medicine Animals Humans Rheumatology/Rheumatoid Arthritis Rheumatology/Autoimmunity Autoimmune and Inflammatory Diseases 030304 developmental biology 0303 health sciences biology business.industry lcsh:R Autoantibody Antibodies Monoclonal General Medicine V-Set Domain-Containing T-Cell Activation Inhibitor 1 medicine.disease 3. Good health Cross-Sectional Studies Mice Inbred DBA Immunology/Leukocyte Activation Rheumatology/Systemic Lupus Erythematosos Rheumatoid arthritis Immunology/Immune Response Models Animal B7-1 Antigen biology.protein Antibody Signal transduction Decoy business Research Article 030215 immunology |
| Zdroj: | PLoS Medicine, Vol 6, Iss 10, p e1000166 (2009) PLoS Medicine |
| ISSN: | 1549-1676 1549-1277 |
| Popis: | Finding an association between soluble B7-H4 and rheumatoid arthritis severity, Lieping Chen and colleagues use a mouse model to show that the soluble form blocks the inhibitory function of cell-surface B7-H4. Background A pathogenic hallmark of rheumatoid arthritis (RA) is persistent inflammatory responses in target tissues and organs. Immune responses mediated by T cells and autoantibodies are known to play pivotal roles. A possible interpretation for this observation is a loss of negative regulation of autoimmune responses. Here we sought to investigate whether B7-H4, a cell surface inhibitory molecule of the B7-CD28 signaling pathway, may play a role in the pathogenesis of RA. Methods and Findings In a cross-sectional study of a clinical convenience sample using monoclonal antibodies against human B7-H4 molecules, we detected high levels of the soluble form of B7-H4 (sH4) in the sera of 65% of patients with RA (n = 68) versus only 13% of healthy donors (n = 24). Elevated sH4 was associated with an increased disease severity score (DAS28) in a cross-sectional analysis. In a mouse model of RA, transgenic expression of sH4 or genetic deletion of B7-H4 accelerated the progression of collagen-induced arthritis, accompanied by enhanced T and B cell–mediated autoimmune responses as well as increased activity of neutrophils. Expression in vivo of an agonist, a B7-H4-immunoglobulin Fc fusion protein, profoundly suppressed disease progression in the mouse model. Conclusions Our findings in mice indicate that sH4 acts as a decoy molecule to block the inhibitory functions of cell-surface B7-H4, leading to exacerbation of collagen-induced arthritis. If the preliminary correlation between sH4 levels and disease activity in patients with RA can be confirmed to reflect a similar mechanism, these findings suggest a novel target for treatment approaches. Please see later in the article for the Editors' Summary Editors' Summary Background Rheumatoid arthritis (RA) is a chronic disease caused by abnormal immune responses. In RA, the body's own immune system mainly attacks the joints, causing inflammation in their lining, but can affect other tissues and organs in the body. About 1% of the population in developed countries suffer from RA, and it can result in long-term joint damage, causing significant illness and disability. Sufferers have chronic pain, loss of function of the joint, and loss of mobility. The cause of RA is unknown and there is no known cure. However, neutrophils (an immune cell important for inflammation) are thought to contribute to the initiation of RA. Understanding the primary mechanisms behind the development of RA, and where the body's immune system goes wrong, is fundamental not only to find new treatments for the disease but also to aid diagnosis to help patients get treatment to help control their often debilitating symptoms. Why Was the Study Done? Regulation of the immune system is necessary to prevent overactivity. Interruptions to the normal signals that moderate the immune response can lead to destruction of normal tissues. Previous studies have shown that the B7 family of proteins, which interact with CD28 signaling proteins on the surface of immune cells, are important regulators of the immune response. B7 proteins have also been found to exist in soluble forms that have been implicated in the development of rheumatoid diseases, but their exact role is not well understood. In the current study, researchers examined a member of the B7 family, B7-H4, which normally acts as an inhibitor of the immune response, to find out whether this signaling molecule affects the immune response and has a role in the development of RA. What Did the Researchers Do and Find? The researchers collected blood from 68 patients with RA and 24 healthy volunteers, and measured levels of soluble B7-H4, also known as sH4. They found sH4 in blood from 65% of patients with RA, compared with only 13% of healthy people. The levels of sH4 were significantly higher in RA patients (96.1 ng/ml) compared to healthy people ( |
| Databáze: | OpenAIRE |
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