The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis
Abstract
:1. Introduction
2. Genetic Susceptibility
3. Environmental and Lifestyle Factors
3.1. Smoking, Other Pulmonary Irritants, and Respiratory Diseases
3.2. Microbial Dysbiosis and Mucosal Inflammation
3.3. Body Weight and Diet
3.4. Hormonal Factors
3.5. Mental Health, Post-Traumatic Stress Disorders, and Depression
3.6. Drugs
4. Immunopathogenesis
4.1. Autoantibodies
4.2. Cytokine Networks
4.3. Synovial Pathology
4.4. Extra-Articular Involvement
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Autoantibody-Positive | Autoantibody-Negative | |
---|---|---|
Genetic associations | shared epitope-containing HLA-DRB1 alleles | HLA-B*08 with aspartate at position 9 and DRB1*03 with serine at position 11 non-HLA genes |
Environmental and endogenous factors | Smoking silica air pollution organic dusts asbestos pulmonary inflammation dysbiosis early menopause | air pollution organic dusts asbestos pulmonary inflammation dysbiosis excess body weight postpartum early menopause depression post-traumatic stress immune checkpoint inhibitors |
Autoantibodies Anti-CarP Anti-acetylated Anti-PAD | 15–65% 40–60% 2–18% | 10–15% 10–25% 3–19% |
Cytokines | TNF-α (lymphoid) IL-6 | TNF-α (myeloid) IL-6 IL-1β |
Synovial pathology | mostly lympho-myeloid pattern higher levels of CD19+ B cells, CD3+ T cells, lymphoid aggregates, germinal centers | lympho-myeloid, diffuse-myeloid and pauci-immune pattern lower antigen processing and presentation activity in B cells lower cytotoxic and exhausted gene expression in T cells higher proinflammatory cytokine expression in macrophages |
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De Stefano, L.; D’Onofrio, B.; Manzo, A.; Montecucco, C.; Bugatti, S. The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis. Int. J. Mol. Sci. 2021, 22, 12386. https://doi.org/10.3390/ijms222212386
De Stefano L, D’Onofrio B, Manzo A, Montecucco C, Bugatti S. The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis. International Journal of Molecular Sciences. 2021; 22(22):12386. https://doi.org/10.3390/ijms222212386
Chicago/Turabian StyleDe Stefano, Ludovico, Bernardo D’Onofrio, Antonio Manzo, Carlomaurizio Montecucco, and Serena Bugatti. 2021. "The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis" International Journal of Molecular Sciences 22, no. 22: 12386. https://doi.org/10.3390/ijms222212386