Autoantibodies: Guardians or Aggressors?

Autoantibodies, also known as natural autoantibodies, are antibodies that target the body's own proteins instead of foreign invaders like bacteria or viruses. In healthy individuals, autoantibodies are mostly IgM, which are encoded by unmutated V(D)J genes and show a moderate affinity and high avidity for self-antigens. They act as a first line of defense against infections, and likely play important roles in housekeeping functions and maintaining immune homeostasis. Meanwhile, pathogenic autoantibodies are commonly high-affinity, somatically mutated, class-switched IgGs. They can disrupt homeostatic pathways involved in cell clearance, antigen-receptor signaling, and cell effector functions.¹

Normally, the immune system distinguishes between self and non-self-molecules, ensuring that it attacks only foreign substances. However, in autoimmune disorders, this recognition is affected. Examples include rheumatoid arthritis, lupus, and Hashimoto's thyroiditis. In these conditions, autoantibodies mistakenly target the body's tissues, causing inflammation, tissue damage, and a range of symptoms.

Detecting these autoantibodies has allowed for the use of disease-associated antigens in better diagnosis, prognosis and treatment. Their stability, for example, is typically much better than their related antigen. In addition, they have valuable potential in therapeutic use in vivo. Research has also shown that autoantibodies for certain diseases like systemic lupus may be detectable long before disease onset and function as biomarkers for therapeutic intervention.²

Systemic lupus erythematosus (SLE) is characterized by multiple organ inflammatory damage and a wide spectrum of autoantibodies. The anti-dsDNA and anti-Sm autoantibodies exhibit high specificity for SLE, contributing to the formation of immune complexes and inflammatory damage to the kidneys, skin, and central nervous system. Unfortunately, the exact mechanisms for autoantibodies in SLE are still unknown, and developing specific therapies against the pathogenic B cell subset and autoantibodies is a major hurdle.³

Besides SLE, recent studies have uncovered the role of autoantibodies in COVID-19. Using rapid extracellular antigen profiling, researchers found that patients with COVID-19 exhibited higher increases in autoantibody reactivities than uninfected individuals, as well as a high prevalence of autoantibodies against immunomodulatory proteins such as cytokines and chemokines. Furthermore, the autoantibodies disrupted immune function and virological control by affecting immunoreceptor signaling and peripheral immune cell composition. Therefore, further research in therapeutics should look at modulating these pathways and attenuating the autoantibodies.⁴

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References: 

1. Elkon, K., & Casali, P. (2008). Nature and functions of autoantibodies. Nature Clinical Practice. Rheumatology, 4(9), 491. https://doi.org/10.1038/ncprheum0895

2. Ma, H., Murphy, C., & Loscher, C. E. (2022). Autoantibodies - enemies, and/or potential allies? Frontiers in Immunology, 13. https://doi.org/10.3389/fimmu.2022.953726

3. Lou, H., Ling, G. S., & Cao, X. (2022). Autoantibodies in systemic lupus erythematosus: From immunopathology to therapeutic target. Journal of Autoimmunity, 132, 102861. https://doi.org/10.1016/j.jaut.2022.102861

4. Wang, E. Y., Mao, T., Klein, J., Dai, Y., Huck, J. D., Jaycox, J. R., Liu, F., Zhou, T., Israelow, B., Wong, P., Coppi, A., Lucas, C., Silva, J., Oh, J. E., Song, E., Perotti, E. S., Zheng, N. S., Fischer, S., Campbell, M., . . . Ring, A. M. (2021). Diverse functional autoantibodies in patients with COVID-19. Nature, 595(7866), 283-288. https://doi.org/10.1038/s41586-021-03631-y