Antibodies to self antigens are a common feature of normal B cell function. And of course, antibodies to self antigens are a cardinal feature of some autoimmune diseases such as Graves Disease, Lupus, Myasthenia Gravis. What’s the difference? Plenty,
- Source of antibodies: Usually the B cell subset is innate in the case of normal anti-self antibodies and adaptive (B2 or Follicular B cells) in the case of pathogenic anti-self antibodies.
- Antigenic targets of the anti-self antibodies: Breakdown products of normal cell and tissue metabolism in the case of normal anti-self antibodies and critical self-components whose function is impaired when targeted in the case of pathogenic anti-self antibodies.
- Antibody affinity: Low and high in the case of normal and pathogenic anti-self antibodies, respectively.
Each of these differences is a key component that helps shape the difference in outcome, benign when it’s part of normal B cell function and pathogenic when it’s not. Thus, anti-self antibodies made by ‘innate’ B cells are considered normal.
OTOH,is the process by which self-reactive B cells from among the adaptive B cell repertoire are deleted during their development in the bone marrow. Specific autoimmunities can ensue when specific parts of this process break down.
Normal anti-self Antibodies
(NAbs) is a term used to describe circulating antibodies found in the absence of overt infections. In particular NAbs are antibodies found ( ) in germ-free mice as well as human Cord blood, meaning they’re made even in the absence of microbial exposure.
Today we know Nabs
- Bind with low affinity to various self-antigens. Low affinity means they bind weakly to their target antigens.
- Are polyreactive, i.e., each NAb can bind multiple different antigens.
- Mostly belong to the IgM (isotype = antibody class).
Major source of NAbs are B1a B cells (), a subset of B cells that, unlike conventional B cells (aka B2 or Follicular), are considered part not of the adaptive but of the innate immune system.
(MZ B cell) are another subset of innate B cells that secrete antibodies that can bind self antigens with low affinity (2).
B1a-derived NAbs are nowadays considered general purpose cleaners/janitors that help clear out varieties of molecules produced as a result of cellular metabolism that may be harmful if they persisted or accumulated (3,).
One compelling example is a study that reported ~30% of such NAbs In both mice and humans bind oxidation-specific(antigenic determinant) ( ). Oxidative stress is an inherent feature of aging, cell death, inflammation and tissue injury. It seems NAbs help maintain tissue homeostasis by clearing expected toxic by-products of these metabolic processes (5, ). NAbs have also been found against other typical products of cell damage and death such as phosphatidylcholine and specific carbohydrate epitopes present on dying and damaged red blood cells (7).
One of the most interesting properties of some NAbs is they function as both general purpose cleaners as well as a first line of defense against specific pathogens. One well-known example in mice is a mouse NAb called the T15.
- T15 NAbs bind the phosphorylcholine (PC) antigen present in the cell wall of ( , , ). In fact, T15 NAbs constitute ~60 to 80% of all the natural anti-PC response in mice (11), where this particular antibody idiotype is conserved across different mouse strains (12), being associated with the use of a specific heavy and light chain (13), experimentally shown to be critical for protection against S. pneumoniae ( ).
- Yet, T15 NAbs seem to also be generated in response to, and to help clear, low-density lipoproteins ( ).
1. Chou, Meng-Yun, et al. “Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans.” The Journal of clinical investigation 119.5 (2009): 1335.
2. Lopes-Carvalho, Thiago, Jeremy Foote, and John F. Kearney. “Marginal zone B cells in lymphocyte activation and regulation.” Current opinion in immunology 17.3 (2005): 244-250.
3. Baumgarth, Nicole. “The double life of a B-1 cell: self-reactivity selects for protective effector functions.” Nature Reviews Immunology 11.1 (2011): 34-46.
4. Kaveri, Srini V., Gregg J. Silverman, and Jagadeesh Bayry. “Natural IgM in immune equilibrium and harnessing their therapeutic potential.” The Journal of Immunology 188.3 (2012): 939-945.
5. Silverman, Gregg J., Caroline Grönwall, and Jaya Vas. “Natural autoantibodies to apoptotic cell membranes regulate fundamental innate immune functions and suppress inflammation.” Discovery medicine 8.42 (2009): 151-156.
6. Vas, Jaya, Caroline Grönwall, and Gregg J. Silverman. “Fundamental roles of the innate-like repertoire of natural antibodies in immune homeostasis.” Frontiers in immunology 4 (2013).
7. Hardy, Richard R., and Kyoko Hayakawa. “Development of B cells producing natural autoantibodies to thymocytes and senescent erythrocytes.” Seminars in Immunopathology. Vol. 26. No. 4. Springer Science & Business Media, 2005.
8. Briles, David E., et al. “Antiphosphocholine antibodies found in normal mouse serum are protective against intravenous infection with type 3 streptococcus pneumoniae.” Journal of Experimental Medicine 153.3 (1981): 694-705.
9. Briles, DAVID E., et al. “Anti-phosphorylcholine antibodies of the T15 idiotype are optimally protective against Streptococcus pneumoniae.” Journal of Experimental Medicine 156.4 (1982): 1177-1185.
10. Yother, Janet, et al. “Protection of mice from infection with Streptococcus pneumoniae by anti-phosphocholine antibody.” Infection and immunity 36.1 (1982): 184-188.
11. Lévy, Martine. “Frequencies of phosphorylcholine‐specific and T15‐associated 10/13 idiotope‐positive B cells within lipopolysaccharide‐reactive B cells of adult BALB/c mice.” European journal of immunology 14.9 (1984): 864-868.
12. Claflin, J. L., and M. Cubberley. “Clonal nature of the immune response to phosphocholine. VII. Evidence throughout inbred mice for molecular similarities among antibodies bearing the T15 idiotype.” The Journal of Immunology 125.2 (1980): 551-558.
13. Crews, Stephen, et al. “A single VH gene segment encodes the immune response to phosphorylcholine: somatic mutation is correlated with the class of the antibody.” Cell 25.1 (1981): 59-66.
14. Mi, Qing-Sheng, et al. “Highly reduced protection against Streptococcus pneumoniae after deletion of a single heavy chain gene in mouse.” Proceedings of the National Academy of Sciences 97.11 (2000): 6031-6036.
15. Shaw, Peter X., et al. “Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity.” Journal of Clinical Investigation 105.12 (2000): 1731.