Self-protein

Self-protein refers to all proteins endogenously produced by DNA-level transcription and translation within an organism of interest. This does not include proteins synthesized due to viral infection, but may include those synthesized by commensal bacteria within the intestines. Proteins that are not created within the body of the organism of interest, but nevertheless enter through the bloodstream, a breach in the skin, or a mucous membrane, may be designated as “non-self” and subsequently targeted and attacked by the immune system. Tolerance to self-protein is crucial for overall wellbeing; when the body erroneously identifies self-proteins as “non-self”, the subsequent immune response against endogenous proteins may lead to the development of an autoimmune disease.[1][2]

Examples
Proteins targeted by the immune system Resulting autoimmune disease
Thyroid stimulating hormone receptor Graves' disease[3]
Pancreatic beta-cell proteins Type 1 diabetes mellitus[4]
Commensal bacteria flagellum Inflammatory bowel disease[5]
Nuclear and cell membrane phospholipids Lupus[6]
Tissue transglutaminase Celiac disease[7]

Of note, the list provided above is not exhaustive; the list does not mention all possible proteins targeted by the provided autoimmune diseases.

Identification by the immune system

Autoimmune responses and diseases are primarily instigated by T lymphocytes that are incorrectly screened for reactivity to self-protein during cell development.

During T-cell development, early T-cell progenitors first move via chemokine gradients from the bone marrow into the thymus, where T-cell receptors are randomly rearranged at the gene level to allow for T-cell receptor generation.[8] These T-cells have the potential to bind to anything, including self-proteins.

The immune system must differentiate the T-cells that have receptors capable of binding to self versus non-self proteins; T-cells that can bind to self-proteins must be destroyed to prevent development of an autoimmune disorder. In a process known as “Central Tolerance”, T-cells are exposed to cortical epithelial cells that express a variety of different major histocompatibility complexes (MHC) of both class 1 and class 2, which have the ability to bind to T-cell receptors of CD8+ cytotoxic T-cells, and CD4+ helper T-cells, respectively. The T-cells that display affinity for these MHC are positively selected to continue to the second stage of development, while those that cannot bind to MHC undergo apoptosis.[9] In the second stage, immature T-cells are exposed to a variety of macrophages, dendritic cells, and medullary epithelial cells that express self-protein on MHC class 1 and class 2. These epithelial cells also express the transcription factor labelled autoimmune regulator (AIRE) - this crucial transcription factor allows the medullary epithelial cells of the thymus to express proteins would normally be present in peripheral tissue rather than in an epithelial cell, such as insulin-like peptides, myelin-like peptides, and more.[10] As these epithelial cells now present a large variety of self-proteins that could be encountered across the body, the immature T-cells are tested for affinity to self-protein and self-MHC. If any T-cell has strong affinity for self-protein and self-MHC, the cell undergoes apoptosis to prevent autoimmune function.[9] T-cells that display low/medium affinity are allowed to leave the thymus and circulate throughout the body to react to novel non-self antigen. In this manner, the body attempts to systematically destroy T-cells that could lead to autoimmunity.

References
  1. Rosenblum MD, Remedios KA, Abbas AK (June 2015). "Mechanisms of human autoimmunity". The Journal of Clinical Investigation. 125 (6): 2228–33. doi:10.1172/JCI78088. PMC 4518692. PMID 25893595.
  2. Devarapu SK, Lorenz G, Kulkarni OP, Anders HJ, Mulay SR (2017). "Cellular and Molecular Mechanisms of Autoimmunity and Lupus Nephritis". International Review of Cell and Molecular Biology. Elsevier. 332: 43–154. doi:10.1016/bs.ircmb.2016.12.001. ISBN 978-0-12-812471-0. PMID 28526137.
  3. Morshed SA, Davies TF (September 2015). "Graves' Disease Mechanisms: The Role of Stimulating, Blocking, and Cleavage Region TSH Receptor Antibodies". Hormone and Metabolic Research. 47 (10): 727–34. doi:10.1055/s-0035-1559633. PMID 26361259.
  4. Roep BO, Peakman M (April 2012). "Antigen targets of type 1 diabetes autoimmunity". Cold Spring Harbor Perspectives in Medicine. 2 (4): a007781. doi:10.1101/cshperspect.a007781. PMC 3312399. PMID 22474615.
  5. Mitsuyama K, Niwa M, Takedatsu H, Yamasaki H, Kuwaki K, Yoshioka S, et al. (January 2016). "Antibody markers in the diagnosis of inflammatory bowel disease". World Journal of Gastroenterology. 22 (3): 1304–10. doi:10.3748/wjg.v22.i3.1304. PMC 4716040. PMID 26811667.
  6. Riemekasten G, Hahn BH (August 2005). "Key autoantigens in SLE". Rheumatology. 44 (8): 975–82. doi:10.1093/rheumatology/keh688. PMID 15901907.
  7. Caja S, Mäki M, Kaukinen K, Lindfors K (March 2011). "Antibodies in celiac disease: implications beyond diagnostics". Cellular & Molecular Immunology. 8 (2): 103–9. doi:10.1038/cmi.2010.65. PMC 4003135. PMID 21278768.
  8. Sambandam A, Bell JJ, Schwarz BA, Zediak VP, Chi AW, Zlotoff DA, et al. (2008-09-16). "Progenitor migration to the thymus and T cell lineage commitment". Immunologic Research. 42 (1–3): 65–74. doi:10.1007/s12026-008-8035-z. PMID 18827982.
  9. Xing Y, Hogquist KA (June 2012). "T-cell tolerance: central and peripheral". Cold Spring Harbor Perspectives in Biology. 4 (6): a006957–a006957. doi:10.1101/cshperspect.a006957. PMC 3367546. PMID 22661634.
  10. Anderson MS, Su MA (April 2011). "Aire and T cell development". Current Opinion in Immunology. 23 (2): 198–206. doi:10.1016/j.coi.2010.11.007. PMC 3073725. PMID 21163636.
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