The first way to protect host cells from infectious agents is the activities of our immune system which requires highly complex interactions between cells and molecules. When the immune system recognizes the auto-antigens in our molecules as a result of inadequate tolerance, it recognizes them as harmful to us and starts to destroy our own tissues1. The presence of B and T lymphocytes can react against the body’s tissues in healthy individuals. For instance, if a laboratory animal is injected with a purified self-protein and together with an adjuvant, which enhances the response to the injected antigen, the animal makes a response against the tissues in which that protein is originally found. B and T cells can react to self-antigens and they are inhibited by an antigen-specific TReg cell or by other suppressive mechanisms. The main elements of our immune system (T and B lymphocytes) protect the body against microbial infections that may come from outside; however, in some cases, these mechanisms fail; a malfunction occurs, and autoimmune diseases such as multiple sclerosis, type-1 diabetes, Systemic lupus erythematosus (SLE) arise2.
Firstly, Multiple Sclerosis (MS) is a progressive neurologic disorder caused by an autoimmune response to self-antigens3. The most characteristic features of this disease are central nervous system (CNS) inflammation, demyelination, and axonal loss or injury4. MS results from an immune cell attack against the myelin sheath which forms the white matter of the CNS2. Pathologically a focal inflammatory white matter plaque is characterized by demyelination in the MS disease4. The demyelination of nerve cells from an immunologic attack leads to dysfunction in nerve impulses along axons and it causes people to be exposed to negative consequences such as diminished eyesight and problems in motor coordination. There is no cure for this disease. For the treatment of MS patients many therapeutic methods, which had proven effective in T cell-mediated inflammatory demyelinating diseases, were carried out but had no effect5. Even if there are some drugs approved for this disease, they could not stop the progression of the disease2.

Secondly, Type 1 Diabetes (TD1) often occurs in children, is immune-associated, and is caused by the destruction of pancreatic β cells that produce insulin2,6. TD1 is characterized by insulin deficiency and consequent hyperglycemia7. Especially in the last 20 years, two main animal models of type 1 diabetes – BioBreeding (BB) rat and non-obese diabetic (NOD) mouse have been used in preclinical studies to examine the effect of genetics, pathophysiology, and environmental influence on disease development8. Many genes have been associated with their effects on susceptibility to autoimmune diseases, and one of the most important is that encode MHC class II polypeptides. People who inherit certain alleles of the MHC locus are more likely to develop type 1 diabetes2. Cells containing MHC molecules can bind to certain peptides that stimulate autoantibody formation against insulin-secreting β cells in the pancreas.2 Furthermore, studies in NOD mice have shown that the disease occurs as a result of a disruption in immune regulation; leading to an expansion of autoreactive CD4+ and CD8+ T cells, autoantibody-producing B lymphocytes8. Additionally, at least 6 loci are shared between the NOD mouse model and humans at risk for type 1 diabetes, and 19 loci are associated with immune regulation. Nowadays, patients diagnosed with TD1 receive a daily dose of insulin, and although this hormone ensures the continuity of their vital activities; these patients may be exposed to kidney and vascular diseases2.
Finally, Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that can lead to morbidity and mortality, which is called “red wolf ” due to the red rashes that develop on the cheeks in the early stages of the disease2,9. The incidence of this disease in women of childbearing age is higher in terms of triggering the disease by hormonal types in women. SLE is not limited to a particular organ, it attacks all tissues of the body, especially the nervous system, heart, and kidneys2. Just like in other autoimmune diseases, genetic factors have an effect on SLE. Studies have revealed that susceptibility to SLE is caused by human leucocyte antigen (HLA) class II gene polymorphisms10. Moreover, the HLA class II genes have been correlated with the presence of some autoantibodies such as anti-Sm (small nuclear ribonuclear protein), anti-Ro, anti-La, anti-nRNP (nuclear ribonuclear protein), and anti-DNA antibodies. According to recent research, autoimmunity occurs as a result of incorrect binding of TLRs, which normally recognize microbial DNA and RNA, to the body’s own informational macromolecules2.

Many new treatments have been developed in recent years because of the great progress made in the study of autoimmunity at the molecular level. The use of immunosuppressive drugs such as Cyclosporin A and CellCept, which inhibit the autoimmune response, is one of the treatment methods. However, because the drugs are not specific, they destroy all autoimmune responses and may therefore make patients susceptible to infections. Among other approaches, one of the most promising methods is restoring immunological tolerance to self-antigens.2 Administering disease-causing peptides (called APLs) that are similar to peptides that will be produced from an individual’s own antigens is one way of inducing tolerance to specific antigens. Such APLs are expected to bind to TCRs, blocking T-cell activation and reducing the secretion of inflammatory cytokines (e.g., TNF- α and IFN- α)2. Glatiramer acetate (GA; Copaxone®) was the first disease-modifying treatment which is successfully tested and approved for Multiple Sclerosis11. A number of similar types of peptide “vaccines” are in clinical trials2. Another method to induce immunological tolerance to myelin-derived proteins in MS patients is the isolation of autoreactive T-cells from the patient; proliferating them in culture, rendering them unable to replicate, and injecting them back into the individual with the purpose of inducing an immune reaction against the reintroduced cells and other autoreactive cells in the body.2 In the last 50 years, improvements have been made in pharmacotherapy that positively affect Systemic Lupus Erythematosus disease, but unfortunately, poor renal outcomes, cardiovascular diseases, and the accumulation of organ damage have been encountered12. Therapeutic methods include antimalarials, corticosteroids, immunosuppressives, ace inhibitors, antibiotics, B-cell therapies and vitamin D supplementation. Despite these therapies, SLE is still related to premature mortality and morbidity.12 Furthermore, transplantation of hematopoietic stem cells from either the patient themselves or a donor is one of the other approaches. This procedure has the potential to cause life-threatening complications, thus, it represents a cure only for patients with severe autoimmune diseases. However, unlike the other drugs, transplant recipients begin the rest of their lives with a greatly altered immune system and the possibility of complete recovery from their disease. About one-third of transplant recipients experience long-term benefits from the procedure, while another third may experience no significant benefit, and the reason for this discrepancy in response is not yet known2.
In the end, our immune system is a warrior mechanism assigned to protect our body from harmful external factors. B and T lymphocytes are the main soldiers in the immune system and this mechanism has the ability to recognize and distinguish millions of foreign microbial enemies that enter our body. In some cases, dysfunctions occur due to some problems in this system and our own warriors perceive our own cells as enemies and declare war on them. As a result, autoimmune diseases occur. For instance, multiple sclerosis is a chronic, demyelinating, and degenerative disease which induced by T cells triggered against structural components of myelin in the CNS. Likewise, Type 1 Diabetes and Systemic Lupus Erythematosus are other autoimmune diseases. In addition to environmental and epigenetic factors, predisposing genes also play a large role in the development of these diseases. For example, people who carry certain alleles of the MHC locus are more likely to develop type 1 diabetes or human leukocyte antigen (HLA) class II gene polymorphisms are effective in developing systemic lupus. With the developing technology and advances in the pharmaceutical industry, many therapeutic methods have been tried and many of them are still in clinical trials. The use of immunosuppressive drugs, restoring immunological tolerance to self-antigens, and autologous hematopoietic stem cell transplantation (HSCT) is one of these methods. Although there are still some unresolved points, the progress made in this regard should never be underestimated. As long as we advance in the light of science, it is not in the distant future to find a permanent solution to many diseases.
References:
- Juarranz Y. Molecular and Cellular Basis of Autoimmune Diseases. Cells. 2021 Feb 23;10(2):474. doi: 10.3390/cells10020474. PMID: 33672111; PMCID: PMC7926515.
- Cell and Molecular Biology by Gerald Karp, 7th Edition
- Axisa, P. P., & Hafler, D. A. (2016). Multiple sclerosis: genetics, biomarkers, treatments. Current opinion in neurology, 29(3), 345–353. https://doi.org/10.1097/WCO.0000000000000319
- Kamm CP, Uitdehaag BM, Polman CH. Multiple sclerosis: current knowledge and future outlook. Eur Neurol. 2014;72(3-4):132-41. doi: 10.1159/000360528. Epub 2014 Jul 30. PMID: 25095894.
- Lassmann H, Brück W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007 Apr;17(2):210-8. doi: 10.1111/j.1750-3639.2007.00064.x. PMID: 17388952; PMCID: PMC8095582.
- Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014 Jan 4;383(9911):69-82. doi: 10.1016/S0140-6736(13)60591-7. Epub 2013 Jul 26. PMID: 23890997; PMCID: PMC4380133.
- DiMeglio, L. A., Evans-Molina, C., & Oram, R. A. (2018). Type 1 diabetes. Lancet (London, England), 391(10138), 2449–2462. https://doi.org/10.1016/S0140-6736(18)31320-5
- Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010 Apr 29;464(7293):1293-300. doi: 10.1038/nature08933. PMID: 20432533; PMCID: PMC4959889.
- Levy, D. M., & Kamphuis, S. (2012). Systemic lupus erythematosus in children and adolescents. Pediatric clinics of North America, 59(2), 345–364. https://doi.org/10.1016/j.pcl.2012.03.007
- Mok, C. C., & Lau, C. S. (2003). Pathogenesis of systemic lupus erythematosus. Journal of clinical pathology, 56(7), 481–490. https://doi.org/10.1136/jcp.56.7.481
- Wynn D. R. (2019). Enduring Clinical Value of Copaxone® (Glatiramer Acetate) in Multiple Sclerosis after 20 Years of Use. Multiple sclerosis international, 2019, 7151685. https://doi.org/10.1155/2019/7151685
- Durcan, L., & Petri, M. (2016). Immunomodulators in SLE: Clinical evidence and immunologic actions. Journal of autoimmunity, 74, 73–84. https://doi.org/10.1016/j.jaut.2016.06.010
Figure References:
- Deepthi Sathyajith (2019). M.Pharm. Reviewed by Lois Zoppi, B.A.
- Shiel William, (2021) Medically Reviewed
Inspector: Eylül ASLAN