The Human Immune System 101: The Overactive Immune System

Foreword:

The immune system is one of the most complex, nuanced biological systems that function to keep the human race alive each and every day. It is both specific and broad, lifelong, and short-term, inherited and acquired, all at the same time. While it defends against deadly threats such as bacteria and viruses, defects in the immune system can be just as fatal. The Immune System 101 articles describe how this contradictory system works and will summarize the variety of functions of the immune system, its importance, and its potential failings in six different articles.


1. The Human Immune System 101: Innate Immunity

2. The Human Immune System 101: Adaptive Immunity

3. The Human Immune System 101: Bacterial & Viral Defenses Against the Immune System

4. The Human Immune System 101: The Overactive Immune System

5. The Human Immune System 101: The Underactive Immune System

6. The Human Immune System 101: The Immune System and Cancer


An overactive immune system may seem like a good thing, even a great thing to have. However, it can be detrimental to one’s health. Autoimmune diseases occur when the immune system fails to recognize and differentiate self vs. non-self-tissue and immune cells, instead of attacking and killing foreign pathogens, target one’s own healthy tissue resulting in an autoimmune disease (Orbital, 2022). There are several different autoimmune diseases, some of which involve multiple organ systems and some of which involve only one system or cell type. These disorders include systemic lupus erythematosus (lupus), type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and a multitude of others (Orbital, 2022).

Figure 1: Autoimmune Symptoms


Systemic Lupus Erythematosus

Systemic lupus erythematosus—or more commonly known simply as lupus or SLE—is a common autoimmune disease that at least five million people worldwide suffer from, according to the Lupus Foundation of America (Unknown, Lupus Foundation of America, 2019). SLE “is a chronic autoimmune disease characterized by the production of autoantibodies specific for components of the cell nucleus and that causes damage to body tissues and organs,” (Arneth, 2019, p. 1). An important aspect of the onset of the disease deals with tolerance: the immune system's ability to distinguish between self and foreign tissue. During the production of antibodies and the B cells that release those antibodies, the antibodies are typically tested for reactivity and tolerance against self-cells. However, testing for self-tolerance that occurs in the bone marrow is not fail-proof and in patients with autoimmune disorders, self-reactive B cells exit the bone marrow despite checkpoints.

At this stage of immature B cell development, the cell-surface antibody can bind antigens. In the bone marrow microenvironment in which immature B cells emerge, antigens that engage the BCR (B cell receptor) will almost always be self-antigens, which makes regulation at this stage essential...These processes are collectively known as central tolerance. (Nemazee, 2017, p. 281).

In a healthy individual, during central tolerance, B cells that react with self-antigens in the bone marrow microenvironment undergo receptor editing in which the self-reactive immunoglobulin receptor is modified. Additionally, after this initial stage of B cell development, B cells go through a process known as peripheral tolerance in the spleen and lymph nodes; during this stage, B cells with BCRs that bind to self tissue are impaired, or induced by other regulatory cells to undergo cell death (Nemazee, 2017).

Figure 2: Mechanisms of Self Tolerance


These mechanisms of tolerance are not fail-proof and in patients with autoimmune diseases, there is a breakdown or error in them resulting in abnormal antibodies circulating in the blood and lymph system. Two of the most common antibody abnormalities found in patients with lupus are antinuclear antibodies (ANAs) and anti-DNA antibodies. ANAs “are a class of antibodies that bind to cellular components in the nucleus including proteins, DNA, RNA, and nucleic acid-protein complexes,” (Nosal, Superville, et al., 2021, p. 1). If antinuclear antibodies are present in a substantial concentration, then the patient’s own immune system begins to target the nucleus of the cell which houses the DNA and contains markers that antinuclear antibodies recognize and bind to. Antinuclear antibodies are able to penetrate living cells and bind to extracellular segments of degraded nuclei after a cell undergoes cell death (Alarco, 2001). This is one of the reasons why lupus patients often experience photosensitivity when exposed to the sun for long periods of time; UV light damages DNA in healthy skin cells, causing those cells to die and release fragmented nuclei parts which allows for a robust response from the antinuclear antibodies (Alarco, 2001). When ANAs bind to these nuclear segments, they form immune complexes which signal for the activation of the complement cascades. The C3 and C4 complement levels may be low in SLE patients during a period of high disease activity as they are used for immune complex clearance.


Figure 3: How Immune Complexes Form With Anti-DNA Antibodies


The most common symptoms of SLE are fatigue, chronic low-grade fever, a malar rash on the face in the shape of a butterfly, joint pain, sensitivity to sunlight (photosensitivity), hair loss, weight loss, shortness of breath, headaches, and chest pains (Unknown, 2021). Additionally, around 80-90% of lupus patients experience neuropsychiatric (mental health) symptoms according to the lupus research alliance. These symptoms include depression, anxiety, and bipolar disorder which patients with lupus are 1.74 times more likely to develop than the general population (Tiosano, Gendelman, et al., 2017). In a case study surveying respiratory involvement in lupus patients it was found that this particular disease manifestation can "present in very different ways, both concerning the clinical picture, acute or chronic, and the anatomic localizations. It is frequent and its detection is essential as the prognosis has been transformed by the use of immunosuppressant treatments," (Carmier, Marchand-Adam, et al., 2010, p. 75). Additionally, low blood oxygen was found in 25% of these cases with chronic interstitial pneumonia being observed in 3 to 13% of lupus patients (Carmier, Marchand-Adam, et al., 2010).


There are many different treatments for SLE despite there being no cure. With these treatments, the disease can often be managed. Steroid treatments are often used for acute flare-ups of disease activity to reduce inflammation and pain, however, due to the long-term effects of steroids such as osteoporosis, this treatment is not typically favored for treating the disease in the long run (Unknown, Center for Disease Control, 2022). Additionally, antimalarial drugs such as hydroxychloroquine are used for long-term treatment to lower the concentration of disease-causing autoantibodies and have been known to help prevent organ damage if taken long-term. Immunosuppressive medications such as methotrexate and mycophenolate mofetil are also used to manage disease activity however one must be careful to prevent contracting infections when taking immunosuppressive (Unknown, Center for Disease Control, 2022). Finally, biologics such as Benlysta are often used. Benlysta is a monoclonal antibody that binds to B lymphocyte stimulators which help B cells to proliferate. When the Benlysta antibodies bind to the B lymphocyte stimulator, the concentration of autoantibody-producing B cells is reduced, and therefore disease activity is reduced too (Unknown, Center for Disease Control, 2022).


Type 1 Diabetes

Type 1 diabetes is another type of common autoimmune disorder, however, unlike SLE, diabetes is specific to the pancreas instead of affecting multiple organ systems. Additionally, type 1 diabetes is “characterized by autoreactive T cell-mediated destruction of insulin-producing pancreatic beta-cells,” (Toren, Burnette, et al., 2021, p. 1). Beta cells are specifically found in the pancreas and are responsible for insulin production which allows glucose to enter the body’s cells and provide them with energy. When a person consumes food, glucose enters the bloodstream, and insulin is needed to allow the sugar to actually enter the cells (Toren, Burnette, et al., 2021). The pancreas also regulates excess glucose in the blood by releasing glucagon—which is made from alpha cells in the pancreas—to store the extra sugar in the form of glycogen in the liver and muscles. In a person without diabetes, insulin binds to insulin receptors on every cell in the body to open up a glucose channel, which in turn allows glucose molecules to enter the cells and lowers a person's blood sugar (Toren, Burnette, et al., 2021). However, in a person with type 1 diabetes, due to the fact that the beta cells of the pancreas are the target of T cells, glucose is unable to enter the cells without the help of insulin (Unknown, Mayo Clinic, 2022).

Figure 4: How Insulin Works


Beta-cells are destroyed in type 1 diabetes by self-reactive T cells, resulting in the inability of cellular uptake of glucose. Both CD4+ and CD8+ T cells have been found to be self-reactive in diabetes patients (Knip & Siljander, 2008). Similar to B cells, T cells undergo tolerance testing to prevent autoimmune diseases, and, this process isn't failproof either. During development in the thymus, T cells "undergo T-cell receptor (TCR)-mediated apoptosis, a process known as negative selection. Negative selection is extremely important for establishing a functional immune system, as it provides an efficient mechanism for ridding the T-cell repertoire of self-reactive and potentially autoimmune lymphocytes," (Palmer, 2003, p. 383). For people without diabetes, this means that the population of T cells within a person's body is largely self-tolerant and won't attack healthy cells. However, in type 1 diabetes, when these processes of tolerance testing fail, T cells-- specifically CD8+ T cells-- attack insulin-producing beta cells.


Patients with diabetes are at a higher risk for heart disease, nerve damage, kidney damage, eye damage, and foot damage; furthermore, the symptoms of type 1 diabetes include fatigue, hunger, weight loss, and increased urination, and increased thirst (Unknown, Mayo Clinic, 2022). While there is no cure for type 1 diabetes, the disease can be managed by monitoring one’s blood sugar levels, injecting insulin when the levels are too high, and eating glucose when one’s blood sugar is too low, also known as hypoglycemia. Diabetic ketoacidosis occurs when a diabetic's blood sugar is too high (hyperglycemia), glucose is unable to enter the cells and the body begins to break down fat. A case study showed a 6-year-old boy was found to be hyperglycemic with a fasting blood sugar level of 300 mg/dl when a healthy fasting blood sugar is considered below 99 mg/dl. This hyperglycemia led to symptoms of diabetic ketoacidosis such as frequent urination, stomach pain, confusion, fatigue, and excessive thirst (Kumar, 2015). The hyperglycemia was treated with insulin and the ketoacidosis resolved.

Figure 4: How the Pancreas Makes and Releases Insulin.


Autoimmune disorders are the result of a failure of a person’s immune system to recognize foreign pathogens versus health self-tissues. These disorders can be broad such as SLE or rheumatoid arthritis or specific to a certain cell type such as type 1 diabetes or multiple sclerosis. Additionally, they are often difficult to manage and can be detrimental to not only one’s physical health but their mental health as well. Cellular mechanisms responsible for preventing immune cells from attacking one's own cells are highly error-prone and a combination of genetic, environmental, and physical factors combined may lead to a breakdown in those systems and result in an autoimmune disease.


Bibliographic References

Alarco, D. (2001). Antinuclear antibodies: to penetrate or not to penetrate, that was the question. Lupus, 10(5), 315–318. https://doi.org/10.1191/096120301669579565


Arneth, B. (2019). Systemic Lupus Erythematosus and DNA Degradation and Elimination Defects. Frontiers in Immunology, 10. https://doi.org/10.3389/fimmu.2019.01697


Carmier, D., Marchand-Adam, S., Diot, P., & Diot, E. (2010). Respiratory involvement in systemic lupus erythematosus. Revue Des Maladies Respiratoires, 27(8), e66–e78. https://doi.org/10.1016/j.rmr.2010.01.003 Knip, M., & Siljander, H. (2008). Autoimmune mechanisms in type 1 diabetes. Autoimmunity Reviews, 7(7), 550–557. https://doi.org/10.1016/j.autrev.2008.04.008


Kumar, S. (2015). Type 1 diabetes mellitus-common cases. Indian Journal of Endocrinology and Metabolism, 19(7), 76. https://doi.org/10.4103/2230-8210.155409

Nemazee, D. (2017). Mechanisms of central tolerance for B cells. Nature Reviews Immunology, 17(5), 281–294. https://doi.org/10.1038/nri.2017.19 Nosal, R. S., Superville, S. S., & Varacallo, M. (2021). Biochemistry, Antinuclear Antibodies (ANA). In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK537071/


Orbital, A. M. (2022, July 22). What Are Common Symptoms of Autoimmune Disease? Johns Hopkins Medicine. https://www.hopkinsmedicine.org/health/wellness-and-prevention/what-are-common-symptoms-of-autoimmune-disease#:%7E:text=Autoimmune%20disease%20happens%20when%20the,wide%20range%20of%20body%20parts.


Palmer, E. (2003). Negative selection — clearing out the bad apples from the T-cell repertoire. Nature Reviews Immunology, 3(5), 383–391. https://doi.org/10.1038/nri1085

Tiosano, S., Gendelman, O., Comaneshter, D., Amital, H., Cohen, A., & Amital, D. (2017). THU0248 The association between systemic lupus erythematosus to bipolar disorder – a real-life study. Poster Presentations. https://doi.org/10.1136/annrheumdis-2017-eular.3667 Toren, E., Burnette, K. S., Banerjee, R. R., Hunter, C. S., & Tse, H. M. (2021). Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes Pathogenesis. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.756548


Unknown. (2022). Type 1 Diabetes. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/type-1-diabetes/symptoms-causes/syc-20353011


Unknown. (2019). Lupus facts and statistics. Lupus Foundation of America. https://www.lupus.org/resources/lupus-facts-and-statistics#:%7E:text=How%20common%20is%20lupus%20and,and%20teenagers%20develop%20lupus%2C%20too.


Unknown. (2021). Lupus - Symptoms and causes. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789


Unknown. (2022). Diagnosing and Treating Lupus. Centers for Disease Control and Prevention. https://www.cdc.gov/lupus/basics/diagnosing.htm


Visual References

Cover Image: Balbusso, A. & Balbusso E. We Thought It Was Just a Respiratory Virus. UCSF Magazine. (2020). [Illustration]. Image retrieved from https://magazine.ucsf.edu/we-thought-it-was-just-respiratory-virus

Figure 1: Roberts, E. Autoimmune Symptoms. Verywell. (2022). [Illustration]. Image retrieved from https://www.verywellhealth.com/autoimmune-disease-symptoms-3232847


Figure 2: Unknown. Self-Tolerance Mechanisms. GenScript. (2020). [Illustration]. Image retrieved from https://www.genscript.com/self-tolerance.html

Figure 3: Pietsky, D., & Lipsky, P. How Immune Complexes Form With Anti-DNA Antibodies. Nature. (2020). [Illustration]. Image retrieved from https://www.nature.com/articles/s41584-020-0480-7.pdf

Figure 4: Unkown. How Insulin Works. Shuttershock. (2020). [Illustration]. Image retrieved from https://www.news-medical.net/health/Insulins-role-in-the-human-body.aspx


Figure 5: Sakkura. How the Pancrease Makes and Releases Insulin. (2020). [Illustration]. Image retrieved from https://researchoutreach.org/articles/focus-beta-cell-mass-could-help-prevent-type-2-diabetes/





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Erica Littman

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