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The Human Immune System 101: The Underactive Immune System


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 underactive immune system, also known as immunodeficiency, can be an extremely dangerous and even fatal disorder for a person to have. Immunodeficiencies are typically either primary or they are secondary. Primary immunodeficiency is something that a person is born with—it is hardwired within their genetic code—whereas secondary immunodeficiency is acquired during a person’s life (McKendrick, 2017).

“In a person with an immunodeficiency disorder, one or more components of either the adaptive or innate immune response is impaired, resulting in the body being unable to effectively resolve infections or disease. This leaves immunodeficient individuals at high risk of recurrent infection, and vulnerable to conditions that would not usually be of concern to otherwise healthy individuals,” (McKendrick, 2017).

Figure 1:Common Symptoms of Common Variable Immunodeficiency. Verywell. Jessica Olah. 2021.

Severe Combined Immunodeficiency (SCID)

Severe combined immunodeficiency or SCID is a rare immune system disorder resulting in a primary immunodeficiency. It is “caused by mutations in different genes involved in the development and function of infection-fighting immune cells” (National Association of Allergy and Infectious Diseases, 2019). SCID is typically fatal during the first two years of life unless appropriate treatment is available; so far the only treatment known to be curative for SCID is stem cell transplantation (Cirillo, et al., 2015, p. 1). As SCID is a primary immunodeficiency, it is often inherited and is encoded into a person’s genome, making it difficult to treat or cure without stem cell transplants. It has been found that certain genetic mutations associated with SCID are inherited in an autosomal recessive manner, similar to cystic fibrosis, sickle cell anemia, or Tay-Sachs disease; while not all forms of SCID are inherited this way, about 15% are (Mayo Clinic, 2022). When something is inherited through an autosomal recessive manner, the disease-causing mutation must be inherited from both parents so that the affected child has two copies of the mutated gene—meaning both parents must carry at least one copy of the mutated gene (Mayo Clinic, 2022). If a child were to inherit only one copy of the mutated disease-causing gene and one non-mutated gene, the child would be a carrier of the disease but would not have the actual disease.

Figure 2: Autosomal Recessive Inheritance. National Institute of Health's National Cancer Institute. 2022.

For a child to have SCID, they must inherit two copies of mutated genes that encode for an enzyme known as adenosine deaminase (ADA), which is necessary for T cell survival (National Association of Allergy and Infectious Diseases, 2019). “Absent or impaired ADA function leads to the accumulation of toxic metabolites… ADA-deficient SCID is characterized by severe lymphocytopenia (low white blood cells) affecting T-and B-lymphocytes and natural killer cells,” (Flinn, et al., 2018, p. 1). ADA is a common enzyme used ubiquitously throughout the body; however, it is mostly expressed in the lymphatic system making it essential for white blood cell proliferation. As the toxic metabolites accumulate in the lymphatic system, signaling pathways between immune cells are altered and cell viability is diminished (Cirillo, et al., 2015, p. 4-5). The cell type most affected by ADA deficiency is the T cell, however, as T cells are central for activating other aspects of the innate and adaptive immune responses, B cells and natural killer cell concentrations are also highly diminished (Purswani, et al., 2019, p. 1).

These sorts of deficiencies often result in the patient contracting opportunistic infections from bacteria, fungi, or viruses and being unable to fight them off when compared to healthy people properly. In a case study, a nine-month-old presented with “a history of failure to thrive and recurrent upper respiratory infections. He was hospitalized with acute respiratory failure requiring intubation and mechanical ventilation,” (Purswani et al., 2019, p. 3-4). He was diagnosed with Pneumocystis jirovecii pneumonia, otherwise known as PJP—an opportunistic fungal infection of the lungs common in people with immunodeficiencies. Additionally, the patient was found to lack both CD4+ and CD8+ naïve T cells, “indicating impaired T cell development in the thymus,” (Purswani et al., 2019, p. 3-4). The patient underwent a stem cell transplant in which hematopoietic stem cells—the stem cells responsible for the production of red and white blood cells in the bone marrow—from a healthy relative donor are given to the SCID patient intravenously to allow for the proliferation of healthy white blood cells (Haddad & Hoenig, 2019, p. 3-4).

Figure 3: David Vetter "Bubble Boy", a SCID Patient. Bettmann Archive & National Public Radio. 1986.


Approximately 35 million people worldwide are living with the human immune deficiency virus (HIV) which infects immune cells and eventually develops into acquired immunodeficiency syndrome (AIDS) (Science of HIV, 2022, p. 1). The HIV virus infects CD4+ helper T cells, which are one of the most essential immune cells in the body as they are responsible for recruiting other immune cells to launch a complete attack against pathogens. “To infect cells, the HIV protein envelope binds to the primary cellular receptor CD4 and then to a cellular coreceptor. This sequential binding triggers fusion of the viral and host cell membranes, initiating infection,” (Wilen et al., 2012, p. 1). HIV is a retrovirus, meaning it utilizes the reverse transcription process during viral replication. After that, the viral envelope fuses with the membrane of the helper T cell, the genetic material of the virus—in this case, a single strand of RNA—along with the mechanisms necessary for reverse transcription: the reverse transcriptase enzyme (Hu & Hughes, 2012, p. 1). The reverse transcriptase enzyme, instead of transcribing RNA from a DNA template, it transcribes HIV viral RNA into double-stranded DNA. The next step in the HIV life cycle is integration, which occurs when the newly synthesized viral DNA is integrated into the host DNA. Once a part of the host DNA, when the host’s genetic material is transcribed, the viral DNA will also be transcribed and translated into viral protein (Craigie & Bushman, 2012, p. 1).

Figure 4: Retrovirus Infection and Reverse Transcription. Encyclopedia Britannica. 2012.

HIV is responsible for the death of CD4+ helper T cells over the course of several years, typically before a patient with HIV develops AIDS. “The hallmark of acquired immunodeficiency syndrome (AIDS) pathogenesis is a progressive depletion of CD4+ T-cell populations in close association with progressive impairment of cellular immunity and increased susceptibility to opportunistic infections,” (Okoye & Picker, 2013, p. 1). As helper T cells are essential for activating B cells, as well as other innate and adaptive immune cells, a patient lacking helper T is susceptible to infections. Similar to SCID, patients with AIDS often develop pneumonia from Pneumocystis jirovecii (PCP) along with other infections. In a case study of a 54-year-old woman with AIDs and a low CD4+ T cell count, it was found that she had PCP along with mycobacterial infection and fungal histoplasmosis (Shah et al., 2013, p. 1-3).

While these infections can be treated with medications, without a proper immune response they are expected to reoccur. However, if HIV infection is caught early, it can be managed with a number of different antiretroviral therapies (ART) that can control the concentration of the virus in a person’s body (Center for Disease Control, 2022, p. 1). Antiretrovirals function as their name suggests: they target and block the mechanisms for reverse transcription which are unique to retroviruses like HIV. The medications target different mechanisms of reverse transcription thereby preventing the virus from replicating. Over time, the viral load in a person’s body can become undetectable which can prevent the spread of the virus to others (Center for Disease Control, 2022, p. 1).

Figure 5: Antiretroviral Mechanisms. Clinical Journal of the American Society of Nephrology. Jeffrey S. Berns and Nishaminy Kasbekar. 2006.

Immunodeficiencies can be devastating afflictions to live with as they can turn the common cold into a deadly virus or cause people to live in literal and metaphorical bubbles. A properly functioning immune system is essential for a person to live a healthy life, however, there are many ways for immunocompromised people to protect themselves against the world. From gene therapies to ARTs to surgical masks, the immunosuppressed and the medical community are finding new inventive ways to protect the vulnerable from opportunistic infections.

Bibliographic References

Center for Disease Control (CDC). (2022). Living with HIV. CDC.

Cirillo, E., Giardino, G., Gallo, V., D’Assante, R., Grasso, F., Romano, R., Lillo, C. D., Galasso, G., & Pignata, C. (2015). Severe combined immunodeficiency-an update. Annals of the New York Academy of Sciences, 1356(1), 90–106.

Craigie, R., & Bushman, F. D. (2012, May 8). HIV DNA Integration. Cold Spring Harbor Perspectives in Medicine, 2(7), a006890–a006890.

Flinn, A. M., & Gennery, A. R. (2018). Adenosine deaminase deficiency: a review. Orphanet Journal of Rare Diseases, 13(1).

Haddad, E., & Hoenig, M. (2019, November 19). Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency (SCID). Frontiers in Pediatrics, 7.

Hu, W. S., & Hughes, S. H. (2012, June 14). HIV-1 Reverse Transcription. Cold Spring Harbor Perspectives in Medicine, 2(10), a006882–a006882.

McKendrick, B. (2017). Immunodeficiency. British Society for Immunology. Retrieved September 7, 2022, from

Mayo Clinic. (2022). Autosomal Recessive Inheritance Pattern. Mayo Clinic.

National Association of Allergy and Infectious Diseases. (2019). Severe Combined Immunodeficiency (SCID). National Institute of Health (NIH).

Okoye, A. A., & Picker, L. J. (2013, June 16). CD4+T-cell depletion in HIV infection: mechanisms of immunological failure. Immunological Reviews, 254(1), 54–64.

Purswani, P., Meehan, C. A., Kuehn, H. S., Chang, Y., Dasso, J. F., Meyer, A. K., Ujhazi, B., Csomos, K., Lindsay, D., Alberdi, T., Joychan, S., Trotter, J., Duff, C., Ellison, M., Bleesing, J., Kumanovics, A., Comeau, A. M., Hale, J. E., Notarangelo, L. D., . . . Walter, J. E. (2019, April 5). Two Unique Cases of X-linked SCID: A Diagnostic Challenge in the Era of Newborn Screening. Frontiers in Pediatrics.

Science of HIV. (2022). The HIV Life Cycle. Science of HIV.

Shah, N., Owen, L., & Bhagani, S. (2013, July 5). “Occam’s Scissors”: opportunistic infections in advanced HIV infection. Case Reports, 2013(jul05 1), bcr2013009544–bcr2013009544.

Wilen, C. B., Tilton, J. C., & Doms, R. W. (2012, April 10). HIV: Cell Binding and Entry. Cold Spring Harbor Perspectives in Medicine, 2(8), a006866–a006866.

Visual References

Cover Image: Unknown. Illustration of coronavirus infecting respiratory system. Iokanan VFX Studios/Shutterstock. (2021). [Illustration]. Image retrieved from Figure 1: Olah, J. Frequent Symptoms of Common Variable Immunodeficiency. Verywell. (2021). [Illustration]. Image retrieved from Figure 2: Unknown. Autosomal Recessive Inheritance. National Institute of Health: National Cancer Institute. (2022). [Illustration]. Image retrieved from Figure 3: Unknown. David Vetter (“Bubble Boy”) Plays in the Enclosed Plastic Environment that He Had to Stay in to Survive. Bettmann Archive. (1984). [Photograph]. Image retrieved from Figure 4: Unknown. Retrovirus Infection and Reverse Transcription. Encyclopedia Britannica. (2012). [Illustration]. Image retrieved from Figure 5: Berns, J.S., Kasbekar, N. Antiretroviral Mechanism. Clinical Journal of the American Society of Nephrology. (2006). [Illustration]. Image retrieved from DOI:

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Erica Littman

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