X-Linked Severe Combined Immunodeficiency (X-SCID)

X-linked severe combined immunodeficiency, or X-SCID, is a chromosomal disorder in which the immune system lacks multiple protective cells that defend the body from disease. As of 2024, approximately one in 75,000 males have X-SCID. X-SCID is the most common type of SCID, which encompasses a range of disorders that all involve defects in immune cells that fight infections, leaving the individual susceptible to life-threatening diseases. X-SCID, which typically only affects males, arises due to a mutation in the interleukin 2 receptor gamma chain, or IL-2RG, gene on the X chromosome. IL-2RG aids certain immune cells to develop their protective functions, so a mutation in the receptor results in a dysfunctional immune system. Doctors most commonly use bone marrow transplants to treat X-SCID. By studying cases of X-SCID, researchers more clearly defined the role of lymphocytes in immune system development and overall disease protection. Unless detected and treated early, the defect in immune cells from X-SCID makes the individual prone to severe, recurrent infections, which are almost always fatal.

1. Background and Context
2. History of Discovery
3. The Bubble Boy
4. TREC Test
5. Current Treatments
6. Support Groups and Outlook

Background and Context

X-SCID, as well as other SCIDs, involve defects in certain lymphocytes, which are a type of immune cell that helps the immune system fight infections. Specifically, those lymphocytes include T cells, B cells, and natural killer, or NK, cells. In the mid-1900s, researchers began delineating the different functions of lymphocytes as well as how they develop. In the following decades, researchers found that some T cells directly attack foreign invaders to ward off disease, while others mediate the activity of other immune cells. For example, a subtype of T cells regulates the development of B cells. B cells produce antibodies, which are molecules that recognize antigens, or foreign proteins, and neutralize them. NK cells, like some T cells, directly attack harmful cells to protect the body from infection. However, while T cells have receptors that have high specificity, which means that they only recognize certain antigens, NK cells are nonspecific and recognize a broader set of antigens. The nonspecific nature of NK cells allows them to quickly kill invaders, though T cells generate a greater overall immune response. Deficiencies in any of those cells impair the immune system’s ability to readily fight off infections from bacteria or viruses. All SCIDs involve at least one deficiency in either T cells, B cells, or NK cells, and X-SCID is generally characterized by deficiencies in T cells and B cells.

History of Discovery

In 1950, pediatricians Eduard Glanzmann and Paul Riniker, who practiced medicine in Switzerland, observed one of the first documented cases of SCID. At the time, researchers had just begun studying lymphocytes and their role in the immune system. Therefore, researchers did not classify all lymphocyte deficiencies under one condition, which is, as of 2024, what we now know as SCID. Glanzmann and Riniker saw two pairs of siblings in their infancy who died from an unknown illness characterized by diarrhea, fungal infections, and a low level of lymphocytes. Doctors observe lymphocyte levels in blood by taking a blood sample and counting the number of lymphocytes in the blood. The infants also had reduced lymphatic tissues, which are tissues associated with the immune system such as lymph nodes. Glanzmann and Riniker called the disorder they observed essential lymphocytophthisis, which means a condition involving the deterioration of lymphocytes.

In the following years, doctors found differences in inheritance patterns when diagnosing patients with what researchers now recognize as SCID. All cases, however, involved low lymphocyte numbers, dysfunctional lymphocytes, or both. In many of those cases, doctors observed an X-linked recessive pattern, which they deduced from the high frequency of disease in males. In X-linked recessive disorders, there is a mutation on the X chromosome, but the disease does not manifest if there is at least one normal, non-mutated X chromosome. Males only have one X chromosome, while females have two, so males have higher incidences of X-linked recessive disorders because unlike females, males do not have a backup X chromosome if their only X chromosome is mutated. Other SCID inheritance patterns were autosomal recessive, which means that the mutation was on a chromosome that was not an X or Y chromosome. Humans have two of every non-sex, or autosomal, chromosome, and in autosomal recessive disorders, the disease will only manifest if both chromosomes have the mutation. From the frequency of disease in the family’s history, doctors can deduce if a disorder has an autosomal recessive inheritance pattern. However, at the time, they were still unclear on the exact chromosomal mutations that led to X-SCID or autosomal recessive SCID.

By the 1960s, according to professor Erwin Gelfand, doctors had witnessed more than thirty SCID cases. In almost all those cases, doctors referred to the disorder by a different name, including Glanzmann-Riniker syndrome, alymphocytosis, thymic alymphoplasia, and other names that translated to a condition involving the absence of lymphocytes. Around that time, researchers began calling the disorder SCID to classify it under one name, but they noted the different inheritance patterns. In both X-SCID and autosomal recessive SCIDs, the infant would have severe, recurrent infections and usually did not live past one year of age.

In the 1960s, doctors began using bone marrow transplants to cure SCID patients, but there were potential deadly complications that could arise from transplants. A bone marrow transplant is a procedure where doctors transfer bone marrow containing normal, functional immune cells and stem cells, which are cells that have the ability to develop into any type of cell, from a donor into the patient. The donor’s immune cells and stem cells are meant to restore the recipient’s immune function. Because bone marrow transplants replace dysfunctional immune cells with normal, functional immune cells, they are a cure for SCID as long as the individual does not acquire any complications after the transplant.

One of the deadliest complications of using bone marrow transplants to treat SCID is graft versus host disease, or GVHD. GVHD is a condition where the donor’s immune cells recognize the recipient’s cells as foreign because they have different sets of human leukocyte antigen, or HLA, molecules. HLA molecules are present on many cell surfaces, and they help determine what the body’s immune cells recognize and attack. Most people have different sets of HLAs, making recipient cells with different HLAs appear foreign to transplanted immune cells. That causes the immune cells to attack the recipient’s cells, often causing death. Therefore, bone marrow donors should be compatible with the recipient, which means they should share the same HLA molecules so that the donor cells do not attack the recipient cells. Researchers in the 1960s were studying HLA to avoid instances of GVHD during bone marrow transplants.

In 1968, doctors performed one of the first bone marrow transplants to cure an individual with SCID. That year, a five-month-old infant male in Minneapolis, Minnesota, presented with SCID. After running tests on the infant’s sister, doctors found that they shared the same HLA molecules and therefore were a compatible match for bone marrow transplantation. The doctors performed the transplant procedure, which ultimately cured his SCID. At the time, most bone marrow transplantations occurred between siblings because they generally have the highest likelihood of sharing the same set of HLA molecules.

The Bubble Boy

By the 1970s, doctors could treat X-SCID when a patient had a compatible bone marrow donor, such as a sibling, but they had fewer treatment options when there was no compatible donor. David Vetter, a boy born in Houston, Texas, in the 1970s, was one of the first individuals without a compatible bone marrow donor to survive past infancy with X-SCID because he grew up in a sterile bubble. When Vetter’s mother was pregnant with Vetter, doctors knew that he would likely have X-SCID due to family history, so they preemptively prepared a plastic, sterile bubble to ensure that bacteria and viruses could not infect him. Vetter had an older sister, but he could not receive a bone marrow transplant from her because they did not have the same HLA molecules. While Vetter grew up in the sterile bubble, researchers monitored the development of his X-SCID-afflicted immune system over twelve years, something that had previously been impossible. Researchers found that over those twelve years, Vetter’s T cells and B cells remained dysfunctional and at low numbers. However, aside from Vetter’s immune system, his other body systems developed normally.

In the 1980s, while Vetter was growing up in his bubble, researchers improved the bone marrow transplant procedure by depleting T cells from donor bone marrow before the transplant so that individuals with SCID could still receive a transplant, even if the donor was not a perfect HLA match. Depletion of T cells in the donor cells before transferring them into the recipient reduces the risk of complications because the donor’s T cells cannot attack the recipient after the transplant. Instead, recipients only receive the donor’s harmless stem cells, which repopulate in the recipient’s body and develop into T cells that will not attack the recipient.

When Vetter was twelve, he received a bone marrow transplant from his sister using the updated transplant technique. Because of the added T cell depletion step in the improved procedure, the transplant seemed to be successful. However, Vetter died later that year due to complications unrelated to GVHD. Because of his famous case and contribution to X-SCID research, the public also began calling X-SCID “the bubble boy disease.” After Vetter’s death, researchers preserved some of his cells to use in later X-SCID studies. They generated an immortalized cell line by genetically altering those cells so that they could divide indefinitely, which regular cells in the body cannot do. By creating the immortalized cell line, researchers could grow Vetter’s cells in a laboratory over long periods of time and study their properties.

In 1993, Masayuki Noguchi, who conducted research at the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and colleagues found that the genetic mutation that caused X-SCID was an X-chromosome mutation in the IL-2RG gene. He used Vetter’s and two other X-SCID individuals’ immortalized cell lines to sequence the DNA, looking for mutations. In all three cell lines, the team found a different mutation on the X chromosome in the region that codes for IL-2RG. IL-2RG, a protein coded for by the IL-2RG gene, is a critical component of multiple receptors that are involved in lymphocyte development. For example, it is part of the IL-2 receptor, which regulates the growth of T cells. Without a functional IL-2 receptor, T cells do not divide properly, which leads to a weak T cell response to infection. In addition, because T cells play a role in B cell development, a T cell defect sometimes also results in dysfunctional B cells. Therefore, individuals with X-SCID present with abnormal T cells and B cells, and with high risk of life-threatening infections.

TREC Test

Around 2008, researchers started using the T cell receptor excision circle, or TREC, test, which is a neonatal screening test for X-SCID and other SCIDs. TRECs are byproduct molecules that T cells make as T cells mature. Individuals with X-SCID do not have functional T cells, so they also produce low amounts of TRECs. The TREC test quantifies the levels of TRECs in the blood, which aids the diagnosis of X-SCID. The test offered an accurate and cost effective option for doctors to catch the disorder early and treat it accordingly. In 2010, the Recommended Uniform Screening Panel of Core Conditions, a US federal recommendation of disorders that doctors should screen all newborns for, added testing for SCID to its list of universal screening tests. A study in 2014 estimated that because of the widespread implementation of the TREC test to neonatal screening, diagnosis of SCID cases during the neonatal period almost doubled in comparison to diagnosis numbers before the implementation of the TREC test. By 2017, all fifty states in the US began implementing the TREC test in their newborn screening programs.

Current Treatments

As of 2024, the primary treatment for X-SCID is still bone marrow transplantation, though doctors also implement variations of the transplant procedure. Because of improvements in neonatal screening, many diagnoses and treatments occur earlier, which increases the chance of survival. The average curative rate of bone marrow transplantation is approximately eighty percent. But, in cases where the patient receives a bone marrow transplant within the first twenty-eight days of life, the curative rate rises to around ninety-five percent. Studies in the early 2000s report that T cell-depleted bone marrow transplants lead to higher incidences of failure to restore the recipient’s immune system. In addition to T-cell depleted bone marrow transplants, scientists have developed umbilical cord blood transplants as another treatment option. The umbilical cord, the cord that connects a growing fetus to the mother’s placenta, is a source of stem cells that doctors can use for transplants. Umbilical cord blood transplants correlate with lower incidences of GVHD because studies have shown that they are still effective even if the recipient and donor are not entirely HLA-compatible, though researchers are still not clear as to why that is. However, recipients of umbilical cord blood transplants usually recover more slowly. Success rates for both umbilical cord blood transplants and T-cell depleted bone marrow transplants range from about fifty to eighty percent, considerably lower than HLA-matched bone marrow transplants, which are eighty to ninety percent successful. As of 2024, researchers continue to work on ways to improve those procedures to increase the rate of successful transplants and recovery.

Starting in the early 2000s, studies have also begun exploring gene therapy as another treatment for individuals with X-SCID. Gene therapy for X-SCID involves artificially correcting the IL-2RG mutation in a laboratory, placing the normal copy of the gene into a viral vector, and then introducing the vector into the X-SCID patient’s cells. Viral vectors are tools that scientists use to deliver genetic material into cells. In the early 2000s, a study in France and the United Kingdom found that when twenty X-SCID patients received gene therapy, eighteen of them saw restored T cell function. However, almost one-third of the patients developed leukemia, a type of cancer, as a side effect of the therapy. Viral vectors insert themselves into random areas of a cell’s DNA, and they sometimes insert into and activate areas that increase the risk of cancer.

As of 2024, several early-stage studies have explored safer alternatives, such as using other types of vectors that are not as likely to cause cancer. X-SCID patients enrolled in those studies still had a successful, curative response to the gene therapy, but they did not develop severe side effects. Several European countries have approved the use of gene therapy for other types of SCID with the use of safer vectors. In the US, gene therapy clinical trials are still underway for SCID.

Support Groups and Outlook

With the plethora of new information coming out from SCID research, new organizations have arisen that focus on providing resources for diagnosing and treating SCID. For example, SCID Compass, a program of the Immune Deficiency Foundation, provides educational resources to inform the public about SCID, screening tests, and treatment options. The Immune Deficiency Foundation is a larger community that allows for education on all types of immune system deficiencies. SCID Compass also offers caregiving support group resources to help caregivers of individuals with SCID to connect with others and share their experiences. When developing SCID Compass, researchers gathered data from interviews and online surveys with parents of children who had SCID. In the interviews and surveys, the developers of SCID Compass asked parents of children with SCID questions about information they wished they had access to sooner. SCID Compass uses that data surrounding gaps in knowledge, as well as ways to offer emotional support, to provide family-centered resources.

As of 2024, X-SCID is the most common type of SCID with a mortality rate of nearly one hundred percent if left untreated. Over the past few decades, with the advancements in early intervention and therapies, the X-SCID survival rate with treatment has risen from around fifty percent to over seventy percent. Scientists continue to research methods to improve treatment options so that they are safe and accessible to all individuals with X-SCID.