The immune defense system is a body-wide network of organs, tissues, cells, and proteins that work together to defend the body against attacks by “foreign” invaders. These invaders, called foreign antigens can be in the form of bacteria, virus, fungi, parasites or even single proteins.
Once a foreign antigen is detected the immune system attacks and destroys it. If the body is strong, it can win the battle most of the time. When a major component of the immune system is not functioning correctly, medical intervention is necessary to stay healthy and ward off infections.
The cells that make up the immune system develop in the bone marrow in the form of the stem cells. These develop into cells called B-lymphocytes, T-lymphocytes, NK-lymphocytes and phagocytes. These primary cell families and the proteins they produce make up the most important components of the immune system. These cells and proteins are all spread throughout the body so they can react quickly to any problem.
The defining characteristic for SCID is always a severe defect in T cell production and function, with defects in B-lymphocytes as a primary or secondary problem and, in some genetic types, in NK cell production as well.
The B-Cells
When a foreign antigen invades the body T-helper cells direct B-lymphocytes (or B-cells) to make antibodies against it. These antibodies bind to the foreign antigen, neutralize it and allow phagocytes to digest and eliminate it completely. Problems within B-cells cause antibody deficiencies that may become evident as recurrent infections as early as seven to nine months of age, at a time when maternal antibodies that had passed through the placenta during pregnancy have fallen to non-protective levels.
The T-Cells
There are three main forms of T-lymphocytes: Helper (T-helper cells), Cytotoxic (cytotoxic T cells) and Regulatory (T-reg or T-supressor) T cells. T-helpers direct and assist all other immune cells in attacking foreign antigens. T-cytotoxic cells kill the unwanted antigens and T-reg cells are the off-switch to an attack. They serve to limit collateral damage. T-cells direct the rest of the immune system to respond to foreign invaders; therefore, problems in the T-lymphocyte system are generally profound, causing severe combined immunodeficiency syndromes (SCID) that declare themselves soon after birth. Milder forms of T-lymphocyte dysfunction (combined immunodeficiency – CID) may present later in life, are generally less severe and are compatible with longer survival.
SCID
SCID or Severe Combine Immune Deficiency is the most severe of the Primary Immune Deficiency diseases. The defining characteristic of SCID is the absence of T cells and, as a result, lack of B cell function as well. Unless these defects are corrected, the child will die of opportunistic infections before their first or second birthday. As of this writing, defects of at least 14 different genes may result in SCID. Additionally, there are a number of cases of SCID for which the genetic cause is still undetermined. No matter what the form of SCID though, the end result is that critical immune defenses are missing and treatment should be considered a pediatric emergency.
With the advancements in SCID newborn screening, new terminology has arisen. The terms Typical SCID vs. Leaky SCID vs. Variant SCID have come into use. While these terms do not precisely define a genetic mutation they give a more generic breakdown:
Typical SCID – describes cases with fewer than 300 autologous T cells /_L
Leaky SCID – describes cases due to incomplete mutation(s) in a typical SCID gene, T cells ranging from 300–1,500/_L and may have a later age of onset of clinical symptoms
Variant SCID – describes cases with no known gene defect and a persistence of 300–1,500 T cells/L that have impaired function
Inheritance
Autosomal recessive inheritance – Autosomal recessive forms of SCID result when a child inherits two defective copies of the same autosomal gene. The parents in this case each carry one normal copy of the gene and one abnormal copy. In the case of an affected child, the child inherits both abnormal copies. One such form of SCID is ADA deficiency. This condition results from the lack of an enzyme that helps cells to get rid of toxic byproducts. Without ADA, poisons build up and kill the lymphocytes. It was in 1972 that the ADA deficiency form of SCID was recognized, but ADA deficiency has an autosomal recessive inheritance pattern that affects males and females equally. It was known though that a predominance of SCID patients were male, leading researchers to suspect that an X-linked inheritance also existed.
X-linked or X-SCID inheritance – A female can be a silent carrier of a defective X-chromosome, because her 2nd X-chromosome compensates and consequently she is unaffected. A male who inherits the defective X chromosome, however, will be affected. X-linked SCID affects only males and accounts for approximately 45% of all cases of SCID. It wasn’t until 1993 that Dr. Jennifer Puck and Dr. Warren Leonard simultaneously, but independently, discovered the genetic defect involved in X-linked SCID. As more X-linked SCID boys grow into adulthood the question arises, can they can give the defect to their children? Since the defect for X-linked SCID is on the X-chromosome and boys carry one X-chromosome and one Y-chromosome then it follows that; any male child of an X-linked SCID will inherit his father’s Y-chromosome which is unaffected; consequently any female child of an X-linked SCID will inherit her father’s X-chromosome which is affected and she will be a carrier of X-linked SCID to the next generation.
SCID is estimated to occur in approximately 1 out of every 50,000 to 100,000 births; however, an exact rate of occurance can not be determined until more states are screening newborns for the disease.
Treatment
Bone Marrow Transplantation – The first two successful bone marrow transplants in the US occurred in 1968. These 2 transplants were both in primary immunodeficient patients, one with SCID and the other with Wiskott-Aldrich Syndrome. Both patients received marrow from related donors who were HLA (Human Leucocyte Antigen) identical. It was in 1973 that the first successful BMT between unrelated patients was performed. This was also on a SCID patient. Although unrelated, the donor in this case was also 100% HLA matched to the patient. The patient required multiple infusions of marrow but ultimately engraftment was achieved.
Bubbles – Between the years of 1968 and 1973 doctors were occasionally able to diagnosis a case of SCID, however, if there was no HLA matched sibling they were unable to correct the defect. Unfortunately, most of these cases were not diagnosed until the child was critically ill. In 1971 an unusual opportunity occurred. A mother who had lost a child to SCID was pregnant with another boy. Since the risk of another affected child was a real possibility, plans were made on how to keep this child healthy until his immune system could be corrected. David was born on September 21, 1971 and was immediately placed into a specially designed isolator crib where the air was specially filtered and all items which went into the crib were sterilized. It was quickly proven that his immune system was indeed defective, but there was hope that his older sister would be a match for a bone marrow transplant. Unfortunately, his sister was not a good match and at that time there were no donor registries. The rest of the family was tested, but no one was a match for David. Consequently, as he grew, so did his bubbles. The media during that time chronicled his life and he became known to the world as the “Bubble Boy”.
It wasn’t until the early 80’s that a technique was developed to use a bone marrow donor who was less than a 100% match. This method eventually made it possible to use a haploidentical or 1/2 matched donor for a successful BMT, which has been and remains the most significant treatment development for this condition over the past two decades.
Advances in Bone Marrow Transplantation – Currently, a BMT provides patients with a functioning immune system that is capable of protecting them from infections. Transplants from sibling matched donors continue to produce the best outcomes, when available. This is still a developing field and as new methods are tested, especially in the newborn population, increasingly better outcomes are being seen even in those without a matched sibling.
Enzyme replacement therapy – For patients with ADA Deficiency SCID which is caused by a deficiency of the enzyme Adenosine Deaminase (ADA), enzyme replacement therapy may be used to enable immune cells to recover and may provide long-term benefit.
Gene Therapy – While it’s been proven over several generations now that bone marrow transplants can save the lives of SCID children, transplants do not always work or they do not always completely correct the defects. The next step in looking for a more successful therapy is gene therapy. The first experiments in gene therapy on humans began in 1990. Two girls with ADA deficiency SCID were treated, several times, over a 2 year period, with T-cells carrying corrected DNA. Basically, the researchers corrected the DNA in a sample of the girls’ T-cells and then returned the T-cells to them. The success of these early trials is debated. Periodic tests on both girls show that their re-engineered cells are surviving and producing the ADA enzyme, but both girls continue to receive replacement enzyme therapy. While this trial did not produce a completely successful correction of the girls’ immune systems, it did, however, prove that if you put a correct gene into enough cells in a patient you can correct the disease.
In April of 2000, an article was published in Science Magazine which presented 2 cases of X-linked SCID which had been treated by gene therapy. These children had no prior treatment such as bone marrow transplantation. These 2 patients, at the time period of 10 and 11 months after therapy, were exhibiting normal growth and development without other treatment. Their cells appeared to be working. These results demonstrated a selective advantage existed for the corrected cells to engraft and produce a corrected cell line. In all, 10 XSCID patients were treated in this trial. However, those studying and watching gene therapy received devastating news in an article published in Science Magazine in October 2003. Two of the boys treated had developed a form of T-cell proliferation similar to leukemia. The insertion of the corrected DNA into the defective cells had occurred next to a specific leukemia inhibitor. With news of this devastating event, most XSCID gene therapy trials were placed on hold worldwide. Out of 20 boys treated in Paris and London, 5 boys from these original XSCID gene therapy trials developed T cell leukemia due to vector insertion related to oncogene activation.
Today, there are new trials for ADA and XSCID in the US and Europe using next generation vectors which appear to be safer and more effective. At this time, gene therapy is still considered to be an investigational treatment option. Trials are also being conducted on XSCID patients who have had poor engraftment or incomplete immune constitution after bone marrow transplantation. Gene therapy still holds the greatest hope for a true cure for this devastating disease.