Severe combined immunodeficiency

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Severe Combined Immune Deficiency
Other namesAlymphocytosis, Glanzmann–Riniker syndrome, Severe mixed immunodeficiency syndrome, and Thymic alymphoplasia [1]
OSC Microbio 19 04 SCID.jpg
David Vetter, a child born in 1971 with severe combined immunodeficiency (SCID).
Specialty Immunology   OOjs UI icon edit-ltr-progressive.svg
TreatmentBone marrow transplantation and prophylaxis against infection
Medication IVIG, gene therapy
Frequency1 in 50,000 to 100,000 (X-linked form)

Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in differing clinical presentations. [2] SCID involves defective antibody response due to either direct involvement with B lymphocytes or through improper B lymphocyte activation due to non-functional T-helper cells. [3] Consequently, both "arms" (B cells and T cells) of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is the most severe form of primary immunodeficiencies, [4] and there are now at least nine different known genes in which mutations lead to a form of SCID. [5] It is also known as the bubble boy disease and bubble baby disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter, have become famous for living in a sterile environment. SCID is the result of an immune system so highly compromised that it is considered almost absent.

Contents

SCID patients are usually affected by severe bacterial, viral, or fungal infections early in life and often present with interstitial lung disease, chronic diarrhea, and failure to thrive. [3] Ear infections, recurrent Pneumocystis jirovecii (previously carinii) pneumonia, and profuse oral candidiasis commonly occur. These babies, if untreated, usually die within one year due to severe, recurrent infections unless they have undergone successful hematopoietic stem cell transplantation or gene therapy in clinical trials. [6]

Classification

TypeDescription
X-linked severe combined immunodeficiency Most cases of SCID are due to mutations in the IL2RG gene encoding the common gamma chain (γc) (CD132), a protein that is shared by the receptors for interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. These interleukins and their receptors are involved in the development and differentiation of T and B cells. Because the common gamma chain is shared by many interleukin receptors, mutations that result in a non-functional common gamma chain cause widespread defects in interleukin signalling. The result is a near complete failure of the immune system to develop and function, with low or absent T cells and NK cells and non-functional B cells.
The common gamma chain is encoded by the gene IL-2 receptor gamma, or IL-2Rγ, which is located on the X-chromosome. For this reason, immunodeficiency caused by mutations in IL-2Rγ is known as X-linked severe combined immunodeficiency. The condition is inherited in an X-linked recessive pattern.
Adenosine deaminase deficiency The second most common form of SCID after X-SCID is caused by a defective enzyme, adenosine deaminase (ADA), necessary for the breakdown of purines. Lack of ADA causes accumulation of dATP. This metabolite will inhibit the activity of ribonucleotide reductase, the enzyme that reduces ribonucleotides to generate deoxyribonucleotides. The effectiveness of the immune system depends upon lymphocyte proliferation and hence dNTP synthesis. Without functional ribonucleotide reductase, lymphocyte proliferation is inhibited and the immune system is compromised.
Purine nucleoside phosphorylase deficiency An autosomal recessive disorder involving mutations of the purine nucleoside phosphorylase (PNP) gene. PNP is a key enzyme in the purine salvage pathway. Impairment of this enzyme causes elevated dGTP levels resulting in T-cell toxicity and deficiency.
Reticular dysgenesis Inability of granulocyte precursors to form granules secondary to mitochondrial adenylate kinase 2 (AK2) malfunction.
Omenn syndrome The manufacture of immunoglobulins requires recombinase enzymes derived from the recombination activating genes RAG-1 and RAG-2. These enzymes are involved in the first stage of V(D)J recombination, the process by which segments of a B cell or T cell's DNA are rearranged to create a new T cell receptor or B cell receptor (and, in the B cell's case, the template for antibodies).
Certain mutations of the RAG-1 or RAG-2 genes prevent V(D)J recombination, causing SCID. [7]
Bare lymphocyte syndrome Type 1: MHC class I is not expressed on the cell surface. The defect is caused by defective TAP proteins, not the MHC-I protein.

Type 2: MHC class II is not expressed on the cell surface of all antigen presenting cells. Autosomal recessive. The MHC-II gene regulatory proteins are what is altered, not the MHC-II protein itself.

JAK3 Janus kinase-3 (JAK3) is an enzyme that mediates transduction downstream of the γc signal. Mutation of its gene causes SCID. [8]
DCLRE1C DCLRE1C "Artemis" is a gene required for DNA repair and V(D)J recombination. A recessive loss-of-function mutation found in the Navajo and Apache population causes SCID and radiation intolerance. [9] [10]
PRKDC PRKDC or DNA-PKcs is a gene required for DNA repair and V(D)J recombination. First found in non-human animals with SCID, a human case was finally found in 2009, followed by another in 2013. [11]

Diagnosis

Early diagnosis of SCID is usually difficult due to the need for advanced screening techniques. Several symptoms may indicate a possibility of SCID in a child, such as a family history of infant death, chronic coughs, hyperinflated lungs, and persistent infections. A full blood lymphocyte count is often considered a reliable manner of diagnosing SCID, but higher lymphocyte counts in childhood may influence results. Clinical diagnosis based on genetic defects is also a possible diagnostic procedure that has been implemented in the UK. [12]

Some SCID can be detected by sequencing fetal DNA if a known history of the disease exists. Otherwise, SCID is not diagnosed until about six months of age, usually indicated by recurrent infections. The delay in detection is because newborns carry their mother's antibodies for the first few weeks of life and SCID babies look normal.[ citation needed ]

Newborn screening

Several countries test all newborns for SCID as a part of routine newborn screening. As of September 2022, the known percentage of newborns screened has increased throughout the world with 100% in the United States, 78% in Europe, 32% in Latin America, 26% in the Middle East and North Africa, 13% in Asia-Pacific, and 0% in Central America. The introduction of newborn screenings and genetic testing in many countries has allowed early detection and treatment before the development of severe infections, which progressively improved the five-year survival rate for newborns with SCID to around 90%. All states in the U.S. [13] are performing screening for SCID in newborns using real-time quantitative PCR to measure the concentration of T-cell receptor excision circles. [14]

Treatment

The most common treatment for SCID is bone marrow transplantation, which has been very successful using either a matched related or unrelated donor, or a half-matched donor, who would be either parent. The half-matched type of transplant is called haploidentical. Haploidentical bone marrow transplants require the donor marrow to be depleted of all mature T cells to avoid the occurrence of graft-versus-host disease (GVHD). [15] Consequently, a functional immune system takes longer to develop in a patient who receives a haploidentical bone marrow transplant compared to a patient receiving a matched transplant. The first reported case of successful transplant was a Spanish child patient who was interned in Memorial Sloan Kettering Cancer Center in 1982, in New York City. [15] David Vetter, the original "bubble boy", had one of the first transplantations also, but eventually died because of an unscreened virus, Epstein-Barr (tests were not available at the time), in his newly transplanted bone marrow from his sister, an unmatched bone marrow donor. Today, transplants done in the first three months of life have a high success rate. Physicians have also had some success with in utero transplants done before the child is born and also by using cord blood which is rich in stem cells. In utero transplants allow for the fetus to develop a functional immune system in the sterile environment of the uterus; [16] however complications such as GVHD would be difficult to detect or treat if they were to occur. [17]

More recently gene therapy has been attempted as an alternative to the bone marrow transplant. Transduction of the missing gene to hematopoietic stem cells using viral vectors is being tested in ADA SCID and X-linked SCID. In 1990, four-year-old Ashanthi DeSilva became the first patient to undergo successful gene therapy. Researchers collected samples of DeSilva's blood, isolated some of her white blood cells, and used a retrovirus to insert a healthy adenosine deaminase (ADA) gene into them. These cells were then injected back into her body, and began to express a normal enzyme. This, augmented by weekly injections of ADA, corrected her deficiency. However, the concurrent treatment of ADA injections may impair the success of gene therapy, since transduced cells will have no selective advantage to proliferate if untransduced cells can survive in the presence of the injected ADA. [18]

David Vetter inside his protective "bubble." David Vetter and John R. Montgomery.JPG
David Vetter inside his protective "bubble."

In 2000, a gene therapy "success" resulted in SCID patients with a functional immune system. These trials were stopped when it was discovered that two of ten patients in one trial had developed leukemia resulting from the insertion of the gene-carrying retrovirus near an oncogene. In 2007, four of the ten patients have developed leukemias. [19] Work aimed at improving gene therapy is now focusing on modifying the viral vector to reduce the likelihood of oncogenesis and using zinc-finger nucleases to further target gene insertion. [20] No leukemia cases have yet been seen in trials of ADA-SCID, which does not involve the gamma c gene that may be oncogenic when expressed by a retrovirus.

From the treatments of Ashanthi DeSilva in 1990, which is considered gene therapy's first success until 2014, around 60 patients were treated for either ADA-SCID or X-SCID [21] using retroviruses vectors. As previously mentioned, the occurrence of leukemia cases forced researchers to make changes to improve safety. [22] In 2019, a new method using an altered version of the HIV virus as a lentivirus vector was reported in the treatment of eight children with X-SCID, [23] [24] [25] [6] and in 2021 the same method was used in 50 children with ADA-SCID, obtaining positive results in 48 of them. [26] [27] [28]

There are also some non-curative methods for treating SCID. Reverse isolation involves the use of laminar air flow and mechanical barriers to avoid physical contact with others in order to isolate the patient from any harmful pathogens present in the external environment. [29] Another non-curative treatment for patients with ADA-SCID is enzyme replacement therapy, in which the patient is injected with polyethyleneglycol-coupled adenosine deaminase (PEG-ADA), which metabolizes the toxic substrates of the ADA enzyme and prevents their accumulation. [18] Treatment with PEG-ADA may be used to restore T cell function in the short term, enough to clear any existing infections before proceeding with curative treatment such as a bone marrow transplant. [30]

Epidemiology

The most commonly quoted figure for the prevalence of SCID is around one in 100,000 births, although this is regarded by some to be an underestimate of the true prevalence; [31] some estimates predict that the prevalence rate is as high as one in 50,000 live births. [3] A figure of about one in 65,000 live births has been reported for Australia. [32]

Due to the particular genetic nature of SCID, a higher prevalence may be found in certain regions and associated cultures where higher rates of consanguineous mating occur (i.e. mating between blood relatives). [33] A Moroccan study reported that consanguineous parenting was observed in 75% of the families of Moroccan SCID patients. [34]

Recent studies indicate that one in every 2,500 children in the Navajo population inherit severe combined immunodeficiency. This condition is a significant cause of illness and death among Navajo children. [9] Ongoing research reveals a similar genetic pattern among the related Apache people. [10]

SCID in animals

SCID mice were and still are used in disease, vaccine, and transplant research, especially as animal models for testing the safety of new vaccines or therapeutic agents in people with weakened immune system. SCID mice also serve as a useful animal model in the study of the human immune system and its interactions with disease, infections, and cancer. [35] For example, normal strains of mice can be lethally irradiated, killing all rapidly dividing cells. These mice then receive bone marrow transplantation from SCID donors, allowing engraftment of human peripheral blood mononuclear cells (PBMC) to occur. This method can be used to study whether T cell-lacking mice can perform hematopoiesis after receiving human PBMC. [36]

A recessive gene, with clinical signs similar to the human condition, affects the Arabian horse. The condition remains a fatal disease, as the horse inevitably succumbs to an opportunistic infection within the first four to six months of life. [37] However, carriers, who themselves are not affected by the disease, can be detected with a DNA test. Therefore, careful breeding practices can avoid the risk of an affected foal being produced. [38]

Another animal with well-characterized SCID pathology is the dog. There are two known forms: an X-linked SCID in Basset Hounds that has similar ontology to X-SCID in humans [39] and an autosomal recessive form seen in one line of Jack Russell Terriers that is similar to SCID in Arabian horses and mice. [40]

See also

Related Research Articles

Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID.

<span class="mw-page-title-main">Adenosine deaminase deficiency</span> Medical condition

Adenosine deaminase deficiency is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–20% of all cases of autosomal recessive forms of severe combined immunodeficiency (SCID) after excluding disorders related to inbreeding.

<span class="mw-page-title-main">Omenn syndrome</span> Medical condition

Omenn syndrome is an autosomal recessive severe combined immunodeficiency. It is associated with hypomorphic missense mutations in immunologically relevant genes of T-cells such as recombination activating genes, Interleukin-7 receptor-α (IL7Rα), DCLRE1C-Artemis, RMRP-CHH, DNA-Ligase IV, common gamma chain, WHN-FOXN1, ZAP-70 and complete DiGeorge syndrome. It is fatal without treatment.

<span class="mw-page-title-main">X-linked agammaglobulinemia</span> Medical condition

X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies, which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene that leads to a severe block in B cell development and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.

Hypogammaglobulinemia is an immune system disorder in which not enough gamma globulins are produced in the blood. This results in a lower antibody count, which impairs the immune system, increasing risk of infection. Hypogammaglobulinemia may result from a variety of primary genetic immune system defects, such as common variable immunodeficiency, or it may be caused by secondary effects such as medication, blood cancer, or poor nutrition, or loss of gamma globulins in urine, as in nonselective glomerular proteinuria. Patients with hypogammaglobulinemia have reduced immune function; important considerations include avoiding use of live vaccines, and take precautionary measures when traveling to regions with endemic disease or poor sanitation such as receiving immunizations, taking antibiotics abroad, drinking only safe or boiled water, arranging appropriate medical cover in advance of travel, and ensuring continuation of any immunoglobulin infusions needed.

Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.

<span class="mw-page-title-main">Common gamma chain</span> Protein-coding gene in humans

The common gamma chain (γc), also known as interleukin-2 receptor subunit gamma or IL-2RG, is a cytokine receptor sub-unit that is common to the receptor complexes for at least six different interleukin receptors: IL-2, IL-4, IL-7, IL-9, IL-15 and interleukin-21 receptor. The γc glycoprotein is a member of the type I cytokine receptor family expressed on most lymphocyte populations, and its gene is found on the X-chromosome of mammals.

<span class="mw-page-title-main">ZAP70 deficiency</span> Medical condition

ZAP70 deficiency, or ZAP70 deficient SCID, is a rare autosomal recessive form of severe combined immunodeficiency (SCID) resulting in a lack of CD8+ T cells. People with this disease lack the capability to fight infections, and it is fatal if untreated.

<span class="mw-page-title-main">X-linked severe combined immunodeficiency</span> Medical condition

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.

<span class="mw-page-title-main">Bare lymphocyte syndrome</span> Medical condition

Bare lymphocyte syndrome is a condition caused by mutations in certain genes of the major histocompatibility complex or involved with the processing and presentation of MHC molecules. It is a form of severe combined immunodeficiency.

Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a primary immunodeficiency (PID), the immune deficiency must be inborn, not caused by secondary factors such as other disease, drug treatment, or environmental exposure to toxins. Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 430 recognized inborn errors of immunity (IEIs) as of 2019, the vast majority of which are PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, auto-inflammatory disorders, tumors, and disorders of various organs. There are currently limited treatments available for these conditions; most are specific to a particular type of PID. Research is currently evaluating the use of stem cell transplants (HSCT) and experimental gene therapies as avenues for treatment in limited subsets of PIDs.

An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways:

The severe combined immunodeficiency (SCID) is a severe immunodeficiency genetic disorder that is characterized by the complete inability of the adaptive immune system to mount, coordinate, and sustain an appropriate immune response, usually due to absent or atypical T and B lymphocytes. In humans, SCID is colloquially known as "bubble boy" disease, as victims may require complete clinical isolation to prevent lethal infection from environmental microbes.

A humanized mouse is a genetically modified mouse that has functioning human genes, cells, tissues and/or organs. Humanized mice are commonly used as small animal models in biological and medical research for human therapeutics.

JAK3 deficiency is a dysfunction in cytokine receptor signalling and their production of cytokines.

The NSG mouse is a brand of immunodeficient laboratory mice, developed and marketed by Jackson Laboratory, which carries the strain NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ. NSG branded mice are among the most immunodeficient described to date. NSG branded mice lack mature T cells, B cells, and natural killer (NK) cells. NSG branded mice are also deficient in multiple cytokine signaling pathways, and they have many defects in innate immunity. The compound immunodeficiencies in NSG branded mice permit the engraftment of a wide range of primary human cells, and enable sophisticated modeling of many areas of human biology and disease. NSG branded mice were developed in the laboratory of Dr. Leonard Shultz at Jackson Laboratory, which owns the NSG trade mark.

<span class="mw-page-title-main">Reticular dysgenesis</span> Medical condition

Reticular dysgenesis (RD) is a rare, inherited autosomal recessive disease that results in immunodeficiency. Individuals with RD have mutations in both copies of the AK2 gene. Mutations in this gene lead to absence of AK2 protein. AK2 protein allows hematopoietic stem cells to differentiate and proliferate. Hematopoietic stem cells give rise to blood cells.

Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence, sold under the brand name Strimvelis, is a medication used to treat severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID).

Granulomatous–lymphocytic interstitial lung disease (GLILD) is a lung complication of common variable immunodeficiency disorders (CVID). It is seen in approximately 15% of patients with CVID. It has been defined histologically as the presence of (non-caseating) granuloma and lymphoproliferation in the lung. However, as GLILD is often associated with other auto-immune features such as splenomegaly, adenopathy and cytopenias, a definition based on abnormalities on lung imaging together with evidence of granulomatous inflammation elsewhere has also been employed.

Mice with severe combined immunodeficiency (SCIDs) are often used in the research of human disease. Human immune cells are used to develop human lymphoid organs within these immunodeficient mice, and many different types of SCID mouse models have been developed. These mice allow researchers to study the human immune system and human disease in a small animal model.

References

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  31. ↑ "Newborn Screening for Primary Immunodeficiency Disease".
  32. ↑ Yee A, De Ravin SS, Elliott E, Ziegler JB (2008). "Severe combined immunodeficiency: A national surveillance study". Pediatr Allergy Immunol. 19 (4): 298–302. doi:10.1111/j.1399-3038.2007.00646.x. PMID   18221464. S2CID   26379956.
  33. ↑ Yeganeh M, Heidarzade M, Pourpak Z, Parvaneh N, Rezaei N, Gharagozlou M, Movahed M, Shabestari MS, Mamishi S, Aghamohammadi A, Moin M (2008). "Severe combined immunodeficiency: A cohort of 40 patients". Pediatr Allergy Immunol. 19 (4): 303–306. doi:10.1111/j.1399-3038.2007.00647.x. PMID   18093084. S2CID   29466366.
  34. ↑ El-Maataoui O, Ailal F, Naamane H, Benhsaien I, Jeddane L, Farouqi B, Benslimane A, Jilali N, Oudghiri M, Bousfiha A (2011). "Immunophenotyping of severe combined immunodeficiency in Morocco". IBS J Sci. 26 (4): 161–164. doi:10.1016/j.immbio.2011.05.002.
  35. ↑ Owen, Judith; Punt, Jenni (2013). Kuby Immunology. New York: W.H. Freeman and Company.
  36. ↑ Lubin, Ido; Segall, Harry; Erlich, Porat; David, Magda; Marcus, Hadar; Fire, Gil; Burakova, Tatjana; Kulova, Lydia; Reisner, Yair (October 1995). "Conversion of Normal Rats into Scid-Like Animals by Means of Bone Marrow Transplantation from Scid Donors Allows Engraftment of Human Peripheral Blood Mononuclear Cells". Transplantation. 60 (7): 740–747. doi: 10.1097/00007890-199510150-00022 . PMID   7570987.
  37. ↑ "FOAL.org, an organization promoting research into genetic lethal diseases in horse".
  38. ↑ "VetGen: Veterinary Genetic Services - Equine - References - The New DNA Test for Severe Combined Immunodeficiency (SCID) in Arabian Horses". www.vetgen.com.
  39. ↑ Henthorn PS, Somberg RL, Fimiani VM, Puck JM, Patterson DF, Felsburg PJ (1994). "IL-2R gamma gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease". Genomics. 23 (1): 69–74. doi: 10.1006/geno.1994.1460 . PMID   7829104.
  40. ↑ Perryman LE (2004). "Molecular pathology of severe combined immunodeficiency in mice, horses, and dogs". Vet. Pathol. 41 (2): 95–100. doi:10.1354/vp.41-2-95. PMID   15017021. S2CID   38273912.

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