X-linked severe combined immunodeficiency

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X-linked severe combined immunodeficiency
Other namesX-SCID
X-linked recessive (2).svg
X-linked recessive is the inheritance pattern of this disorder
Specialty Hematology   OOjs UI icon edit-ltr-progressive.svg

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

Contents

In the absence of T cell help, B cells become defective. [1] It is an X-linked recessive inheritance trait, stemming from a mutated (abnormal) version of the IL2RG gene located on the X-chromosome. This gene encodes the interleukin receptor common gamma chain protein, which is a cytokine receptor sub-unit that is part of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. [2] [3]

Symptoms and signs

People with X-SCID often have infections very early in life, before three months of age. This occurs due to the decreased amount of immunoglobulin G (IgG) levels in the infant during the three-month stage. [4] This is followed by viral infections such as pneumonitis, an inflammation of the lung which produces common symptoms such as cough, fever, chills, and shortness of breath. [5] A telltale sign of X-SCID is candidiasis, a type of fungal infection caused by Candida albicans . [6] Candidiasis involves moist areas of the body such as skin, the mouth, respiratory tract, and vagina; symptoms of oral candidiasis include difficulty in swallowing, pain on swallowing and oral lesions. Recurrent eczema-like rashes are also a common symptom. Other common infections experienced by individuals with X-SCID include diarrhea, sepsis, and otitis media. [4] Some other common symptoms that are experienced by X-SCID patients include failure to thrive, gut problems, skin problems, and muscle hypotonia. [4]

In some patients symptoms may not appear for the first six months after birth. [6] This is likely due to passive immunity received from the mother in order to protect the baby from infections until the newborn is able to make their own antibodies. [6] As a result, there can be a silent period where the baby displays no symptoms of X-SCID followed by the development of frequent infections.[ citation needed ]

Genetics

X-SCID is caused by a mutation occurring in the xq13.1 locus of the X-chromosome. [7] Most often, this disease affects males whose mother is a carrier (heterozygous) for the disorder. Because females have two X-chromosomes, the mother will not be affected by carrying only one abnormal X-chromosome, but any male children will have a 50% chance of being affected with the disorder by inheriting the faulty gene. Likewise, her female children will have a 50% chance of being carriers for the immunodeficiency. X-SCID can also arise through de novo mutations and can be prevented in females by X-inactivation. In X-inactivation the preferential selection of the non-mutant X chromosome during development results in the outcome that none of the mature female cells actively express the X-SCID mutation, they are immunologically unaffected and have no carrier burden. A de novo mutation is an alteration in a gene caused by the result of a mutation in a germ cell (egg or sperm) or in the fertilized egg itself, rather than having been inherited from a carrier. Since only 1/3 of all X-SCID patients have a positive family history of SCID, it is hypothesized that de novo mutations account for a significant percentage of cases. [8] X-inactivation occurs in a completely random manner, in females, very early in embryonic development. Once an X is inactivated, it remains inactivated throughout the life of that cell and any of its daughter cells. It is important to note that X-inactivation is reversed in female germline cells, so that all new oocytes receive an active X. Regardless of which X is inactivated in her somatic cells, a female will have a 50% chance of passing on the disease to any male children. [9]

Pathophysiology

Interleukins are produced by lymphocytes, among other cell types, and are released in response to antigenic and non-antigenic stimuli. The gene IL2RG codes for the common gamma chain protein, which is a common subunit of the individual receptors for Interleukin 2, Interleukin 4, Interleukin 7, Interleukin 9, Interleukin 15 and Interleukin 21. [10] Signalling from these receptors normally promotes growth and differentiation of T-cells, B cells, natural killer cells, glial cells, and cells of the monocyte lineage, depending on the cell type and receptor activated. [11] The most important receptors for X-SCID are those for Interleukin 2, Interleukin 4, Interleukin 7, and Interleukin 15. Specifically, Interleukin 2 and Interleukin 7 are responsible for T-cell proliferation and survival. [12] Likewise, the action of Interleukin 4 and Interleukin 15 will lead to proliferation and differentiation of B-cells into antibody secreting plasma cells. [12] Lastly, Interleukin 15 helps generate developed and matured natural killer cells. [5]

The gene that encodes the common gamma chain in these interleukin receptors is mutated in X-SCID. The mutation leads to an absent or abnormally functioning common gamma chain. The mutation can occur through large, or even single nucleotide, deletions in the IL2RG gene, that disable the common gamma chain so that it is unable to bind with other receptor subunits and signal cytokine activation. [11] Normally, when the interleukin binds to the trimeric receptor protein containing the alpha, beta, and gamma subunits, the common gamma subunit activates Janus Kinase 3 (JAK3), which leads to the phosphorylation of Signal Transducer and Activator of Transcription 5, STAT5. The STAT5 proteins dimerize and translocate to the nucleus, controlling subsequent downstream signalling. [1] Due to the fact that the common gamma chain is absent or abnormal, this downstream pathway is inhibited. This change prevents the T-lymphocytes from signaling other cells, like B-lymphocytes and natural killer cells. Because these cells never receive these signals, they can never mature and differentiate into full grown immune cells.[ citation needed ]

Diagnosis

Diagnosis of X-SCID is possible through lymphocyte cell counts, lymphocyte function tests, and genetic testing. A healthy immune system should contain large amounts of lymphocytes, but individuals with X-SCID will contain unusually small amounts of T-cells, non-functional B-cells, and some natural killer cells. [9]

Cell typeNormal lymphocyte count average (range)X-SCID count average (range)Refs
T-cells3,680 (2,500–5,500)200 (0-800) [9]
B-cells730 (300–2,000)1,300 (44 - >3,000)
NK cells420 (170–1,100)<100
Total0–3 months: 5,400 (3,400–7,300)<2,000

Individuals with X-SCID often have decreased lymphocyte function. This can be tested through the introduction of agents to the immune system; the reaction of the lymphocytes is then observed. In X-SCID, Antibody responses to introduced vaccines and infections are absent, and T-cell responses to mitogens, substances that stimulate lymphocyte transformation, are deficient. IgA and IgM immunoglobulins, substances that aid in fighting off infections, are very low. [ citation needed ]

The absence of a thymic shadow on chest X-rays is also indicative of X-SCID. [9] In a normal child, a distinctive sailboat shaped shadow near the heart can be seen. [6] The thymus gland in normal patients will gradually decrease in size because the need for the thymus gland diminishes. The decrease in the size of the thymus gland occurs because the body already has a sufficient number of developed T-cells. [13] However, a patient with X-SCID will be born with an abnormally small thymus gland at birth. [9] This indicates that the function of thymus gland, of forming developed T-cells, has been impaired.

Since the mutation in X-SCID is X-linked, there are genetic tests for detecting carriers in X-SCID pedigrees. One method is to look for family-specific IL2RG mutations. Finally, if none of those options are available, there is an unusual pattern of nonrandom X-chromosome inactivation on lymphocytes in carriers, thus looking for such inactivation would prove useful.

If a mother is pregnant and the family has a known history of immunodeficiency, then doctors may perform diagnostic assessment in-utero. Chorionic Villus Sampling, which involves sampling of the placental tissue using a catheter inserted through the cervix, can be performed 8 to 10 weeks into gestation. [14] Alternatively, Amniocentesis, which entails extracting a sample of the fluid which surrounds the fetus, can be performed 15 to 20 weeks into gestation. [14]

Early detection of X-SCID (and other types of SCID) is also made possible through detection of T-cell recombination excision circles, or TRECs. TRECs are composed of excised DNA fragments which are generated during normal splicing of T-cell surface antigen receptors and T-cell maturation. [15] This maturation process is absent across all SCID variants, as evidenced by the low counts of T-lymphocytes. The assay is performed using dried blood from a Guthrie card, from which DNA is extracted. [16] Quantitative PCR is then performed and the number of TRECs determined. [17] Individuals who have the SCID phenotype will have TREC counts as low as <30, compared to approximately 1020 for a healthy infant. [18] A low TREC count indicates that there is insufficient development of T-cells in the thymus gland. [19] This technique can predict SCID even when lymphocyte counts are within the normal range. Newborn screening of X-SCID based on TREC count in dried blood samples has recently been introduced in several states in the United States including California, Colorado, Connecticut, Delaware, Florida, Massachusetts, Michigan, Minnesota, Mississippi, New York, Texas, and Wisconsin. [20] In addition, pilot trials are being performed in several other states beginning in 2013. [21]

Treatments

Treatment for X-linked SCID can be divided into two main groups, the prophylactic treatment (i.e. preventative) and curative treatment. [22] The former attempts to manage the opportunistic infections common to SCID patients [22] and the latter aims at reconstituting healthy T-lymphocyte function. [23]

From the late 60s to early 70s, physicians began using "bubbles", which were plastic enclosures used to house newborns suspected to have SCIDS, immediately after birth. [24] The bubble, a form of isolation, was a sterile environment which meant the infant would avoid infections caused by common and lethal pathogens. [24] On the other hand, prophylactic treatments used today for X-linked SCID are similar to those used to treat other primary immunodeficiencies. [23] There are three types of prophylactic treatments, namely, the use of medication, sterile environments, and intravenous immunoglobulin therapy (IVIG). [23] First, antibiotics or antivirals are administered to control opportunistic infections, such as fluconazole for candidiasis, and acyclovir to prevent herpes virus infection. [25] In addition, the patient can also undergo intravenous immunoglobulin (IVIG) supplementation. [26] Here, a catheter is inserted into the vein and a fluid, containing antibodies normally made by B-cells, is injected into the patient's body. [27] Antibodies, Y-shaped proteins created by plasma cells, recognize and neutralize any pathogens in the body. [28] However, the IVIG is expensive, in terms of time and finance. [29] Therefore, the aforementioned treatments only prevent the infections, and are by no means a cure for X-linked SCID. [23]

Bone marrow transplantation (BMT) is a standard curative procedure and results in a full immune reconstitution, if the treatment is successful. [30] Firstly, a bone marrow transplant requires a human leukocyte antigen (HLA) match between the donor and the recipient. [31] The HLA is distinct from person to person, which means the immune system utilizes the HLA to distinguish self from foreign cells. [32] Furthermore, a BMT can be allogenic or autologous, which means the donor and recipient of bone marrow can be two different people or the same person, respectively. [31] The autologous BMT involves a full HLA match, whereas, the allogenic BMT involves a full or half (haploidentical) HLA match. [33] Particularly, in the allogenic BMT the chances of graft-versus-host-disease occurring is high if the match of the donor and recipient is not close enough. [32] In this case, the T-cells in the donor bone marrow attack the patient's body because the body is foreign to this graft. [34] The depletion of T-cells in the donor tissue and a close HLA match will reduce the chances of graft-versus-host disease occurring. [35] Moreover, patients who received an exact HLA match had normal functioning T-cells in fourteen days. [36] However, those who received a haploidentical HLA match, their T-cells started to function after four months. [36] In addition, the reason BMT is a permanent solution is because the bone marrow contains multipotent hematopoietic stem cells [30] which become common lymphoid or common myeloid progenitors. [37] In particular, the common lymphoid progenitor gives rise to the lymphocytes involved in the immune response (B-cell, T-cell, natural killer cell). [37] Therefore, a BMT will result in a full immune reconstitution but there are aspects of BMT that need to be improved (i.e. GvHD). [38]

Gene therapy is another treatment option which is available only for clinical trials. [34] X-linked SCID is a monogenic disorder, the IL2RG gene is mutated, so gene therapy will replace this mutated gene with a normal one. [39] This will result in a normal functioning gamma chain protein of the interleukin receptor. [35] In order to transfer a functional gene into the target cell, viral or non-viral vectors can be employed. [35] Viral vectors, such as the retrovirus, that incorporate the gene into the genome result in long-term effects. [34] This, coupled with the bone marrow stem cells, has been successful in treating individuals with X-SCID. [40] In one particular trial by Cavazzana-Calvo et al., ten children were treated with gene therapy at infancy for X-SCID. [41] Nine of the ten were cured of X-SCID. [41] However, about three years after treatment, two of the children developed T-cell leukemia due to insertion of the IL2RG gene near the LMO2 gene and thereby activating the LMO2 gene (a known oncogene). [42] A third child developed leukemia within two years of that study being published, likely as a direct result of the therapy. [43] This condition is known as insertional mutagenesis, where the random insertion of a gene interferes with the tumor suppressor gene or stimulates an oncogene. [34] There is currently no approved gene therapy on the market, but there are many clinical trials into which X-SCID patients may enroll. Therefore, research in the field of gene therapy today and in the future is needed to avoid the occurrence of leukemia. [35] In particular, research into the use of insulator and suicide genes is warranted as this may prevent cancer from developing. [34] The insulator gene inhibits the activation of adjacent genes. On the other hand, the suicide gene is stimulated when a tumour begins to form, and this will result in the deactivation of the therapeutic gene. [34] Moreover, the use of restriction enzymes such as the zinc-finger nuclease (ZFN) is being studied. [34] The ZFN allows the researcher to choose the site of gene integration. [34] Vector safety is important in the field of gene therapy, hence vectors that self-inactivate the promoter and enhancer (SIN) and adenoviruses that creates no immune response are prominent areas of research for vector biologists. [34]

Prognosis

X-linked SCID is a known pediatric emergency which primarily affects males. [31] If the appropriate treatment such as intravenous immunoglobulin supplements, medications for treating infections or a bone marrow transplant is not administered, then the prognosis is poor. [17] The patients with X-linked SCID usually die two years after they are born. [38] For this reason, the diagnosis of X-linked SCID needs to be done early to prevent any pathogens from infecting the infant.

However, the patients have a higher chance of survival if the diagnosis of X-linked SCID is done as soon as the baby is born. [17] This involves taking preventative measures to avoid any infections that can cause death. For example, David Vetter had a high chance of having X-linked SCID because his elder sibling had died due to SCID. [44] This allowed the doctors to place David in the bubble and prevented infections. [44] In addition, if X-linked SCID is known to affect a child, then live vaccines should not be administered and this can save the infant's life. Live attenuated vaccines, which consist of weakened pathogens inserted into the body to create an immune response, can lead to death in infants with X-linked SCID. [45] Moreover, with proper treatments, such as a bone marrow transplant, the prognosis is good. The bone marrow transplant has been successful in treating several patients and resulted in a full immune reconstitution and the patient can live a healthy life. [46] The results of bone marrow transplant are most successful when the closest human leukocyte antigen match has been found. [47] If a close match is not found, however, there is a chance of graft-versus-host-disease which means the donor bone marrow attacks the patient's body. [35] Hence, a close match is required to prevent any complications.

Epidemiology

There is no information on birth ratios/rates, but "X-Linked SCID is the most common form of SCID and it has been estimated to account for 46% to 70% of all SCID cases." [48]

See also

Notes and references

  1. 1 2 Fisher, A.; Hacein-Bey, S.; Cavazzana-Calvo, M. (August 2002). "Gene therapy of severe combined immunodeficiencies". Nature Reviews Immunology. 2 (8): 615–621. doi:10.1038/nri859. PMID   12154380. S2CID   39791932.
  2. ↑ Buckley, R.H. (2000). "Advances in the Understanding and Treatment of Human Severe Combined Immunodeficiency". Immunologic Research. 22 (2–3): 237–251. doi:10.1385/ir:22:2-3:237. PMID   11339359. S2CID   36855063.
  3. ↑ Puck, J.M.; de Saint Basil, G.; Schwarz, K.; Fugmann, S.; Fischer, R.E. (November 1996). "IL2RGbase: a database of γc-chain defects causing human X-SCID". Immunology Today. 17 (11): 507–511. doi:10.1016/0167-5699(96)30062-5. PMID   8961626.
  4. 1 2 3 Vickers, Peter (2009). Severe Combined Immune Deficiency: Early Hospitalisation and Isolation . Wiley. pp.  29–47. ISBN   978-0-470-31986-4.
  5. 1 2 Sponzilli, Ivonne; Notarangelo, Luigi D. (2011). "Severe Combined Immunodeficiency (SCID): from molecular basis to clinical management". Acta Bio-medica: Atenei Parmensis. 82 (1): 5–13. PMID   22069950.
  6. 1 2 3 4 Gennery, A.R.; Cant, A.J. (2001). "Diagnosis of severe combined immunodeficiency". Journal of Clinical Pathology. 54 (3): 191–5. doi:10.1136/jcp.54.3.191. PMC   1731376 . PMID   11253129.
  7. ↑ Buckley, Rebecca H. (1 April 2004). "Molecular Defects in Human Severe Combined Immunodeficiency and Approaches to Immune Reconstitution". Annual Review of Immunology. 22 (1): 625–655. doi:10.1146/annurev.immunol.22.012703.104614. PMID   15032591.
  8. ↑ Shwartz, R.A. "Pediatric Severe Combined Immunodeficiency". MedScape. Retrieved January 18, 2012.
  9. 1 2 3 4 5 GeneReviews 2016
  10. ↑ Cavazzana-Calvo, Marina; Fischer, A. (June 2007). "Gene therapy for severe combined immunodeficiency: are we there yet?". The Journal of Clinical Investigation. 117 (6): 1456–65. doi:10.1172/jci30953. PMC   1878528 . PMID   17549248.
  11. 1 2 Spolski, Rosanne; Leonard, Warren J. (1 April 2008). "Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity*". Annual Review of Immunology. 26 (1): 57–79. doi:10.1146/annurev.immunol.26.021607.090316. PMID   17953510.
  12. 1 2 Leonard, Warren J. (December 2001). "Cytokines and immunodeficiency diseases". Nature Reviews Immunology. 1 (3): 200–8. doi: 10.1038/35105066 . PMID   11905829. S2CID   5466985.
  13. ↑ Rehan, Kelly M. "An Overview of the Thymus: The Gland that Protects You Long after It's Gone". EndocrineWeb.
  14. 1 2 Fischer, A. (2000). "Severe combined immunodeficiencies". Clinical & Experimental Immunology. 122 (2): 143–9. doi:10.1046/j.1365-2249.2000.01359.x. PMC   1905779 . PMID   11091267.
  15. ↑ Puck, Jennifer M. (1 March 2012). "Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: The winner is T-cell receptor excision circles". Journal of Allergy and Clinical Immunology. 129 (3): 607–616. doi:10.1016/j.jaci.2012.01.032. PMC   3294074 . PMID   22285280.
  16. ↑ Shearer, William T. (1 March 2012). "Screening for severe combined immunodeficiency in newborns". Journal of Allergy and Clinical Immunology. 129 (3): 619–621. doi:10.1016/j.jaci.2011.12.992. PMID   22277197.
  17. 1 2 3 Verbsky, James W.; Baker, Mei W.; Grossman, William J.; Hintermeyer, Mary; Dasu, Trivikram; Bonacci, Benedetta; Reddy, Sreelatha; Margolis, David; Casper, James; Gries, Miranda; DeSantes, Ken; Hoffman, Gary L.; Brokopp, Charles D.; Seroogy, Christine M.; Routes, John M. (10 November 2011). "Newborn Screening for Severe Combined Immunodeficiency; The Wisconsin Experience (2008–2011)". Journal of Clinical Immunology. 32 (1): 82–88. doi:10.1007/s10875-011-9609-4. PMID   22068910. S2CID   14226544.
  18. ↑ Chan, K.; Puck, J. M. (2005). "Development of population-based newborn screening for severe combined immunodeficiency". Journal of Allergy and Clinical Immunology. 115 (2): 391–8. doi:10.1016/j.jaci.2004.10.012. PMID   15696101.
  19. ↑ Puck, Jennifer M.; Routes, Jack; Filipovich, Alexandra H.; Sullivan, Kate (20 October 2011). "Expert Commentary: Practical Issues in Newborn Screening for Severe Combined Immune Deficiency (SCID)". Journal of Clinical Immunology. 32 (1): 36–38. doi:10.1007/s10875-011-9598-3. PMC   4380147 . PMID   22012274.
  20. ↑ "IDF SCID Newborn Screening Campaign". Immune Deficiency Foundation.
  21. ↑ Wilkerson, Sarah. "Updates from Washington – Day 2". Save Babies Through Screening Foundation.
  22. 1 2 Fischer, A. (2000). "Severe Combined Immunodeficiencies (SCID)". Clinical & Experimental Immunology. 122 (2): 143–9. doi:10.1046/j.1365-2249.2000.01359.x. PMC   1905779 . PMID   11091267.
  23. 1 2 3 4 Rans, T.S.; England, R. (2009). "The evolution of gene therapy in X-linked severe combined immunodeficiency". Annals of Allergy, Asthma & Immunology. 102 (5): 357–363. doi:10.1016/S1081-1206(10)60504-2. PMID   19492655.
  24. 1 2 Johnston Jr., R.B. (2006). "The Boy in the Bubble". JAMA: The Journal of the American Medical Association. 296 (4): 453–4. doi:10.1001/jama.296.4.453.
  25. ↑ Freeman, A. F.; Holland, S. M. (2009). "Antimicrobial prophylaxis for primary immunodeficiencies". Current Opinion in Allergy and Clinical Immunology. 9 (6): 525–530. doi:10.1097/ACI.0b013e328332be33. PMID   19812481. S2CID   205434961.
  26. ↑ Nolte, M. T.; Pirofsky, B.; Gerritz, G. A.; Golding, B. (1979). "Intravenous immunoglobulin therapy for antibody deficiency". Clinical and Experimental Immunology. 36 (2): 237–43. PMC   1537711 . PMID   477026.
  27. ↑ Farrington, E.; Hochwald, C. (1996). "Intravenous immunoglobulin". Pediatric Nursing. 22 (4): 344–7. PMID   8852117.
  28. ↑ Shishido, S.N.; Varahan, S.; Yuan, K.; Li, X.; Fleming, S. D. (2012). "Humoral innate immune response and disease". Clinical Immunology. 144 (2): 142–158. doi:10.1016/j.clim.2012.06.002. hdl:2097/16670. PMC   3576926 . PMID   22771788.
  29. ↑ "I.V. immunoglobulin therapy for infectious diseases". Drug and Therapeutics Bulletin. 48 (5): 57–60. 6 May 2010. doi:10.1136/dtb.2009.07.0032. PMID   20447982. S2CID   26258054.
  30. 1 2 Burg, Mirjam; Gennery, Andy R. (9 April 2011). "Educational paper: The expanding clinical and immunological spectrum of severe combined immunodeficiency". European Journal of Pediatrics. 170 (5): 561–571. doi:10.1007/s00431-011-1452-3. PMC   3078321 . PMID   21479529.
  31. 1 2 3 Buckley, Rebecca H. (15 November 2004). "The multiple causes of human SCID". Journal of Clinical Investigation. 114 (10): 1409–11. doi:10.1172/JCI23571. PMC   525750 . PMID   15545990.
  32. 1 2 Martelli, Massimo F; Aversa, Franco; Bachar-Lustig, Ester; Velardi, Andrea; Reich-Zelicher, Shlomit; Tabilio, Antonio; Gur, Hilit; Reisner, Yair (1 January 2002). "Transplants across human leukocyte antigen barriers". Seminars in Hematology. 39 (1): 48–56. doi:10.1053/shem.2002.29255. PMID   11799529.
  33. ↑ de la Morena MT, Wayne AS, Day NK, Haag MM, Hinds-Frey KR, Nelson RP, Sutcliffe MJ, Good RA (December 1995). "Recipient T-cell immune reconstitution in X-linked SCID after haploidentical maternal bone marrow transplant". Ann. N. Y. Acad. Sci. 770 (1): 376–7. Bibcode:1995NYASA.770..376M. doi:10.1111/j.1749-6632.1995.tb31074.x. PMID   8597380. S2CID   35195857.
  34. 1 2 3 4 5 6 7 8 9 Kohn, Donald B.; Sadelain, Michel; Glorioso, Joseph C. (1 July 2003). "Occurrence of leukaemia following gene therapy of X-linked SCID". Nature Reviews Cancer. 3 (7): 477–488. doi:10.1038/nrc1122. PMID   12835668. S2CID   62790581.
  35. 1 2 3 4 5 Rans, Tonya S.; England, Ronald (1 May 2009). "The evolution of gene therapy in X-linked severe combined immunodeficiency". Annals of Allergy, Asthma & Immunology. 102 (5): 357–363. doi:10.1016/S1081-1206(10)60504-2. PMID   19492655.
  36. 1 2 Buckley, Rebecca H.; Schiff, Sherrie E.; Schiff, Richard I.; Markert, M. Louise; Williams, Larry W.; Roberts, Joseph L.; Myers, Laurie A.; Ward, Frances E. (18 February 1999). "Hematopoietic Stem-Cell Transplantation for the Treatment of Severe Combined Immunodeficiency". New England Journal of Medicine. 340 (7): 508–516. doi: 10.1056/NEJM199902183400703 . PMID   10021471.
  37. 1 2 Kondo, Motonari; Wagers, Amy J.; Manz, Markus G.; Prohaska, Susan S.; Scherer, David C.; Beilhack, Georg F.; Shizuru, Judith A.; Weissman, Irving L. (1 April 2003). "Biology of Hemaptopoietic Stem Cells and Progenitors: Implications for Clinical Application". Annual Review of Immunology. 21 (1): 759–806. doi:10.1146/annurev.immunol.21.120601.141007. PMID   12615892.
  38. 1 2 Fischer, A. (1 November 2000). "Severe combined immunodeficiencies (SCID)". Clinical and Experimental Immunology. 122 (2): 143–9. doi:10.1046/j.1365-2249.2000.01359.x. PMC   1905779 . PMID   11091267.
  39. ↑ Buckley, Rebecca H. (15 November 2004). "The multiple causes of human SCID". Journal of Clinical Investigation. 114 (10): 1409–11. doi:10.1172/JCI23571. PMC   525750 . PMID   15545990.
  40. ↑ Woods N-B, Bottero V, Schmidt M, von Kalle C, Verma IM (21 September 2006). "Gene therapy: Is IL2RG oncogenic in T-cell development?: X-SCID transgene leukaemogenicity (reply)". Nature. 443 (7109): E6–E7. Bibcode:2006Natur.443E...6W. doi:10.1038/nature05220. PMID   16988660. S2CID   4418027.
  41. 1 2 Cavazzana-Calvo, M. (28 April 2000). "Gene Therapy of Human Severe Combined Immunodeficiency (SCID)-X1 Disease". Science. 288 (5466): 669–672. Bibcode:2000Sci...288..669C. doi:10.1126/science.288.5466.669. PMID   10784449.
  42. ↑ "Gene Therapy Insertional Mutagenesis Insights" (PDF). Science. 16 January 2004.
  43. ↑ "X-SCID Gene Therapy Poses Substantial Cancer Risk". Medical News Today. 30 April 2006.
  44. 1 2 Cossu, Fausto (1 January 2010). "Genetics of SCID". Italian Journal of Pediatrics. 36 (1): 76. doi: 10.1186/1824-7288-36-76 . PMC   2999594 . PMID   21078154.
  45. ↑ Nima Rezaei; Asghar Aghamohammadi; Luigi Notarangelo, eds. (2008). Primary immunodeficiency diseases : definition, diagnosis, and management . Berlin: Springer. p.  45. ISBN   978-3-540-78537-8.
  46. ↑ Dvorak, C C; Cowan, M J (29 October 2007). "Hematopoietic stem cell transplantation for primary immunodeficiency disease". Bone Marrow Transplantation. 41 (2): 119–126. doi:10.1038/sj.bmt.1705890. PMID   17968328. S2CID   9424204.
  47. ↑ Mikkers, Harald; Pike-Overzet, Karin; Staal, Frank J.T. (8 February 2012). "Induced pluripotent stem cells and severe combined immunodeficiency: merely disease modeling or potentially a novel cure?". Pediatric Research. 71 (4–2): 427–432. doi: 10.1038/pr.2011.65 . PMID   22430378.
  48. ↑ Davis J, Puck JM (1993). "X-Linked Severe Combined Immunodeficiency". In Pagon RA, Bird TD, Dolan CR, Stephens K (eds.). GeneReviews. Seattle WA: University of Washington. PMID   20301584.[ clarification needed ]

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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">Wiskott–Aldrich syndrome</span> Medical condition

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea. It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present with similar but less severe symptoms and are caused by mutations of the same gene.

<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.

Lymphoproliferative disorders (LPDs) refer to a specific class of diagnoses, comprising a group of several conditions, in which lymphocytes are produced in excessive quantities. These disorders primarily present in patients who have a compromised immune system. Due to this factor, there are instances of these conditions being equated with "immunoproliferative disorders"; although, in terms of nomenclature, lymphoproliferative disorders are a subclass of immunoproliferative disorders—along with hypergammaglobulinemia and paraproteinemias.

<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">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.

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.

<span class="mw-page-title-main">IL2RA</span> Mammalian protein found in Homo sapiens

The Interleukin-2 receptor alpha chain is a protein involved in the assembly of the high-affinity Interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and the common gamma chain (IL2RG). As the name indicates, this receptor interacts with Interleukin-2, a pleiotropic cytokine which plays an important role in immune homeostasis.

X-linked lymphoproliferative disease is a lymphoproliferative disorder, usually caused by SH2DIA gene mutations in males. XLP-positive individuals experience immune system deficiencies that render them unable to effectively respond to the Epstein-Barr virus (EBV), a common virus in humans that typically induces mild symptoms or infectious mononucleosis (IM) in patients. There are two currently known variations of the disorder, known as XLP1 and XLP2. XLP1 is estimated to occur in approximately one in every million males, while XLP2 is rarer, estimated to occur in one of every five million males. Due to therapies such as chemotherapy and stem cell transplants, the survival rate of XLP1 has increased dramatically since its discovery in the 1970s.

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.

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">T cell deficiency</span> Medical condition

T cell deficiency is a deficiency of T cells, caused by decreased function of individual T cells, it causes an immunodeficiency of cell-mediated immunity. T cells normal function is to help with the human body's immunity, they are one of the two primary types of lymphocytes(the other being B cells).

<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.

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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