X-SCID

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Classification according to ICD-10
D81.1 Severe combined immunodeficiency [SCID] with low T and B cell counts
ICD-10 online (WHO version 2019)

X-SCID (Severe Combined Immunodeficiency) , also SCID-X1 , is a form of the immunodeficiency disease SCID , in which a mutation in the common interleukin receptor γ gene or the common chain encoded by this gene (γc for short, CD132 ) , several interleukin receptors are no longer functional. One example is the interleukin-2 receptor (IL-2Rγ). Due to these errors, no precursor T lymphocytes and no NK cells can develop from haematopoietic stem cells (blood stem cells) . However, since T H 2 cells (= a "sub-class" of T lymphocytes) are essential as a stimulus for antibody production by B lymphocytes , not only the cellular but also the humoral immune system is unable to work, i.e. the entire adaptive system Defective immune system. The gene for the receptor is located on the X chromosome, hence the name X-SCID. X-SCID is the genetic cause of about 50% of all SCID cases.

Affected patients are prone to infections of any kind, such as pneumonia or meningitis, and can only survive briefly without appropriate medical treatment (or shielding in a sterile tent).

Forms of treatment

Stem cell transplant

As with many other immune diseases, e.g. B. leukemia , the entire immune system is classically destroyed by chemotherapy (although this is hardly necessary here), then lymphocytes from a suitable donor are implanted by a bone marrow transplant , which are then to form a new immune system in the patient.

Gene therapy

The gene therapy is a newer, experimental treatment that due to the nature of this monogenic disease (only one gene involved) seems suitable for the treatment of X-linked severe combined immunodeficiency. Alain Fischer and colleagues from the Paris Hôpital Necker des Enfants Malades carried out gene therapy treatment on five children suffering from X-SCID in 1999–2000. For this purpose the patients hematopoietic stem cells were removed (CD34-positive), ex vivo using a retroviral vector (from the murine leukemia virus ) transformed and infused to the patient. After four months, T cells and NK cells were found in four of the five patients. In the fifth patient, the transformation did not succeed and an HLA-incompatible bone marrow transplant had to be carried out on him, which also succeeded. After the therapy was successful in a total of 9 out of 10 patients, the authors published an article in 2003 in which they pointed out that " approximately three years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells [...] took place in two of their patients " . The authors conducted as a possible cause of leukemia integration of the vector near the LMO2 proto - Promoter on. However, more recent work in the mouse model suggests that the gene itself could have an oncogenic effect: 33% of the transformed mice developed leukemia after 1.5 years. The insertion mutagenesis cannot therefore have been the only reason for the mutation. The authors are in favor of long-term studies, since follow-up studies are usually ended after six months. Studies showing that LMO2 does not appear to play a role in the development of lymphocytes also speak against the involvement of LMO2 in oncogenesis.

So far, gene therapy has only been used in a few cases in patients without HLA-compatible donors.

literature

  1. ^ HB Gaspar, KL Parsley, S. Howe, D. King, KC Gilmour, J. Sinclair, G. Brouns, M. Schmidt, C. Von Kalle, T. Barington, MA Jakobsen, HO Christensen, A. Al Ghonaium, HN White, JL Smith, RJ Levinsky, RR Ali, C. Kinnon, AJ Thrasher: Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. In: The Lancet  9452/364/2004. Pp. 2181-2187 doi : 10.1016 / S0140-6736 (04) 17590-9
  2. ↑ a b S. hacein Bey-Abina-, F. Le Deist, F. Carlier, C. Bouneaud, C. Hue, J.-P. De Villartay, AJ Thrasher, N. Wulffraat, R. Sorensen, S. Dupuis-Girod, A. Fischer, M. Cavazzana-Calvo: Sustained Correction of X-Linked Severe Combined Immunodeficiency by ex Vivo Gene Therapy. In: The New England Journal of Medicine 16/346/2002. Pp. 1185-1193 abstract
  3. ↑ S. Hacein-Bey-Abina, C. Von Kalle, M. Schmidt, MP McCormack, N. Wulffraat, P. Leboulch, A. Lim, CS Osborne, R. Pawliuk, E. Morillon, R. Sorensen, A. Forster, P. Fraser, JI Cohen, G. de Saint Basile, I. Alexander, U. Wintergerst, T. Frebourg, A. Aurias, D. Stoppa-Lyonnet, S. Romana, I. Radford-Weiss, F. Gross , F. Valensi, E. Delabesse, E. Macintyre, F. Sigaux, J. Soulier, LE Leiva, M. Wissler, C. Prinz, TH Rabbitts, F. Le Deist, A. Fischer, M. Cavazzana-Calvo: LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1 In: Science 5644/302/2003. Pp. 415-419 Abstract doi : 10.1126 / science.1088547
  4. ↑ N.-B. Woods, V. Bottero, M. Schmidt, C. von Kalle, IM Verma: Therapeutic gene causing lymphoma In: Nature 7088/440/2006. S. 1123 First paragraph doi : 10.1038 / 4401123a
  5. ^ MP McCormack, A. Forster, L. Drynan, R. Pannell, TH Rabbitts: The LMO2 T-Cell Oncogene Is Activated via Chromosomal Translocations or Retroviral Insertion during Gene Therapy but Has No Mandatory Role in Normal T-Cell Development In: Molecular and Cellular Biology 24/23/2003. Pp. 9003-9013 Abstract doi : 10.1128 / MCB.23.24.9003-9013.2003