Severe Combined Immunodeficiency

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Classification according to ICD-10
D81.0 SCID with reticular dysgenesis
D81.1 SCID with low T and B cell counts
D81.2 SCID with low or normal B-cell counts
D81.3 Adenosine deaminase deficiency (SCID due to ADA deficiency)
D81.4 Nezelof syndrome
D81.5 Purine nucleoside phosphorylase deficiency (PNP deficiency)
D81.6 Major histocompatibility complex class I (MHC class I) defect

Bare lymphocyte syndrome I.

D81.7 Major histocompatibility complex class I (MHC class II) defect

Bare lymphocyte syndrome II

D81.8 Other combined immunodeficiency (SCID)
D81.9 Combined immunodeficiency (SCID), unspecified
ICD-10 online (WHO version 2019)

SCID ( severe combined immunodeficiency ; severe combined immunodeficiency ) is a collective term for diseases or a syndrome that have in common a congenital severe disorder of the immune system. A malfunction or deficiency of T lymphocytes is typical for all forms of SCID . This causes a disruption of the cellular immune response in all forms of SCID. Depending on the type of SCID, the function or number of B lymphocytes and NK cells is also defective. Accordingly, humoral immunity (antibody-supported defense) can also be impaired. The individual forms of SCID are caused by congenital defects or disorders of genes. The diseases manifest themselves through repeated severe infections with "unusual" pathogens and developmental delays in infancy and early childhood. If left untreated, SCID diseases are usually fatal within a few months or at best years. Symptomatic treatment consists in isolating the patient from the causative agents of infectious diseases. The only curative treatment currently available is allogeneic blood stem cell transplantation (transferring blood-forming stem cells from another person). Newer therapy methods based on gene therapy try to correct the various gene defects by introducing a “healthy” gene. However, these procedures are still in the experimental stage. Their first human applications with a certain form of SCID successfully corrected the underlying genetic defect. The development of acute leukemia as a result of the introduced gene was also observed as a very serious side effect, so that no further applications are currently taking place in humans.

causes

The various forms of SCID are caused by congenital defects in genes. Depending on the type of SCID, different individual genes are affected; however, several genes can also be affected at the same time. The genes affected are:

Cytokine receptor genes
Interleukin-2 receptor gamma chain gene (IL-2R-γ; CD132 ) - X-SCID
JAK3 gene
Interleukin- 7 receptor alpha gene (IL-7R-α; CD127 )
Antigen receptor genes
Recombination activating gene 1 gene (RAG1)
Recombination activating gene 2 gene (RAG2)
Artemis gene - RS-SCID
CD3delta gene (CD3δ)
CD3epsilon gene (CD3ε)
Other genes
Adenosine deaminase gene (ADA)
CD45 gene

Forms of SCID (classification)

The individual SCID forms are named according to the genetic cause and the resulting disorders of the immune system.

Forms of (congenital) severe combined immunodeficiency (SCID)
SCID form genetics Immunological functions
designation abbreviation OMIM code Affected gene chromosome Inheritance T cells B cells NK cells
X-linked SCID X-SCID # 300400 IL-2R γ chain Xq13 XR absence available absence
SCID with sensitivity to ionizing radiation;
SCID, Athabasca type 		RS-SCID
SCIDA 		# 602450 DCLRE1c (Artemis) 10p AR absence absence available
SCID due to lack of adenosine deaminase ADA-SCID # 102700 ADA 20q13.11 AR (SM) absence absence absence
SCID with RAG1 mutation RAG1-SCID # 601457 RAG1 11p13 AR absence absence available
SCID with RAG2 mutation RAG2-SCID # 601457 RAG2 11p13 AR absence absence available
SCID with JAK3 mutation JAK3-SCID # 600802 JAK3 11q23; 5p13 AR absence available absence
SCID with IL7R mutation IL-7R # 608971 IL-7R 5p13 AR absence available available
SCID with CD45 mutation CD45 # 608971 CD45 1q31-q32 AR absence available available
SCID with CD3δ mutation CD3δ # 608971 CD3δ 11q23 AR absence available available
SCID with CD3ε mutation CD3ε # 608971 CD3ε 11q23 AR absence available available
SCID with purine nucleoside
phosphorylase deficiency (PNP deficiency) 		PNP-SCID +164050 PNP mutation 14q13.1 AR defective or missing variable defect available
Explanations: AR: autosomal recissive; AD: autosomal dominant; XR: X-linked recessive; SM: somatic mosaic; GI: genomic imprinting

Epidemiology (frequency and occurrence)

The incidence of SCID is estimated at 1 in 50,000 to 1 in 100,000 newborns.

Clinic and Symptoms

The vast majority of SCID forms are already noticeable through symptoms in infancy and early childhood. Occurrence in childhood, adolescence or adulthood is very rare. Typical symptoms of all forms of SCID are

  • Failure to thrive in the sense of development and growth retardation
  • Recurrent (recurring) infections, especially pneumonia
  • Chronic diarrhea (diarrhea)

diagnosis

If there is clinical suspicion, the diagnosis of SCID is made using immunophenotyping (usually in the form of flow cytometry ). Using fluorescence-marked antibodies, the presence of certain proteins on white blood cells (leukocytes) is detected or their absence or reduced presence (expression) is confirmed. A lack of CD3 expression on leukocytes speaks very strongly for the absence of T lymphocytes and thus for the presence of a SCID. A further limitation of the SCID form can be detected by examining the B lymphocytes (protein markers : CD19 or CD20) and NK cells (protein markers: CD56) using the same method.

The exact type of a SCID can only be determined through molecular genetic tests with evidence of defining mutations.

Differential diagnosis

A distinction must be made from SCID forms

  • T lymphopenia caused by external factors (radiation therapy, especially chemotherapy)
  • Combined variable immunodefiencies
  • HIV infections

therapy

Symptomatic therapy

Symptomatic therapy consists of minimizing exposure to infectious agents through reverse isolation. When used strictly, infants and children were isolated in sterile plastic tents (so-called bubble babies ). Furthermore, infections are combated with antibiotics (for bacteria), antimycotics (for fungi) and antivirals (for viruses). It is noteworthy that uncomplicated infections (for example rotavirus gastroenteritis) in SCID patients can take on severe courses in people with poor immunity. If there is a lack of antibodies (especially IgG), immunoglobulins can also be substituted.

Curative (healing) therapy

The only curative therapy that has currently been tried and tested is allogeneic (donor and patient) blood stem cell transplantation. This can be done either as a transplant of peripheral hematopoietic stem cells or as a bone marrow transplant. The transplantation of allogeneic umbilical cord blood including the blood-forming stem cells contained in it is also possible.

In addition to the allogeneic blood stem cell transplantation, great hopes were placed in the gene therapy of the SCID forms. Here, healthy versions of the pathological or mutated genes should be smuggled into the cells of the immune system by means of viral vectors (carriers). In addition to some impressive successes in small clinical studies, there were also very serious side effects due to the development of acute leukemia in several patients precisely due to the viral carrier. This was caused by the incorporation of the gene to be transferred into genetic loci, which thereby become oncogenes .

forecast

If left untreated, the vast majority of SCID forms are fatal. With symptomatic treatment, life can be prolonged; a permanent thwarting of infections is not possible even with strict application of isolation measures and infection treatment or prophylaxis.

A blood stem cell transplant helps most forms of SCID to cure permanently. The very intensive treatment associated with this (chemotherapy ± whole-body radiation to destroy the defective immune system) can lead to secondary diseases including malignant diseases. The frequency of these diseases is not known with sufficient certainty in the long term, as the follow-up times for blood stem cell transplants in SCID patients are not yet several decades.

See also

Web links

Individual evidence

  1. ^ RH Buckley: The multiple causes of human SCID. In: J Clin Invest. 2004, 114, pp. 1409-1411.
  2. ^ HB Gaspar, KC Gilmour, AM Jones. Severe combined immunodeficiency-molecular pathogenesis and diagnosis. In: Arch Dis Child . 2001 Feb; 84 (2), pp. 169-173. PMID 11159300
  3. ↑ H. Huangund, KG Manton: Newborn screening for severe combined immunodeficiency (SCID): a review. In: Front Biosci. 10, 2005, pp. 1024-1039.
  4. ↑ Salima Hacein-Bey-Abina and a .: Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. In: Journal of Clinical Investigation. 2008; 118 (9), p. 3132. PMC 2496963 (free full text)