SCID -Severe combined immunodeficiency

Also known as alymphocytosis,

Glanzmann–Riniker syndrome, severe mixed immunodeficiency

It is an extremely rare genetic disorder characterized by the disturbed development of functional T cells and B cells

This disturbed development is caused by numerous genetic mutations that result in heterogeneous clinical presentations

The overall frequency is estimated to one in 75000–100000 births

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.

SCID is the most severe form of primary immunodeficiencies, and there are now at least nine different known genes in which mutations lead to a form of SCID

It is also known as the bubble baby disease and bubble boy diseaseSCID patients are usually affected by severe bacterial, viral, or fungal infectionsPatient need hematopoietic stem cell transplantation for survival.

the description of SCID conditions relies on several parameters including immunological phenotype, inheritance pattern, gene identification and mechanism

Classification:-• X-linked severe combined immunodeficiency• Adenosine deaminase deficiency• Purine nucleoside phosphorylase deficiency• Reticular dysgenesis• Omenn syndrome• Bare lymphocyte syndrome• JAK3• Artemis/DCLRE1C

Symptoms.• very severe respiratory infections• include poor growth• rashes that look like eczema• chronic diarrhea • recurrent thrush in the mouth

although all of these symptoms may not be present.

Screening.

SCID is not diagnosed until about six months of age

The delay in detection is because newborns carry their mother's antibodies for the first few weeks of life

Purine metabolism deficiency

• The first SCID condition to be characterized at the molecular level was adenosine deaminase (ADA) deficiency. ADA is an enzyme involved in purine metabolism, and transforms adenosine and deoxyadenosine (dado) into inosine and deoxynosine respectively. Deoxyadenosine is phosphorylated into deoxyadenosine triphosphate (dATP) in immature lymphocytes; accumulation of dATP results in a block in synthesis of deoxyribonucleic acid (DNA) and also induces chromosomal breaks. A complete deficiency of ADA leads to almost total disappearance of T, B and natural killer (NK) lymphocytes. Partial deficiency results in an incomplete block in lymphocyte differentiation. ADA deficiency also leads to primary bone, lung and liver abnormalities. The immunodeficiency resulting from adenosine deaminase (ADA) gene mutations can be cured by allogeneic hematopoietic stem cell transplantation (HSCT) but can also be alleviated in part by enzymatic supplementation. Gene therapy is being tested in this setting.

Purine metabolism deficiency

Another defect in purine metabolism, that is, purine nucleoside phosphorylase (PNP) deficiency, also causes

T-cell immunodeficiency because of the toxicity of accumulating deoxyguanosine triphosphate.

γc-Dependent Cytokine Receptor Pathway Deficiencies • The most common form of SCID consists of a block in development of both

T and NK lymphocytes. Its inheritance pattern is either recessive X-linked or autosomal recessive. The X-linked form of SCID (SCID-X1) accounts for more than half of all SCID cases. It is caused by mutations of the gene encoding γc.

• Multiple distinct mutations have been described, leading to the same phenotype. This observation illustrates the important role of the cytokine-dependent phase of T/NK lymphocyte development. Surprisingly, B-cell differentiation occurs normally despite defective IL-7 signaling. Actually, in most patients the peripheral B-cell counts is even increased. These B lymphocytes are at least partially functional in vitro as well as in vivo following HSCT in some cases; γc-negative B cells have been shown to undergo class-switch recombination and produce protective antibodies following physiological activation

γc-Dependent Cytokine Receptor Pathway Deficiencies ..contd• Deficiency in JAK-3 accounts for the autosomal recessive form of T(−),

NK(−), B(+) SCID demonstrating that γc-dependent signals require JAK-3 activation. Recently, six SCID patients were shown to exhibit deleterious mutations in the gene encoding the IL-7 receptor (IL-7R) α chain. IL-7Rα associates with γc to form IL-7R. IL-7Rα deficiency results in a selective block in T-lymphocyte development, demonstrating the crucial role of IL-7 in a very early step of T-cell differentiation

CD45 Deficiency

•Finally, a CD45 deficiency was found to be responsible in two patients of a SCID phenotype consisting of absence of TCRαβ+ T cells. CD45, a membrane-associated phosphatase, plays a major role in pre-TCR/TCR-induced signaling by removing an inhibitory phosphate in the CD4/CD8 associated src kinase p56 Lck

V(D)J Recombination Deficiencies

• A subset of SCID is typically characterized phenotypically by an absence of both mature T and B lymphocytes while NK cells are spared. It accounts for approximately 20% of cases. Inheritance is autosomal recessive. This condition has turned out to be genetically heterogeneous.

• This SCID condition is reminiscent of the scid mouse model, a natural mutant in which the V(D)J recombination process of the T- and B-cell receptor genes is impaired, due to a deficiency in the DNA-dependent protein kinase activity within the nonhomologous end-joining (NHEJ) repair process. It was therefore reasoned that this form of SCID also results from defective V(D)J recombination.

• The first phenotype is accounted for by deficiencies in recombination activating gene 1 or 2 proteins (Rag-1 or Rag-2) (Schwartz et al., 1996). These elements, which are lymphocyte specific, initiate V(D)J recombination by creating site-specific DNA breaks at recombination signal sequences flanking coding elements of the variable part of T-cell receptors (TCRs) and B-cell receptors (BCRs). Complete defects result in an absence of mature T and B lymphocytes.

• The second phenotype, associating defective V(D)J recombination and defective repair of DNA double-strand breaks (dsb), has been shown to be the consequence of mutations of the gene encoding the artemis protein (DNA cross-link repair 1C (PSO2 homolog, S. cerevisiae) (DCLRE1C)) (Moshous et al., 2001). It appears that this ubiquitously expressed protein is involved in the NHEJ process required for both TCR and BCR gene rearrangements and dsb DNA repair. The artemis sequence has some homology with proteins involved in repair of DNA lesions caused by inter-DNA strand bonds, but its exact function remains unknown. Artemis deficiency accounts for the SCID observed in the Athabascan-speaking Native Americans, where it is the most frequent inherited disease (about one in 1000 live births).

Treatment.The most common treatment for SCID is bone marrow transplantationThrough either a matched related or unrelated donor, or a half-matched donor, who would be either parentDavid Vetter, the original "bubble boy", after transplantations died because of an unscreened virus.Today, transplants done in the first three months of life have a high success rate.

Treatment ..contd

utero transplants done before the child is born using cord blood which is rich in stem cells.gene therapy, but few patients developed Leukemia.Non-curative treatment for patients with ADA-SCID is enzyme replacement therapy