Excerpt from Severe Combined Immunodeficiency

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Background

Severe combined immunodeficiency (SCID) is a syndrome first coined by John Soothill, MD, in 1975 at a World Health Organization Expert Committee on primary immunodeficiency. The immunodeficiency is severe because, if unrecognized, it often proves fatal before the patient is aged 2 years, and it is combined because of a pronounced defect in both cell-mediated and humoral immunity. Therefore, patients with SCID have profound defects in the adaptive immune system, and both T-cell and B-cell functions are affected. Combined deficiencies account for approximately 20% of primary immunodeficiencies.

SCID can be classified into 2 groups: SCID with B cells (70% of patients with SCID) and SCID without B cells. T-cell function is affected in all forms of SCID. A T-cell abnormality can lead to defects in B-cell function because B cells require T-cell help for proper activation of the production of antibodies.

Over the past few decades, the diverse molecular genetic causes of SCID have been identified. Despite the heterogeneity in the pathogenesis, common cutaneous manifestations and typical infections can provide clinical clues in diagnosing this pediatric emergency. Appropriate diagnosis is essential because treatment to save the patient can be initiated. With the advances in bone marrow transplantation and gene therapy, patients now have a better likelihood of recovering normal immune function in a previously lethal genetic disease. However, once an infant develops serious infections, intervention is rarely successful.

Pathophysiology

SCID can be caused by a variety of distinct genetic defects that interfere with lymphocyte development and function. These defects lead to loss of function of both B and T cells. A defect that affects early lymphocyte development, such as progenitor cells, can lead to an inability to produce both B cells and T cells. Also, a defect of T cells alone can lead to combined immune defects because B cells are dependent on T-cell help for a response to antigen and immunoglobulin class-switching. Although novel causes of SCID continued to be revealed, the pathogenesis can be grouped into mechanisms that are related to lymphocyte development and function.

A defect in lymphoid stem cell development can lead to profound deficiency of both B cells and T cells, such as reticular dysgenesis.

An early block may occur within the T-cell differentiation pathway. The most common form, occurring in 40-60% of patients with SCID, is the X-linked form, SCID-X1, which arises from defects in the common g chain of interleukin receptors. This molecular defect results in absent T- and natural killer (NK)–cell maturation, although recent evidence suggests that the g chain is also involved in B-cell development.

The g chain is a member of the hematopoietic cytokine receptor family. Interleukin 2Ra (IL-2Ra) and interleukin 2Rb (IL-2Rb), in combination with the g chain, recruits interleukin 2 (IL-2), resulting in signal transduction by means of activation of its tyrosine kinase Janus kinase 3 (JAK3). Phosphorylation of signal transducers and activators of transcription 5 (STAT-5) proceeds, enabling its translocation to the nucleus for transcription of genes involved in cell division. Mutation of JAK3 results in the absence of T- and NK-cell function as in SCID-X1.

In addition, the g chain is a member of the interleukin 4 (IL-4), interleukin 7 (IL-7), interleukin 9 (IL-9), interleukin 15 (IL-15) and interleukin 21 (IL-21) receptors, which also function to increase cytokine binding affinity and signal transduction. In addition, defects in signaling molecules that associate with the T-cell receptor can lead to SCID; examples include mutations in the Lck and Zap70 genes. Other cytokine receptor–associated genes include JAK1 and JAK3, which, when defective, can lead to SCID.

Defects in the CD45 molecule, the common leukocyte antigen that functions as a protein phosphatase, can lead to SCID. CD45 is essential in regulating the transmission of cell surface signals in B cells and T cells.

Defects in the expression of the major histocompatibility complex (MHC) lead to bare lymphocyte syndrome, which then results in an inability of the T cells to function. Patients with this condition can have defects in the regulatory region of the MHC class II gene or a defect in a transcription regulator, CTIIA, which is responsible for controlling the expression of MHC class II genes.

Abnormal purine metabolism may be involved. Adenosine deaminase (ADA) deficiency accounts for 20% of all SCID cases. The enzyme deficiency results in the accumulation of intermediates, such as adenosine diphosphate, guanosine triphosphate, and deoxyadenosine triphosphate (dATP), which results in lymphocyte toxicity, particularly with immature thymic lymphocytes. Purine nucleoside phosphorylase (PNP) deficiency is mechanistically similar to ADA deficiency in that the accumulation of deoxyguanosine triphosphate (dGTP) exerts a lymphotoxic effect. In both conditions, T-cell function is most severely affected.

Abnormal recombination of genes may occur. Both B-cell maturation and T-cell maturation involve a process of recombination in which various combinations of variable, diversity, and joining (VDJ) genes are assembled to create unique and specific antigen receptors. Two recombination activating genes, recombinase activating gene 1 (RAG1) and recombinase activating gene 2 (RAG2), which mediate initial DNA double-strand breaking at specific sequences, enable subsequent joining of the various gene segments. Both RAG1 and RAG2 mutations result in a T-B-NK+ SCID phenotype and Omenn syndrome, in which residual VDJ recombination activity occurs.

The gene DNA-PK is a DNA-dependent serine-threonine protein kinase that is required for correct recombination. Mutations in this gene are autosomal recessive and can also lead to combined deficiency. DNA from the cells of these patients is associated with an increased radiosensitivity.

The ARTEMIS gene, located on chromosome 10, encodes a product that plays a role in VDJ recombination and is associated with SCID that develops from an early block in B- and T-cell development.

Reticular dysgenesis is a rare form of SCID that arises from the lack of appropriate stem cell development. Patients with this disease have agranulocytosis in addition to a lack of both B cells and T cells in the adaptive immune system.

Frequency

United States

To the author's knowledge, no population surveys have been performed. However, interest has been garnered in implementing screening to identify affected newborns.¹

International

The frequency is estimated to be 1 case in 50,000-500,000 births.

Mortality/Morbidity

Diagnosis must be made before severe life-threatening infections occur so that the immunity can be restored with enzyme replacement or bone marrow transplantation. Otherwise, the mortality rate is close to 100%.

Sex

Overall, the male-to-female ratio is 3:1 because some forms of SCID are X-linked, whereas other forms of SCID are autosomal recessive.

Age

The mean patient age at diagnosis is 6.5 months.

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