Severe combined immunodeficiencies (SCIDs) are a rare group of genetic disorders characterized by the body's inability to create functional T cells and B cells. SCIDs are the most severe form of primary immunodeficiency, making their sufferers extremely vulnerable to infection due to their highly compromised immune system. There are at least seven different known genes in which mutations lead to a form of SCID, each of which has different clinical presentations. 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. Consequently, both "arms" (B cells and T cells) of the adaptive immune system are impaired due to a defect in one of several possible genes. Some SCID sufferers, such as David Vetter, have become famous for living in a sterile environment to avoid infection, leading to the name bubble boy disease and bubble baby disease. SCID patients are usually affected by severe bacterial, viral, or fungal infections early in life and often present with interstitial lung disease, chronic diarrhea, and failure to thrive. Ear infections, recurrent Pneumocystis jirovecii pneumonia, and profuse oral candidiasis commonly occur. These babies, if untreated, usually die within one year due to severe, recurrent infections unless they have undergone successful hematopoietic stem cell transplantation or gene therapy in clinical trials.
Types
X-linked severe combined immunodeficiency
Most cases of SCID are due to mutations in the IL2RG gene encoding the common gamma chain (γc) (CD132), a protein that is shared by the receptors for interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. These interleukins and their receptors are involved in the development and differentiation of T and B cells. Because the common gamma chain is shared by many interleukin receptors, mutations that result in a non-functional common gamma chain cause widespread defects in interleukin signalling. The result is a near complete failure of the immune system to develop and function, with low or absent T cells and NK cells and non-functional B cells.The common gamma chain is encoded by the gene IL-2 receptor gamma, or IL-2Rγ, which is located on the X-chromosome. For this reason, immunodeficiency caused by mutations in IL-2Rγ is known as X-linked severe combined immunodeficiency. The condition is inherited in an X-linked recessive pattern.
Adenosine deaminase deficiency
The second most common form of SCID after X-SCID is caused by a defective enzyme, adenosine deaminase (ADA), necessary for the breakdown of purines. Lack of ADA causes accumulation of dATP. This metabolite will inhibit the activity of ribonucleotide reductase, the enzyme that reduces ribonucleotides to generate deoxyribonucleotides. The effectiveness of the immune system depends upon lymphocyte proliferation and hence dNTP synthesis. Without functional ribonucleotide reductase, lymphocyte proliferation is inhibited and the immune system is compromised.
Purine nucleoside phosphorylase deficiency
An autosomal recessive disorder involving mutations of the purine nucleoside phosphorylase (PNP) gene. PNP is a key enzyme in the purine salvage pathway. Impairment of this enzyme causes elevated dGTP levels resulting in T-cell toxicity and deficiency.
Reticular dysgenesis
Inability of granulocyte precursors to form granules secondary to mitochondrial adenylate kinase 2 (AK2) malfunction.
Omenn syndrome
The manufacture of immunoglobulins requires recombinase enzymes derived from the recombination activating genes RAG-1 and RAG-2. These enzymes are involved in the first stage of V(D)J recombination, the process by which segments of a B cell or T cell's DNA are rearranged to create a new T cell receptor or B cell receptor (and, in the B cell's case, the template for antibodies).Certain mutations of the RAG-1 or RAG-2 genes prevent V(D)J recombination, causing SCID.
Bare lymphocyte syndrome
In type 1, MHC class I is not expressed on the cell surface. The defect is caused by defective TAP proteins, not the MHC-I protein. In type 2, MHC class II is not expressed on the cell surface of all antigen presenting cells. Autosomal recessive. The MHC-II gene regulatory proteins are what is altered, not the MHC-II protein itself.
JAK3 mutation Janus kinase-3 (JAK3) is an enzyme that mediates transduction downstream of the γc signal. Mutation of its gene causes SCID.
DCLRE1C mutation DCLRE1C "Artemis" is a gene required for DNA repair and V(D)J recombination. A recessive loss-of-function mutation found in the Navajo and Apache population causes SCID and radiation intolerance.
PRKDC mutation PRKDC or DNA-PKcs is a gene required for DNA repair and V(D)J recombination. First found in non-human animals with SCID, a human case was finally found in 2009, followed by another in 2013.
Diagnosis Early diagnosis of SCID is usually difficult due to the need for advanced screening techniques. Several symptoms may indicate a possibility of SCID in a child, such as a family history of infant death, chronic coughs, hyperinflated lungs, and persistent infections. A full blood lymphocyte count is often considered a reliable manner of diagnosing SCID, but higher lymphocyte counts in childhood may influence results. Clinical diagnosis based on genetic defects is also a possible diagnostic procedure that has been implemented in the UK. Some SCID can be detected by sequencing fetal DNA if a known history of the disease exists. Otherwise, SCID is not diagnosed until about six months of age, usually indicated by recurrent infections. The delay in detection is because newborns carry their mothers' antibodies for the first few weeks of life and SCID babies look normal.
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