Severe Immunodeficiencies: Bone Marrow Transplantation or Gene Therapy?

Sara M. Mariani, MD, PhD

In This Article


Immune deficiencies occur infrequently in the immune system, but when they do, they are generally associated with severe manifestations owing to the lack of protections from life-threatening infections. As most are linked to a genetic defect, they are present at birth. A timely and correct diagnosis is of critical importance since routine vaccinations of these infants with attenuated but viable vaccinal strains may have dire consequences, including poliomyelitis, polioencephalitis, giant cell pneumonia (measles vaccine), or fatal progressive vaccinia. Still, a majority of cases are diagnosed only around the sixth or seventh month of life, when infective complications may have already severely compromised the very young patients.[1]

Boys are at a higher risk than girls, with a sex ratio of 3:1 owing to the relatively higher incidence within this group of X-linked syndromes. Conventional treatment is based on transplantation of HLA-identical bone marrow from siblings, HLA-haploidentical bone marrow from family members, or HLA-matched unrelated donors.

Immune deficiencies are generally classified depending on the arm of the immune system that is impaired. Accordingly, there are T-cell immunodeficiencies, B-cell immunodeficiencies, combined immunodeficiencies in which both T and B compartments are compromised (eg, X-linked severe combined immunodeficiency [SCID-X]), and other cases involving defects in phagocytic cells (eg, leukocyte adhesion deficiency [LAD]) and/or natural killer (NK) cells ( Table 1 ).[1,2]

According to the molecular defect,[2,3] T-cell immunodeficiency syndromes can be divided into 4 main groups. A defective adenosine deaminase (ADA) enzyme, involved in purine phosphorylation, leads to apoptosis in precursor T cells by deoxynucleotides; a defective RAG1/2 gene, involved in T-cell receptor (TCR) and B-cell receptor (BCR) rearrangement, leads to generation of abnormal T and B cells; defects in the TCR-associated complex CD3, in the surface molecule CD45, and in ZAP70 all contribute to expansion of defective T-cell precursors.

In addition, abnormalities in the gamma chain, in the IL-7 receptor alpha, and in JAK3 kinase all contribute to defective signaling of gamma-chain dependent cytokines that include interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21.[1] The outcome is a nonfunctional or only partially functional immune system that cannot rely on the generation, activation, and expansion of sufficient numbers of normal T, B, and/or NK cells ( Table 2 ).


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