As of 2017, at least 150 different(PIDs) have been reported in the literature with mutations in >120 genes implicated therein ( ).
For the innate immune system to sustain on its own means having a non-functioning adaptive immune system, i.e., to have missing or non-functioning T and/or B cells.
Rather than our innate immune system being able to sustain health in the absence of the adaptive immune system, famous examples of the so-called Bubble boy disease or(SCID) instead show that the condition is instead unsustainable, at least without intensive, expensive, high-tech medical intervention. Until fairly recently, despite such intensive care, a famous example such as still died by 12 years of age.
T-B-SCID (missing/non-functioning T and B cells) is one of the most severe PIDs (see below fromand 3)
- Inherited as either X-linked Recessive or Autosomal Recessive, depending on whether or not the gene(s) involved is/are on the X chromosome.
- Its hallmarks are failure to thrive, and recurrent, serious and/or life-threatening infections.
As with many other immunodeficiencies, the degree of severity of the T-B-SCID is directly related to
- Nature of the underlying genetic defect(s): degree of deletion or nature of mutation ( ).
- Degree of feto-maternal chimerism ( ), i.e., degree to which functional T and/or B cells from the mother transferred to the baby in utero are able to survive and function, and for how long.
- Unpredictable gene-environment interactions.
Such unpredictable mitigating factors being in play means even though without intensive medical intervention, severe T-B-SCIDs are nearly always fatal, it cannot always be predicted when the condition tips past the point of no return. Consider for example anpatient who survived for 6 years without (HSCT) and yet was found to carry in both alleles of the RAG1 ( ), one of two genes necessary for T and B cell development ( ). Patient turned out to have maternal-derived circulating T cells.
However, rather than a savior in all instances, such feto-maternal chimerism in T-B-SCIDs can also turn out to be quite the double-edged sword since the maternal-derived cells could just as often end up attacking the recipient infant’s cells and tissues, a form of(GVHD).
, considered one of the founders of modern immunology, pioneered the use of bone marrow transplants for treating PIDs such as T-B-SCID. Better known these days as HSCT, it’s the treatment of choice while is also being intensively explored. While back in 1977, HSCT was successful in only 14 of 69 transplanted patients (~20%) (5), by 2004, this had climbed to 63 to 84% ( ). However, HSCT is still no panacea since patients remain at risk for infection complications and (GVHD) (see below from 3).
1. Le Deist, Françoise, et al. “Combined T-and B-Cell Immunodeficiencies.” Primary immunodeficiency diseases. Springer Berlin Heidelberg, 2017. 83-182.
3. Buckley, Rebecca H. “A historical review of bone marrow transplantation for immunodeficiencies.” Journal of allergy and clinical immunology 113.4 (2004): 793.
4. Kumaki, Satoru, et al. “Identification of anti–herpes simplex virus antibody–producing B cells in a patient with an atypical RAG1 immunodeficiency.” Blood 98.5 (2001): 1464-1468.
5. Bortin, Mortimer M., and Alfred A. Rimm. “Severe combined immunodeficiency disease: characterization of the disease and results of transplantation.” Jama 238.7 (1977): 591-600.
6. Buckley, Rebecca H. “Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution.” Annu. Rev. Immunol. 22 (2004): 625-655.