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As of 2017, at least 150 different Primary immunodeficiency – Wikipedia (PIDs) have been reported in the literature with mutations in >120 genes implicated therein (1).

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 Severe combined immunodeficiency – Wikipedia (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 David Vetter – Wikipedia 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 from 2 and 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 (Muller’s morphs – Wikipedia).
  • Degree of feto-maternal chimerism (Chimera (genetics) – Wikipedia), 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 an Omenn syndrome – Wikipedia patient who survived for 6 years without Hematopoietic stem cell transplantation – Wikipedia (HSCT) and yet was found to carry Missense mutation – Wikipedia in both alleles of the RAG1 (Recombination-activating gene – Wikipedia), one of two genes necessary for T and B cell development (4). 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 Graft-versus-host disease – Wikipedia (GVHD).

Robert A. Good – Wikipedia, 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 Gene therapy – Wikipedia 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% (6). However, HSCT is still no panacea since patients remain at risk for infection complications and Graft-versus-host disease – Wikipedia (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. http://content.schweitzer-online…

2. http://www.newbornscreening.info…

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. http://www.bloodjournal.org/cont…

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. https://www.researchgate.net/pro…