A more relevant re-wording of this question would be ‘Can the immune system compensate for an inherited defect in B cell development?‘, and the answer is it depends on the specific mutation (illustrative example below).
As well, since there’s no overlap in fundamental functionality between B and gamma-delta T cells, increase in the latter cannot compensate for B cell deficiency anyway. Hypothetically, let’s say gamma-delta T cells increase commensurate to a particular inherited B cell development defect. So what? Can gamma-delta T cells secrete antibodies? No. Thus, since gamma-delta T cells can’t recapitulate that essential function of B cells, any hypothetical increase in their numbers can’t help plug the unique gap in immune function created by a B cell defect. And this applies to any other compensatory mechanism because it wouldn’t be able to overcome lack of B cell-derived antibodies.
In inherited defects in B cell development, what does the compensatory capacity of the immune system depend on?
- On the severity of B cell development block that mutations associated with those defects impose. Outcomes of certain mutations are milder than others, i.e., different mutations in the same gene impair B cell development to different degrees. Thus, it’s possible a few or enough B cells might make it through developmental check-points, at least enough to prevent fulminant immunodeficiency (illustrative example below). That’s only one part of it though.
- The other part stems from the integrated make-up of the immune system in that B cell development and function can also be affected indirectly by mutations that are non-B cell specific, i.e., by mutations in genes involved in earlier stages of morphogenesis or hematopoiesis.
- In the former, multiple physiological systems including the immune are affected.
- In the latter, multiple components of the immune system including B cells are affected.
- In other words, inherited B cell development defects can stem from either B cell-specific or non-specific mutations (see tables and figure below from 1).
Thus, whatever compensatory mechanisms might develop in response to an inherited B cell defect would be unique to each specific mutation.
- Predictably, the clinical features of immunodeficiency mutations in genes involved in morphogenesis or hematopoiesis are broader than those of B cell-specific mutations.
- However, the main biological features, i.e., outcomes, as they pertain to B cell functions overlap more or less fully.
BTK ,, offers an illustrative example for why generalization about compensatory mechanisms is difficult with mutations associated with B cell development defects
BTK mutations account for ~85% of patients with, i.e., tremendously reduced levels of circulating antibodies, primarily IgGs (2). However, some BTK mutations don’t affect protein expression. As a result, such patients have low levels of both circulating B cell and antibodies (3, 4).
Situation is further complicated by the fact that phenotype for the same mutation can be dramatically different as observed in the case of a sibling pair with the exact same T134→C mutation in the translation initiation ATG of BTK (5). The first diagnosed member of the family, the younger brother, lacked detectable circulating antibodies and B cells, and had recurrent infections while the older with the exact same mutation had normal levels of IgM and IgG, and very few infections. Complete sequencing of the BTK gene in both brothers revealed no other mutations. What gives?
- For one, 1996 technology may have missed other mutations in other genes in the younger brother.
- For another, though the authors don’t speculate about it, the siblings may have been differentially microchimeric. Feto-Maternal microchimerism is the process of bi-directional transfer of cells between mother and fetus such that each ends up with some cells of the other. In other words, randomly, the older brother may have ended up with substantially greater maternal cells in utero, cells presumably normal for the BTK gene, that then expanded in his body to generate enough B cells and antibodies to maintain near-normal B cell immunity. If such maternally-derived B cells remained sequestered in bone marrow or spleen, etc., but absent in circulating blood, they could be easily missed. They could also be easily missed if they were present in circulation but at very low percentages, such as <1 in a million. Molecular technologies available circa.1996 may have been too insensitive to detect them. Pure speculation but it may explain the discordant data between two siblings with the exact same mutation.
Since non-B cell-specific mutations are upstream of B cell development, leading to defects in several cell types including B cells (see 2nd figure above), the range of possible phenotypes is that much broader (6, 7, 8, 9), again making generalizations nigh impossible.
1. Chapter 25. Immune Deficiencies Caused by B Cell Defects. pp. 463-479. Anne Durandy , Sven Kracker and Alain Fischer. In Honjo, Tasuku, et al., eds. Molecular biology of B cells. Elsevier, 2014.
2. Vetrie, David, et al. “The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases.” (1993): 226-233.
3. López-Granados, Eduardo, et al. “A genotype-phenotype correlation study in a group of 54 patients with X-linked agammaglobulinemia.” Journal of allergy and clinical immunology 116.3 (2005): 690-697.
4. Conley, Mary Ellen, et al. “Primary B cell immunodeficiencies: comparisons and contrasts.” Annual review of immunology 27 (2009): 199-227.
5. Bykowsky, Michael J., et al. “Discordant phenotype in siblings with X-linked agammaglobulinemia.” American journal of human genetics 58.3 (1996): 477.
6. Lagresle-Peyrou, Chantal, et al. “Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness.” Nature genetics 41.1 (2009): 106-111.
7. Pannicke, Ulrich, et al. “Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2.” Nature genetics 41.1 (2009): 101-105.
8. Moshous, Despina, et al. “Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis.” Journal of Clinical Investigation 111.3 (2003): 381.
9. Dickinson, Rachel Emma, et al. “Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency.” Blood 118.10 (2011): 2656-2658.