Bruton’s Tyrosine Kinase Is Not Essential for B Cell Survival beyond Early Developmental Stages

Abstract

Bruton's tyrosine kinase (Btk) is a crucial regulator of B cell signaling and is a therapeutic target for lymphoma and autoimmune disease. BTK-deficient patients suffer from humoral immunodeficiency, as their B cells fail to progress beyond the bone marrow. However, the role of Btk in fully developed, mature peripheral B cells is not well understood. Analysis using BTK inhibitors is complicated by suboptimal inhibition, off-target effects, or failure to eliminate BTK's adaptor function. Therefore a mouse model was developed and used to excise after B cell populations were established. Mice lacking from birth are known to have reduced follicular (FO) compartments, with expanded transitional populations, suggesting a block in development. In adult mice, excision did not reduce FO B cells, which persisted for weeks. Autoimmune-prone B1 cells also survived conditional excision, contrasting their near absence in global -deficient mice. Therefore, Btk supports BCR signaling during selection into the FO and B1 compartments, but is not needed to maintain these cell populations. B1-related natural IgM levels remained normal, contrasting global deficiency, but B cell proliferation and T-independent type II immunization responses were blunted. Thus, B cells have nuanced signaling responses that are differentially regulated by Btk for development, survival, and function. These findings raise the possibility that Btk may also be expendable for survival of mature human B cells, therefore requiring prolonged dosing to be effective, and that success of BTK inhibitors may depend in part on off-target effects.

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

“…The differences in TD immune responses between IPMK cKO and Btk-deficient mice might be, at least in part, due to their difference in B cell development. These differences in TD immune responses between the two mice is in line with the results that inducible Btk deletion in mature B cells, in which B cell development is normal, results in a milder phenotype in immune responses than that by Btk deletion in the whole body (46).…”

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

“…In diseased NZB/W mice, marginal zone B cells were increased, as well, but their numbers were not affected significantly by evobrutinib treatment. The lack of effect of evobrutinib on marginal zone B cells is in line with the observation that an inducible deletion of BTK in adult animals does not affect these cells (69). In contrast, published data for the covalent reversible BTK inhibitor PF-06260112 showed an 11-fold and 20-fold reduction of marginal zone and B1 B cells, respectively, in a nonaccelerated NZB/W lupus model.…”

“…However, in these mice, BTK is absent throughout development. Experiments in which BTK was knocked down after B cell subsets were established showed that follicular B cell numbers dropped within 5 wk of BTK depletion to the low levels observed in global BTK knockouts (69). The fact that evobrutinib normalized follicular B cell numbers without signs of depletion may be explained by the remaining scaffolding function of BTK, even when its kinase activity is blocked by evobrutinib.…”

“…Certain B cell subsets, such as B1 and An1 cells, have been described as autoimmune-prone. Whereas B1 cells did not depend on BTK, An1 cells, sometimes termed T3, are reduced in global and conditional BTK-deficient mice (69,76). Based on these published data, it will be interesting to determine potential effects of evobrutinib or other BTK inhibitors on An1/T3 B cell subsets in future studies.…”

“…Inhibition of additional B cell functions such as Ag presentation cannot be excluded either. A better understanding of the processes involved may be possible using tissue-specific and induced BTK-deficient models in the future (69).…”