B-lymphocytes as Key Players in Chemical-Induced Asthma

Abstract

T-lymphocytes and B-lymphocytes are key players in allergic asthma, with B-lymphocytes producing antigen-specific immunoglobulins E (IgE). We used a mouse model of chemical-induced asthma and transferred B-lymphocytes from sensitized animals into naïve wild type mice, B-lymphocyte knock-out (B-KO) mice or severe combined immunodeficiency (SCID) mice. On days 1 and 8, BALB/c mice were dermally sensitized with 0.3% toluene diisocyanate (TDI) (20µl/ear). On day 15, mice were euthanized and the auricular lymph nodes isolated. B-lymphocytes (CD19+) were separated from the whole cell suspension and 175,000 cells were injected in the tail vein of naïve wild type, B-KO or SCID mice. Three days later, the mice received a single oropharyngeal challenge with 0.01% TDI (20µl) or vehicle (acetone/olive oil (AOO)) (controls). Airway reactivity to methacholine and total and differential cell counts in the bronchoalveolar lavage (BAL) fluid were measured 24 hours after challenge. B-lymphocytes of AOO or TDI-sensitized mice were characterized for the expression of surface markers and production of cytokines. We found that transfer of B-cells obtained from mice dermally sensitized to toluene diisocyanate (TDI) into naïve wild type mice, B-KO mice or SCID mice led, within three days, to an acute asthma-like phenotype after an airway challenge with TDI. This response was specific and independent of IgE. These B-lymphocytes showed antigen presenting capacities (CD80/CD86 and CD40) and consisted of B effector (Be)2- (IL-4) and Be1-lymphocytes (IFN-γ). The transferred B-lymphocytes were visualized near large airways, 24 hours after TDI challenge. Thus, B-lymphocytes can provoke an asthmatic response without the action of T-lymphocytes and without major involvement of IgE.

Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms

“…the mouse chitinase YM-1 (Wisnewski et al, 2015). It has also been suggested that B1-lymphocytes, transferred from dermally TDI-sensitized mice, contribute to an innate-like rapid defense upon a TDI challenge in recipient mice (De Vooght et al, 2013). How these previous studies are related to our study remains to be shown.…”

Neuro-immune interactions in chemical-induced airway hyperreactivity

“…Based on previous evidence [49], a role for allergen cross-linking with IgEs seems unlikely. However, there is no doubt that the adaptive immune system is also involved, both because the induction of AHR relies on an antigen-specific challenge and because our model is dependent on properly functioning lymphocytes, as shown here with Rag2 knockout mice and previously in severe combined immunodeficiency disease mice [11] and in adoptive lymphocyte transfer experiments [33,34].…”

“…Taken together, the above results allowed us to conclude, first, that TRPA and TRPV1 are necessary, but not sufficient, to induce AHR in TDI-sensitised animals and, second, that a specific adaptive immune response is involved and necessary to induce AHR in such TDI-sensitised animals. Previous research on our mouse model has shown that lymphocytes are crucially involved in the development of TDI-induced asthma in Balb/c mice [33,34]. To determine whether this is also the case in the current model of chemical-induced AHR, using C57Bl/6 mice, we used Rag2 knockout mice, lacking mature lymphocytes.…”

Autotaxin signaling, purinergic receptors and lung damage

“…The observation that diisocyanates induce skin contact hypersensitivity, and that skin exposure to TDI is employed in experimental models to induce sensitization [32] , is of interest for us. In unpublished work we note that many genes/proteins downstream of ATX signaling are the same as those induced by test substances in cell-based tests for skin sensitizers [33] .…”