Complement factor C5 inhibition reduces type 2 responses without affecting group 2 innate lymphoid cells in a house dust mite induced murine asthma model

Abstract

Background Complement factor C5 can either aggravate or attenuate the T-helper type 2 (T H 2) immune response and airway hyperresponsiveness (AHR) in murine models of allergic asthma. The effect of C5 during the effector phase of allergen-induced asthma is ill-defined. Objectives We aimed to determine the effect of C5 blockade during the effector phase on the pulmonary T H 2 response and AHR in a house dust mite (HDM) driven murine asthma model. Methods BALB/c mice were sensitized and challenged repeatedly with HDM via the airways to induce allergic lung inflammation. Sensitized mice received twice weekly injections with a blocking anti-C5 or control antibody 24 h before the first challenge. Results HDM challenge in sensitized mice resulted in elevated C5a levels in bronchoalveolar lavage fluid. Anti-C5 administered to sensitized mice prior to the first HDM challenge prevented this rise in C5a, but did not influence the influx of eosinophils or neutrophils. While anti-C5 did not impact the recruitment of CD4 T cells upon HDM challenge, it reduced the proportion of T H 2 cells recruited to the airways, attenuated IL-4 release by regional lymph nodes restimulated with HDM ex vivo and mitigated the plasma IgE response. Anti-C5 did not affect innate lymphoid cell (ILC) proliferation or group 2 ILC (ILC2) differentiation. Anti-C5 attenuated HDM induced AHR in the absence of an effect on lung histopathology, mucus production or vascular leak. Conclusions Generation of C5a during the effector phase of HDM induced allergic lung inflammation contributes to T H 2 cell differentiation and AHR without impacting ILC2 cells. Electronic supplementary material The online version of this article (10.1186/s12931-019-1136-5) contains supplementary material, which is available to authorized users.

Mechanisms of Allergen Immunotherapy in Allergic Rhinitis

“…Surface CD40 secreted IL-4, IL-13, IL-21 [36,39] Induction of B cell ε-germline transcription, differentiation and affinity maturation and sIgE production [39,41] Decreased circulating numbers [38,83] Restored [74] Antigen presentation [74] Reduced activation (157)…”

“…Moreover, a study on birch pollen-allergic peripheral blood neutrophils demonstrated their capability to fully process and present the allergen subsequently promoting Bet v 1-specific T cell proliferation and cytokine production [ 73 •]. In a HDM-sensitized murine asthma model, inhibition of the complement component C5a was shown to reduce T H 2 infiltration and IL-4 concentration in the lung tissue without affecting their counterparts ILC2s, suggesting it has a role in amplifying type 2 inflammation [ 74 ].…”

The Value of Targeting Complement Components in Asthma

“…In preclinical models, systemic blockade of C5 using the same mAb led to alleviation of bronchoconstriction when ovalbumin induced respiratory inflammation was established [27] and to a reduction on airway resistance without effect on leukocyte numbers in bronchoalveolar lavage fluids in response to house dust mite induced airway hypersensitivity [28]. Joint intranasal and intraperitoneal administrations of C3aR antagonist and anti-C5aR mAb led to a significant reduction of IL-4 in the bronchoalveolar lavage fluids of Aspergillus fumigatus stimulated mice [16].…”

Innate lymphoid cell and adaptive immune cell cross-talk: A talk meant not to forget

“…The inflammatory action of ILC2s in HDM‐induced asthma requires Th2 cells 231 . The complement component C5 increases in BALF during HDM‐induced allergic asthma, which increases airway hyperresponsiveness and Th2 cell differentiation without affecting ILC2s 232 . The anti‐C5a therapy decreases the proportion of Th2 cells recruited to the lungs and attenuates the IL‐4 release without impacting the eosinophil and neutrophil influx 232 .…”

“…The complement component C5 increases in BALF during HDM‐induced allergic asthma, which increases airway hyperresponsiveness and Th2 cell differentiation without affecting ILC2s 232 . The anti‐C5a therapy decreases the proportion of Th2 cells recruited to the lungs and attenuates the IL‐4 release without impacting the eosinophil and neutrophil influx 232 . Due to the expression of IL‐25R or IL17RB and ST2 (IL‐33R), ILC2s produce IL‐13 (increases mucus production) and IL‐5 (recruits eosinophils) in response to IL‐25 and IL‐33, causing allergic asthma 230,233,234 .…”