CD11b suppresses Th17 response in collagen-induced arthritis
B6 mice have the wrong MHC haplotype for collagen-induced arthritis --> resistant to developing arthritis upon collagen challenge.
CD11bko B6 mice do develop arthritis upon collagen challenge. *How does severity compare to e.g. Balb/c mice?
Elevated Th17 response in challenged CD11bko mice: - increased %CD4 producing IL-17 (PMA/iono stimulation ex vivo) - increased IL-17 in ‘joint cell lysates’ (synovium?) - increased serum IL-6
Reduced immune regulation: - decreased IL-10 producing B cells (splenocytes, LPS stimulation) - decreased Tregs in draining lymph nodes
IL-6 receptor blocking Ab (15A7) - in vitro: reduced Th17 differentiation (presumed IL-6/IL-17 positive feedback loop) - in vivo: reduced arthritis severity, reduced Th17 cell, increased %Tregs to WT levels
CD11b+ DC clonal line adoptive transfer - reduced arthritis severity - cells shown to produce less IL-6 upon CD11b binding with antibody
FIg. 4
INTERESTING:
Role for DC-derived IL-6 and a proposed mechanism to control this production through CD11b (albeit very preliminary).
Problems:
* Why would ADDING CD11b+ DCs which produce LESS IL-6 affect the pre-existing CD11b- DCs as a whole? Does it change serum IL-6 or IL-17?
* Does addition of CD11b into the system affect Treg numbers? Is it just a homeostatic reciprocal relationship with Th17, a negative feedback to IL-6, or does CD11b affect Treg expansion directly?
* What is the purpose of CD11b expression on other (non-DC) myeloid cells? How do they affect inflammation?
* How would anti-CD11b antibodies affect disease progression in non-resistant mice? Can we stimulate Th-17 suppression by binding CD11b?
Source: Stevanin, Mathias (Ehirchiou, Driss) 2017 Eur. J. Immunol. CD11b Regulates the Treg/Th17 balance in murine arthritis via IL-6 http://doi.wiley.com/10.1002/eji.201646565