Gut-specific eosinophils suppress IL-17 production by antagonizing IL-1 signaling

Prior to discovery of Toll-like receptors (TLR) in late 90s, immunology was dominated by concepts involving adaptive immune cells. However, for past 15 years it has become evident that innate immune cells of "all shapes and forms that exist out there" are equal partners with T and B cells and frequently provide instructions and actually control the magnitude and directions of adaptive immune response. For example, development of successful, next generation vaccines would require incorporation of these new concepts. 

It seems innate immune system is even more complex and unpredictable than T or B cells are. For instance, this week Journal of Experimental Medicine published new study wherein the authors reported that eosinophils, a cell population usually implicated in allergy and anti-helminth response, suppressed Th17 cells by antagonizing IL-1 signaling.

First, the authors observed that Th17 cells in ΔdblGATA-1 mice [which lack eosinophil-lineage cells] were significantly increased in the small intestine, but not in the spleen or mesenteric LNs (MLNs).

In vitro generation of Th17 cells were inhibited by presence of small intestinal eosinophils. 

Functional profiling revealed that small intestinal eosinophils secreted high amount of IL-1 receptor antagonist (IL-1Ra), which competes with IL-1β for receptor binding (IL-1 signaling is involved in Th17 development).

Interestingly, eosinophils were the major producers of IL-1Ra in small intestine, since no IL-1Ra was detected in small intestinal tissue from ΔdblGATA-1 mice. Of note, eosinophils from blood or bone marrow produced little or no IL-1Ra. 

In addition, the authors showed that small intestinal eosinophils derived from MyD88-KO or Germ Free (GF) mice produced WT-level IL-1Ra, suggesting its independence from gut flora or major TLR signaling.

Role of IL-1Ra in eosinophil mediated Th17 suppression in small intestine was confirmed in experiments with eosinophils derived from IL-1Ra-KO mice.   

In summary, this study showed that small intestine harbors specialized eosinophils secreting high amount of IL-1Ra and suppressing steady-state development of Th17. 

David Usharauli

Depletion of "hybrid" B cells could explain benefits of anti-CD20 immunotherapy in MS patients

Multiple Sclerosis (MS) is believed to be an autoimmune disease. During MS, the patient's own immune cells attack peripheral nerves' myelin sheath disrupting proper signal transmission. In mouse model of MS, called experimental autoimmune encephalomyelitis (EAE), several myelin proteins have been identified as such targets (such as MBP and MOG). 

While self-specific T cells are widely thought to play a pathogenic role in MS progression, clinical trials revealed surprising benefits of B cell depletion in MS. Mechanism is unknown.    

Now new paper is Science Translational Medicine provided initial data suggesting that depletion of pro-inflammatory GM-CSF secreting B cell subset could explain the clinical benefits of anti-CD20 antibody therapy in MS.

First, the authors showed that activated peripheral B cells from healthy donors express pro-inflammatory cytokine GM-CSF. Interestingly, this B cell population does not overlap with B cell population expressing anti-inflammatory cytokine IL-10.

Next, the authors showed that activated B cells from MS patients tend to express more GM-CSF compared to B cells from healthy donors.

In vitro co-culture of B cells and macrophages revealed that B cell-derived GM-CSF contributed to Th1-type macrophage polarization.

More complex co-culture experiments showed that macrophages derived from MS patients soon after B cell depletion produced less of pro-inflammatory cytokine IL-12p40.

And more importantly, this tendency was maintained even after 1 year of B cell depletion, even though new B cell came back by this time.

This points to a re-configuration of cytokine network in anti-CD20 antibody treated MS patients such as reversal of B cell-derived GM-CSF/IL-10 ratio.

In summary, this study provides additional clues why anti-CD20 antibody depletion might benefit MS patients. Antibody-independent function of B cells is a novel concept [and not widely known or accepted]. One of the reasons for this resistance is lack or inadequate knowledge of B cell receptor specificity of such specialized B cell subset. We need to go one step further and connect the dots between BCR specificity or other innate receptors and B cell's "hybrid" function. Only by developing this biological "framework" can we fully understand the role B cells play in health or diseases.

If you are interesting in science of MS, I will recommend a book by Susan Quinn's "Human Trials: Scientists, Investors, And Patients In The Quest For A Cure" (2001).

David Usharauli