IL-33 → MyD88 pathway drives type II immunity in female genital mucosa

Type II immunity underlies several types of immune conditions such as asthma, allergy or response to parasitic helminths. It is not yet fully clear how type II immunity contributes to host's defenses. At this stage scientific inquiry is mostly focused on uncovering cellular and molecular mechanism behind type II immunity.

For example, PNAS has published new paper supporting role of locally produced IL-33 in promoting type II immunity.

For these experiments the authors have used papain, a well established experimental type II inducer protease. As reported before, papain required enzymatic activity for its type II response.

Papain application to female vaginal mucosa induced IL-33, a member of IL-1 family implicated in type II immunity.

Indeed, IL-33 deficient mice showed reduced secretion of components of type II immunity (IL-4, IgE).

Interestingly, type II immunity in response to papain in female genital tract depended on IRF4⁺ CD11c⁺ dendritic cells but it was independent of basophils and eosinophils.

Furthermore, type II immunity in response to papain application to female vaginal tissue depended on MyD88 signaling.  

In summary, this study confirms the role of IL-33 in type II immunity.

David Usharauli

Group 3 innate lymphoid cells express RET and respond to glia-neuron network

Few days back journal Nature reported very interesting study from Portugal. In there, the authors showed that intestine glial cells (which are neuron-satellites expressing the glial fibrillary acidic protein (GFAP) signal local innate ILC3 cells via tyrosine kinase receptor RET.

First, they showed that ILC3 express RET that receives signals from glial-derived neurotrophic factor family ligands.

Second, mice lacking RET specifically in ILC3 cells, Rorgt-CreRet fl/fl (RetΔ), displayed marked reduction of IL-22, a cytokine involved in epithelial homeostasis.

Third, RetΔ mice showed heightened T cell-independent susceptibility to chemical [DSS]-induced colitis and to intestinal infection with the attaching and effacing bacteria Citrobacter rodentium.

Fourth, it showed that glial cells (RFP, red) are located in close proximity to ILC3 cells (GFP, green).

Fifth, mice lacking MyD88 specifically in glial cells, Gfap-CreMyd88Δ mice, also displayed heightened susceptibility to DSS colitis, indicating cross-talk between TLR signaling, glial-derived RET ligands and IL-22 produced by ILC3.

In summary, this study revealed existence of a complex network of neuro-glial-immune interactions that result in optimal defense against intestinal irritation. 

David Usharauli

Tissue-specific immunopathology initiated by microbiota

Frequently, autoimmune disorders come in combinations. For example, a subset of human patients with type 1 diabetes (T1D) develop autoimmune polyglandular syndrome (APS) that depending on type (APS types 1-4) involves other tissues such as thyroid, adrenal, submandibular, and lacrimal glands. 

New study published in Journal of Immunology and conducted in autoimmune-prone mouse strain, NOD, showed that presence of microbiota modifies immunopathology in a tissue-specific manner.

For instance, female NOD mice devoid of microbiota (GF NOD mice) showed reduced pathology in salivary glands (sialitis) but as expected no change or worsening of pathology in pancreas (insulitis).  

Similarly, MyD88 deficiency completely abolished sialitis in both WT and GF female mice but it couldn't rescue insulitis phenotype on GF background (as reported prevously).

In summary, this short study suggests that microbiota → MyD88 pathways directly influence development of sialitis, while for insulitis (and diabetes development) microbiota/MyD88 pathways diverge.

David Usharauli

Microbiota drives airway IgA class switch via DC-derived TGF-β

IgA is a class of antibody specifically designed for protection and tolerance at mucosal surfaces. Since vast majority of antigens [both infectious or noninfectious nature] interact with mucosal tissues, knowledge of signals controlling IgA production would help to develop more robust vaccination protocols.

So I decided to review this paper from Journal of Experimental Medicine where the authors have analysed IgA promoting capacity of lung DCs.

Most experiments were done ex vivo on sorted DC and B cells. Most cultures included α-IgM and α-CD40 antibody to "mimic" T-dependent Ab production. First, the authors noticed that lung CD103⁺ and CD24⁺ DCs (but not CD64⁺ Mφ) could provide necessary signals to naive B cells to switch to IgA (similar to MLN DCs).

Next, the authors found that this IgA switch capacity of lung CD103⁺ and CD24⁺ DCs  were dependent of their ability to produce TGF-β and Retinoic Acid (Vitamin A metabolites).

Next, the authors found that microbiota influenced lung DCs capacity to drive IgA switch in naive B cells [though it is not clear whether it is airway or gut microbiota that does it].

Follow up experiments revealed that MyD88/TRIF signaling [most likely from microbiota] in lung DC cells increased TGF-β production and their IgA switch potential.

Finally, the authors showed that i.n (intra-nasal) or i.t. (intra-tracheal) immunization [but not s.c. immunization] with small dose of cholera toxin (CT) provided system-wide protection against cholera toxin re-challenge, implying body-wide re-distribution of airway primed CT-specific B cells.

In summary, this study showed the role of microbiota/MyD88/TGF-β/CD103⁺ DCs axis in driving airway mucosal IgA class switch.

David Usharauli

Gut microbiota controls clinical severity of sickle-cell disease via neutrophil "ageing"

Our knowledge of the role of gut microbiome in human health and disease is expanding on a daily basis.

For example, just few days ago journal Nature published a study where the authors showed that in mouse model of sickle-cell disease (Hba^-/- Hbb ^-/-) the presence gut microbiome influenced clinical severity via neutrophil "ageing".      

In sickle-cell disease, neutrophils expressing Mac-1 capture sickle red blood cells that leads to vaso-occlusion and tissue damage. It appears that "ageing", or mature neutrophils, defined as CD62L^low CXCR4^high population, express more Mac-1 and those neutrophils can capture more RBCs per cell basis (that contributes to development of sickle-cell disease symptoms). [the authors does not discuss the difference between "ageing", "senescence" and "mature" neutrophils].

Next, the authors showed that germ-free mice or antibiotic treated mice have reduced number of "ageing" neutrophils.

Using BM chimera, the authors found that absence of MyD88 adaptor molecule or TLR4 receptor also mimicked the effect of antibiotic treatment on neutrophil "ageing".

Finally, the authors found that antibiotic treatment of sickle-cell disease model mice reduced number of circulating "ageing" Mac-1 expressing neutrophils and showed reduction in tissue damage.

In summary, this study proposed a novel therapeutic path for treatment for sickle-cell disease by modulation of gut microbiota and neutrophil maturation ("ageing").

David Usharauli