Gut IgA are naturally microbiota-reactive and polyreactive (cross-reactive)

Gut immune system naturally produces large quantities of IgA, an antibody isotype frequently found at mucosal surfaces. Since these IgA antibodies are found in mice in absence of immunization and infection they were dubbed natural and were thought to be specific for microbiota or food antigens. However a formal proof for such conclusions were lacking. 

This week journal Science published a new study from Bendelac's Lab to show that these naturally occurring IgA antibodies are present even in mice devoid of microbiota or food antigens.

In this study the authors analyzed specificity of IgA antibodies using single cell analysis. Interestingly, IgA bound to some but not to all microbiota species. 

Furthermore, most of gut IgA bound to all kind of microbiota-derived components showing a broad polyreactivity (cross-reactivity). Separate test using broadly-neutralizing antibody (bnAb) panel directed against influenza stalk region showed co-staining for microbiota coated by IgA. 

Interestingly, unlike other tissues, numbers of IgA+ plasma cells in small intestine were not reduced in germ-free mice.

Even more surprising, numbers of IgA+ plasma cells in small intestine were not reduced in germ-free mice fed antigen-free diet (amino acid diet).

These results suggest that 

(a) not all microbiota species are targeted by IgA that by itself requires further studies to understand why it is the case.

(b) natural, microbiota-reactive IgA in small intestine develop in absence of exogenous antigenic stimulation that suggests that such specificities are inherited and accumulate spontaneously. 

(c) selection of broadly neutralizing antibodies against viruses could be influenced by microbiota-derived antigens (polyreativity, cross-reactivity)  

posted by David Usharauli

Tolerance to insulin is maintained by Foxp3+ Tregs

A new study in Journal of Immunology suggests that tolerance to insulin is maintained by Foxp3+ Tregs rather than by deletion of insulin-reactive T cell clones. 

 

Here, the authors reconstituted mice with T cells on scid background transduced either with high (4-8) or low (12-4.1) affinity TCR specific for native insulin peptide (insulin epitope B:9–23). In addition, each of TCR construct were fused with either native insulin (INS) or modified insulin carrying super-affinity peptide (R22E). All mice expressing either INS or R22E but not irrelevant HEL were protected from developing diabetes.

The authors showed that while R22E deleted developing insulin-specific T cell clones in the thymus, native INS did not.

In fact, the authors showed that if the T cells also lacked Foxp3 molecule (scid-scurfy), then protection against diabetes was lost in mice exposed to native INS.

This study could be interpreted to show that with the exception of  epitopes which are able to delete (purge) cognate T cell clones in the thymus, tolerance to self in the periphery is maintained by thymic-derived Foxp3+ Tregs.

posted by David Usharauli 





    

It is really hard to replicate human autoimmune diseases in mice

A new study in PNAS highlights the challenges scientists face when trying to reproduce human diseases in mice.  

Here, the authors tried to reproduce human type I diabetes by creating humanized mice by transplantation of HLA-DQ8+ human fetal thymus and CD34+ stem cells into immunodeficient mice (to recreate human immune system in mouse) followed by transfer of autologous [hu-mice]-derived HLA-DQ8/insulin-B:9–23 specific TCR transduced human CD4+ T cells and followed by two successive low doses of streptozotocin (a chemical to damage islet β cells and release auto-antigen).

However, even these steps were not enough to induce diabetes in hu-mice. Only immunization with insulin B:9–23 peptide + adjuvant (HLA class II-restricted T-cell response to InsB:9–23 peptide is highly associated with T1D in humans) in addition to above mentioned "conditioning" were able to induce diabetes in hu-mice.

No one really knows how autoimmune diseases are initiated in humans and these study shows that it is really hard to "reproduce" it in mice. Of course, it is not known what factors could play the role of "streptozotocin" and "B:9–23 peptide immunization" in natural context in humans. 

posted by David Usharauli

Loss of microbiota depletes cross-reactive Foxp3+ Tregs leading to selective immunopathologies

Check out our follow-up manuscript in PeerJ Preprints that provides a brief guide to SPIRAL, a novel interpretive framework that demonstrates the central role of microbiota-Treg axis in the initiation of immune disorders.

Kamala T, Usharauli D. (2017)

 

Loss of microbiota depletes cross-reactive Foxp3+ Tregs leading to selective immunopathologies.

PeerJ Preprints 5:e3237v1

https://doi.org/10.7287/peerj.preprints.3237v1

 

The 'Hygiene hypothesis', a cornerstone model to account for the role of exogenous pathogens and later of endogenous microbiota in immune disorders, is currently presumed to operate at the innate immunity and metabolite levels to properly 'educate' the immune system. Doing so however fails to satisfactorily account for the antigen-specific nature of such disorders. SPIRAL is a novel interpretive framework that resolves this dilemma. It represents the periodic table of cross-reactive Foxp3+ regulatory T cell (Treg) epitopes selected from commensal microbiota over evolutionary time to mediate self-nonself discrimination and effector class regulation. Here, we utilize the SPIRAL's predictive power to provide a mechanistic antigen-specific basis for the initiation of allergies and autoimmune diseases as well as for the failure to mount effective anti-tumor and vaccine responses through selective loss of microbiota and corresponding cross-reactive Foxp3+ Tregs.



 

IL-27 protects against autoimmunity through its effect on Tregs

IL-27 is a heterodimeric cytokine composed of the p28 and Ebi3 subunits produced by APCs. It binds to IL-27 receptors (IL 27Rα:gp130) expressed on several cell types, including T lymphocytes. IL-27Ra-/- mice are shown to be highly susceptible to experimental autoimmune encephalomyelitis (EAE), a mouse of human MS. Earlier studies suggested that effect of IL-27 is mediated through its suppression of pro-inflammatory Th17 cells and generation of anti-inflammatory IL-10 producing Tr1 cells.

A new study in PNAS, however, showed that mice with Treg-specific IL-27Rα-deficiency displayed similar susceptibility to EAE as total IL-27Rα-deficient mice pointing to the role of Tregs in mediating IL-27 effect on EAE.

Compared to WT mice, mice with Treg-selective IL-27Rα-deficiency were not able to recover from EAE, a similar trend seen in total IL-27Rα-deficient mice. IL-10 levels were not different between WT and KO littermates.

Furthermore, in contrast to WT mice, injection of "therapeutic" dosage of IL-27 had no effect on EAE dynamics in Treg-selective IL-27Rα-deficient mice. Nor did antibody-blockade of IL-10 diminish effect of IL-27 on WT mice.

These results suggest that in addition to other cell types or even in contrast to other studies, the role of IL-27 in controlling severity of EAE could be solely mediated through its effect on Foxp3+ Tregs.

posted by David Usharauli