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