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