Failure to tolerate gut microbiota transforms immunodeficiency into immunopathology

Here is a paradox for you that many don't even know that it exists: frequently, genetic immunodeficiency (weak immune response) syndromes are associated with immunopathologies (excessive immune response). So how could it be explained?   

New study published in Journal of Experimental Medicine may have some new answers. This study described mouse model of human immunodeficiency syndrome called, Omenn syndrome (after its discoverer) and showed that immunopathology was driven by gut microbiota.

Omenn syndrome is caused by hypomorphic (low active) RAG mutations. Analysis of intestinal tissue from Rag2^R229Q [Omenn] mice revealed pathological infiltration with inflammatory T cell subsets, T_H17 and T_H1.

Adoptive transfer showed that intestinal immunopathology was mediated by Rag2^R229Q mutant T cells.

Interestingly, Rag2^R229Q mouse harbored comparable numbers of Foxp3⁺ CD4⁺ T cells, implying that simple presence of regulatory T cells [generated in Rag2^R229Q mice] was not enough to control tissue inflammation.

Defect of Tregs derived from Rag2^R229Q mice was confirmed in adoptive transfer experiment with WT Tregs.

Besides T cell-driven immunopathology, Rag2^R229Q mice displayed IgA deficiency (failure to properly coat gut microflora). These data pointed to the possibility of microbial translocation causing excessive inflammatory response.

Indeed, antibiotic treatment of Rag2^R229Q mice could reduce intestinal immunopathology.

The role of antibiotic-sensitive gut flora in driving immunopathology in Rag2^R229Q mice was confirmed in adoptive fecal transfer experiments.

In summary, this study suggests the following scenario: hypomorphic RAG defect in Rag2^R229Q mice leads to "narrowing" of TCR and BCR repertoire. This in turn leads to outgrowth of oligoclonal T and B cells in Rag2^R229Q mice (wherein Rag2^R229Q mice contain T and B cells with limited, restricted, deficient TCR and BCR repertoires). Without proper TCR and BCR repertoire diversity, however, Rag2^R229Q mice fails to develop tolerance (IgA and Tregs) to gut flora or commensal microbial antigens present at mucosal surfaces (such as lung, intestine). Repertoire restriction also leads to failure to mount adequate and proper immune response.

David Usharauli

Stimulating CTLA4-Ig mimetic abatacept relieves autoimmune inflammation

It is quite counter-intuitive to believe that human common immune deficiencies are characterized by autoimmune inflammations in various organs. Such observations suggest that what we call immune deficiencies are actually immune disregulations. Immune disregulation would imply that such patient is not able to produce for example sufficient amount of IgA to mucosal antigens but will have excessive response dominated with TNF-alpha that would appear as autoimmune inflammation.

New paper in journal Science provided an example for such immune deficiency, LRBA, and its rescue by abatacept, a drug that mimics natural CTLA4 action.       

The authors described several patients with deficiency in LRBA (lipopolysaccharide responsive beige-like anchor protein) expression and showing signs of autoimmune inflammation.

The authors found that these LRBA deficient patients had reduced CTLA4 protein level (but not other molecules such as CD40L, CD107a), a phenotype that could be reproduced in healthy cells with LRBA siRNA. 

Interestingly, chloroquine, a drug that reduces lysosomal degradation could improve CTLA4 expression in cells from LRBA patients implying that excessive degradation of CTLA4 protein in LRBA deficient patients.

Finally, the authors showed that CTLA4 and LRBA colocalize in endosomal vesicles, providing a mechanistic explanation for low levels of CTLA4 protein in LRBA patients.

In summary, these results provide a rationale for use of stimulating CTLA4-Ig mimetic in treatment of LRBA deficiency.

David Usharauli