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.