CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency

Abstract

CTLA-4 is a critical inhibitory “checkpoint” molecule of immune activation. Several recent reports have described patients with immune dysregulation and lymphoproliferative disease resulting from 2 different genetic diseases that directly or indirectly cause CTLA-4 deficiency. Numerous articles have also been published describing CTLA-4 blockade in cancer immunotherapy and its side effects, which are ultimately the consequence of treatment-induced CTLA-4 deficiency. Here, we review these 2 diseases and CTLA-4 blockade therapy, emphasizing the crucial role of CTLA-4 in immune checkpoint regulation.

Immunological phenotype of the murine Lrba knockout

“…However, in the absence of LRBA‐CTLA‐4 interaction (as seen in LRBA‐deficient patients), CTLA‐4‐containing vesicles are shuttled to lysosomes for degradation, thereby dampening the surface expression of CTLA‐4 4 . Impaired regulatory Treg functionality owing to the absence of LRBA might account for the development of autoimmune manifestations in LRBA‐deficient patients who are in fact similar to those reported in patients with heterozygous loss‐of‐function mutations in CTLA‐4 19 , 20 . However, the reduced CTLA‐4 expression does not explain the poor formation of memory B cells, and the defective production of specific antibodies (Abs) as reflected by the high frequency and recurrence of infections associated with LRBA deficiency 2 , 3 .…”

Zero tolerance! A perspective on monogenic disorders with defective regulatory T cells and IBD‐like disease

“…LRBA deficiency leads to a secondary loss of CTLA‐4 protein and, consequently, defects in Treg function . LRBA has been found to bind the cytoplasmic tail of CTLA‐4 and protect it from degradation by blocking the trafficking of CTLA‐4 to lysosomes . This finding not only elucidated why the abundance of CTLA‐4 protein in LRBA patients was significantly lower than normal but also explained the overlap in clinical phenotype between CHAI and LATAIE patients .…”

“…LRBA has been found to bind the cytoplasmic tail of CTLA‐4 and protect it from degradation by blocking the trafficking of CTLA‐4 to lysosomes . This finding not only elucidated why the abundance of CTLA‐4 protein in LRBA patients was significantly lower than normal but also explained the overlap in clinical phenotype between CHAI and LATAIE patients . Importantly, there is now extensive clinical experience using abatacept, which is a recombinant CTLA‐4 fusion protein drug, for the treatment of LATAIE, indicating its efficacy in ameliorating disease …”

“…Another CTLA‐4 deficiency disorder, but without mutations in CTLA‐4, results from defects in the gene LRBA (lipopolysaccharide‐responsive vesicle trafficking, beach‐ and anchor‐containing) and is called LATAIE (LRBA deficiency with autoantibodies, Treg defects, autoimmune infiltration, and enteropathy) . LATAIE resembles CHAI, but often with an earlier age of onset and greater disease penetrance . LRBA deficiency leads to a secondary loss of CTLA‐4 protein and, consequently, defects in Treg function .…”

“…The declining cost and increasing availability of next‐generation DNA sequencing technologies has enabled the discovery of the genetic defects underlying many new Mendelian disorders, especially monogenic immune disorders. Although autoimmune diseases are generally considered polygenic, there have been a growing number of rare, monogenic autoimmune disorders in which the causative genetic defects have been identified . The study of these disorders facilitated a deeper understanding of the mechanisms involved in immune regulation and tolerance, especially in the role and function of regulatory T cells (Treg).…”