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

An article published in : BLOOD, 25 AUGUST 2016 x VOLUME 128, NUMBER 8

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.

Interesting points from the article:

-“CTLA-4 haploinsufficiency with autoimmune infiltration” (CHAI) patients have heterozygous loss-of-function mutations in CTLA-4 and develop lymphocytic infiltration of multiple nonlymphoid organs -“LRBA deficiency with autoantibodies,regulatory T (Treg) cell defects, autoimmune infiltration, and enteropathy”(LATAIE), results from biallelic mutations in the“lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing”(LRBA) gene rather than in CTLA4.

-CTLA-4 is a crucial T-cell inhibitory receptor. It restrains immune responses by negative signaling or competing with its homolog CD28,the principal T-cell costimulatory molecule, critical for inducing maximal T-cell proliferation. CD28 and CTLA-4 compete for the same ligands, CD80 and CD86, on the surface of antigen-presenting cells . Moreover, CTLA-4 binds CD80 and CD86 with significantly higher affinity and avidity than CD28 and outcompetes CD28 for its ligands.

-CD28 is expressed constitutively on all naıve and most resting T cells; however, CTLA-4 is expressed only after activation in conventional T cells while it is constitutively expressed on Tregs. Thus, Tregs are the chief mediator of CTLA-4 inhibitory function. Most CTLA-4 is stored in recycling endosomes, which cycle to the cell surface following T-cell activation.

-LRBA is a member of a gene family involved in vesicle trafficking,and the author found that LRBA regulates CTLA-4 turnover in endosomes. LRBA helps maintain an intracellular vesicular pool of CTLA-4 for immediate mobilization to the cell surface as needed.Loss of LRBA leads to the rapid shuttling of CTLA-4 vesicles to lysosomes for degradation. The author found that inhibiting lysosomal degradation with the drug chloroquine or other inhibitors of the lysosome rescued CTLA-4 loss in vitro.

-Abatacept, a CTLA-4–immunoglobulin fusion drug, which may act as a pharmacologic “replacement” of CTLA-4, has achieved substantial and lasting improvement of interstitial lung disease in LATAIE patients. Abatacept has also been reported to mitigate autoimmune symptoms in a CHAI patient.

-Chloroquine, a lysosomal inhibitor drug, was found to augment CTLA-4 levels in vitro in Treg or activated T cells, especially for LRBA deficient cells. Therefore, chloroquine or hydroxychloroquine, a more widely used derivative,warrant further study of their utility as a therapy for CTLA-4–deficiency diseases. Although chloroquine/hydroxychloroquine are most widely used as antimalarials, they have also shown efficacy in treating rheumatoid arthritis and lupus.It would be interesting to investigate whether the latter may be attributable to CTLA-4.

Comment:

This finding of CTLA-4 level augmentation in Treg or activated T cells by hydroxychloroquine, is very interesting. Belatacept; a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, has been shown effective as an immunosuppressive agent in kidney transplant recipients. Patient who were on Belatacept had a lower incidence of donor specific antibody than those treated with Cyclosporine A.

Above augmentation of CTLA-4, in addition to other reported effects of hydroxychloroquine on the immune system ( blocking costimulation of B cell antigen receptor and TLR-9 pathways , inhibition of activation of intracellular TLR-3 and TLR-7, interference with receptor recycling, intracellular processing, and the secretion of proteins, which can leads to a decreased production of cytokines and other inflammatory mediators, consequently, this can lead to decreased lymphocyte proliferation , interference with natural killer cell activity , and, possibly, alteration of autoantibody production , interference with the binding of autoantigenic peptides to major histocompatibility complex (MHC) class II molecules, thereby interfering with antigen processing and ultimately with the immune response to autoantigens (source: UpToDate in Medicine), justify ,in my opinion, studying the effects of Hydroxychloroquine as an add-on drug to the current triple immunosuppressive therapy in kidney transplant recipients. Primary end points would be the incidence of acute cellular rejection, development of donor-specific antibodies and graft survival.

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