Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4

Abstract

A novel homozygous Fas ligand mutation leads to early protein truncation, abrogation of death receptor and reverse signaling and a severe form of the autoimmune lymphoproliferative syndrome. Clin Immunol 2014;155:231-7. 6. Bi LL, Pan G, Atkinson TP, Zheng L, Dale JK, Makris C, et al. Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) type Ib.

Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations

“…6,31,32 We have been repeatedly unable to show any intrinsic effects of CTLA-4 deficiency on CD4 T-cell responses in the absence of Treg 5 and are likewise unable to demonstrate an effect of anti-CTLA-4 blockade on proliferation of CD4 Tcon, suggesting they are not subject to intrinsic CTLA-4 regulation. 11 We would urge caution in using CD4 T-cell proliferation as a measure of CTLA-4 defects because there is abundant literature showing that CTLA-4 has little intrinsic ability to directly affect these aspects of T-cell function.…”

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

“…12 Abatacept has also been reported to mitigate autoimmune symptoms in a CHAI patient. 36 CTLA-4 is critical for the proper immunosuppressive function of Tregs, which preserve immune homeostasis and tolerance. 28 Sirolimus, a widely used mechanistic target of rapamycin inhibitor, suppresses conventional T-cell responses but allows Tregs to preferentially expand and maintain their suppressive function because they resist its inhibitory effects.…”

Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies

“…It has been associated with a broad clinical spectrum of autoimmunity including high rates of ITP and AIHA ( Table I ). Here, direct complementation of the underlying immunoregulatory defect with CTLA4-Ig (abatacept) has been anecdotally reported to treat pancytopenia and associated life-threatening autoimmunity otherwise refractory to corticosteroids, tacrolimus, azathioprine, cyclophosphamide, and sirolimus (47). LRBA deficiency is an associated autosomal-recessive PID where Treg impairment occurs secondary to aberrant recycling of CTLA4 to the cell surface (48).…”

“…To this end, infiltrating T cells have been demonstrated on intestinal biopsy in CTLA4 haploinsufficiency (83), and lack of response to traditional therapeutics including TNF-α inhibitors has been demonstrated in LBRA deficiency (120). By contrast, sirolimus has been reliably efficacious in CTLA-4 haploinsufficient patients, and immune reconstitution with abatacept has been shown to markedly reduce AIE (47). …”