Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies

Abstract

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a crucial immune checkpoint that is constitutively expressed in regulatory T (Treg) cells. Following T-cell activation, CTLA-4 is rapidly mobilized from its intracellular vesicle pool to the cell surface to control the availability of co-stimulatory B7 molecules, thereby maintaining immune homeostasis. Heterozygous mutations in CTLA-4 lead to defects in (i) CTLA-4 ligand binding, (ii) homo-dimerization, (iii) B7-transendocytosis, and (iv) CTLA-4 vesicle trafficking, resulting in an inborn error of immunity with predominant autoimmunity. CTLA-4 vesicle trafficking impairment is also observed in patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency or the differentially expressed in FDCP6 homolog (DEF6) deficiency, caused by biallelic mutations in LRBA and DEF6, respectively. Therefore, patients with CTLA-4 insufficiency, LRBA deficiency, and—most recently reported—DEF6 deficiency present an overlapping clinical phenotype mainly attributed to a defective suppressive activity of Tregs, as all three diseases reduce overall surface expression of CTLA-4. In this paper, we describe the clinical phenotypes of these immune checkpoint defects, their patho-mechanisms, and visually compare them to other immune regulatory disorders (IPEX syndrome, CD27, and CD70 deficiencies) by using the immune deficiency and dysregulation (IDDA version 2.1) “kaleidoscope” score. This illustrates the variability of the degrees and manifestations of immune deficiency and dysregulation. Patients characteristically present with an increased risk of infections, autoimmune cytopenias, multi-organ autoimmunity, and inflammation, which are often severe and life-threatening. Furthermore, these patients suffer an increased risk of developing malignancies, especially Non-Hodgkin's lymphoma. Successful treatment options include regular administration of soluble CTLA-4-Ig fusion protein, Treg cell-sparing immune suppressants like sirolimus or mycophenolate mofetil, and hematopoietic stem cell transplantation. This mini-review highlights the most relevant biological and clinical features as well as treatment options for CTLA-4 insufficiency and LRBA and DEF6 deficiencies.

The Immune Deficiency and Dysregulation Activity (IDDA2.1 ‘Kaleidoscope’) Score and Other Clinical Measures in Inborn Errors of Immunity

“…The kaleidoscope function makes use of 17 out of 22 parameters documented in the IDDA score (terms #1–14; #20; #18; and #22, see Table 2 ), reduced to qualitative information about organ involvement and other features in a patient or a patient cohort, plotted according to the fixed order of parameters in a radar (spider) chart on 17 y -axes arranged in a circle. A Primary immune regulatory disorders, modified from [ 30 ] and supplemented with additional IEI, with data derived from reviews, case series, or large cohorts [ 1 , 20 , 31 – 36 ]; B Predominantly antibody deficiencies and combined immunodeficiencies [ 37 – 43 ]; C Diseases of immune regulation with EBV-susceptibility [ 44 – 50 ]. Data for part of the CARD11GOF and all of the XIAP plots were derived from unpublished data to appear in Hauck et al, 2021, and a manuscript in preparation by Yang and Burns et al, 2021, respectively.…”

Primary immune regulatory disorders: Undiagnosed needles in the haystack?

“…Reduced class-switched memory B-lymphocytes, Tregs and immunoglobulin levels are the most common abnormalities in immune parameters [ 35 ]. As expected, due to the shared pathogenetic mechanisms, the phenotype of LRBA deficiency overlaps significantly with that of CTLA haploinsufficiency, although severe infections appear to be a more prominent feature in LRBA deficiency [ 34 , 37 ]. A recent analysis of long-term outcomes in a large cohort of patients with LRBA deficiency demonstrated the superior effect of targeted therapy with abatacept or sirolimus with decreased disease activity scores compared to conventional immune suppression [ 34 ].…”

Pathogenesis of Autoimmune Cytopenias in Inborn Errors of Immunity Revealing Novel Therapeutic Targets

“…The reduction of CTLA-4 on the T-cell surface is the common hallmark of ctla -4 insufficiency, lrba, and def 6 deficiency, and induces immune homeostasis disruption due to the prolonged T-cell activation and migration, with subsequent multiorgan lymphocytic infiltration and a breakdown of the peripheral immune tolerance. A higher circulation of autoreactive lymphocytes may explain the development of autoimmunity, including AIC ( 51 ). Autoimmunity (AIC, enteropathy) is often associated with recurrent and/or severe infections, hypogammaglobulinemia, and lymphoproliferation.…”