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.
Highlights
Primary immune regulatory disorders (PIRDs) are inborn errors of immunity (IEI) with immune dysregulation [category IV of the international classification of human IEI; [1, 2]], that pose a major challenge to physicians, because they are difficult to diagnose and hard to treat
We provide a visual comparison between the phenotypic features of cytotoxic T-lymphocyte antigen 4 (CTLA-4) insufficiency and lipopolysaccharide-responsive beige-like anchor protein (LRBA)/differentially expressed in FDCP6 homolog (DEF6) deficiency as checkpoint defects on one hand with other IEI with immune dysregulation, such as IPEX syndrome representing a “classical Tregopathy” and, as a contrast, two PIRDs that are linked to EBV susceptibility and malignancies and, as receptorligand pair, share the same pathomechanism, namely CD27 and CD70 deficiencies (Figure 2)
These decisions will hopefully be facilitated and guided in near future by studies that compare the natural and pharmacologically influenced course of the disease by using a standardized measure for disease activity [8, 11]; ideally within prospective studies like the ongoing, but no longer recruiting, P-CID study [63]; the currently ongoing CHAI-morbidity score that is based on 203 CTLA-4 insufficiency patients; the ABACHAI trial that evaluates the safety and efficacy of abatacept in patients with CTLA4 insufficiency and LRBA deficiency (000972-40 EU Clinical Trial Registry); and various other new modules included in the European Society for Immunodeficiencies (ESID) registry
Summary
Primary immune regulatory disorders (PIRDs) are inborn errors of immunity (IEI) with immune dysregulation [category IV of the international classification of human IEI; [1, 2]], that pose a major challenge to physicians, because they are difficult to diagnose and hard to treat. The different phenotypes observed in human and mice in the context of these three PIRDs, despite the fact that CTLA-4, LRBA and DEF6 proteins have the same biological functions in both species, indicate that mice may rely less on the CTLA-4 route to maintain immune homeostasis, or that the murine immune system is more resistant to developing immune dysregulation. Increased levels of DEF6 protein correlate with a poor prognosis in patients with renal cell carcinoma [50] These results could be explained biologically by the fact that DEF6 is involved in TCR signaling, and in the activation of NFAT through Ca2+ release. Few studies have described the prognostic value of CTLA-4 levels in the tumor site, its expression has been associated with decreased survival in patients with nasopharyngeal carcinoma and increased survival in those with non-small-cell lung cancer [52]
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