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.

Keywords: cytotoxic T lymphocyte antigen 4 (CLTA-4); differentially expressed in FDCP6 homolog (DEF6); hematopoietic stem cell transplantation (HSCT); immune deficiency and dysregulation activity (IDDA) kaleidoscope score; inborn error of immunity (IEI); lipopolysaccharide-responsive beige-like anchor protein (LRBA); primary immune regulatory disorder (PIRD); primary immunodeficiency (PID).

Figure 1

Model of the biological mechanisms involved in the pathophysiology of the three checkpoint defects: CTLA-4 insufficiency, LRBA and DEF6 deficiency.

Figure 2

Phenotypic characteristics and differences between CTLA-4 insufficiency, LRBA and DEF6 deficiencies, and other “classic” primary immune regulatory disorders as visualized by the immune deficiency and dysregulation activity (IDDA) “kaleidoscope” score. The phenotypic characteristics of the diseases indicated above in the spider web plots were taken from published large cohort reviews (CTLA-4, LRBA deficiency, CD27 and CD70 deficiency) (6, 9, 10) or small case series of seven patients with DEF6 deficiency (16, 17) and compared to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX syndrome) (8) as Tregopathy and to CD27 and CD70 deficiency (4, 53) as contrasting primary immune regulatory disorders. The patient numbers presented in the title of each plot vary slightly regarding some features that were not available from all patients, but are always presented as a percentage on 17 y-axes arranged in a circle. Within the regular (22-parametric) IDDA score originally developed for LRBA deficiency (11), each criterion is semi-quantified per patient from 0–4°. The full-length y-axis titles are: AI-cytopenia; hemophagocytosis | HLH (according to clinical AND lab criteria of the Histiocyte Society); enteropathy | IBD (inflammatory bowel disease); lymphoproliferation | splenomegaly | hepatomegaly; parenchymal lung disease | LIP (lymphocytic interstitial pneumonitis)| GLILD (granulomatous lymphocytic interstitial lung disease); skin or eye manifestations | eczema, uveitis, alopecia, vitiligo, other; granulomatous disease in any organ (other than GLILD); endocrinopathy | IDDM (insulin-dependent diabetes mellitus), thyroiditis, other; arthritis | other musculoskeletal manifestations; AI-hepatitis | cholangitis | pancreatitis; glomerulonephritis | nephropathy, tubulopathy; neurologic manifestations; failure to thrive | malresorption, wasting; severe infections | opportunistic (excl. asymptomatic chronic infestation; excluding “EBV-susceptibility”); any other organ or immune dysfunction/malady (e.g., cardiomyopathy, kidney failure, autoinflammation, allergy); hypogammaglobulinemia and/or immunoglobulin substitution therapy; malignancy, lymphoma (separately added to IDDA score, not included in the score calculation).