Table 1.
Summary of flow cytometry contributions for the immunopathological characterization of Hemophagocytic Lymphohistiocytosis (HLH) and Epstein–Barr virus (EBV) susceptibility.
| HLH and EBV susceptibility | Flow cytometric (FC) application and immunopathological mechanisms identified | Genetic defect (References) | Inheritance |
|---|---|---|---|
| Hypopigmentation Syndromes | |||
| Chediak Higashi sd | Reduced degranulation based on the surface up-regulation of CD107a (49) in Natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) | LYST (50, 51) | AR |
| Griscelli sd type 2 | Reduced degranulation based on the surface up-regulation of CD107a (49) in NK and CTLs | RAB27A (52) | AR |
| Hermansky-Pudlak sd type 2 | Reduced degranulation based on the surface up-regulation of CD107a (49) in NK and CTLs | AP3B1 (53) | AR |
| Hermansky-Pudlak sd, type 10 | Reduced degranulation based on the surface up-regulation of CD107a (49) in NK and CTLs | AP3D1 (54) | AR |
| Familial HLH | |||
| Perforin deficiency (FHL2) | Perforin expression in NK cells and CTLs Normal CD107a expression in NK and CTLs |
PRF1 (55) | AR |
| UNC13D or Munc13-4 deficiency (FHL3) | Munc13-4 expression in NK cells, CTLs, and platelets. | UNC13D (56) | AR |
| Syntaxin 11 deficiency (FHL4) | STX11 expression not available by FC (no antibody validated). Reduced CD107a expression in NK and CTLs |
STX11 (57) | AR |
| STXBP2 or Munc18-2 deficiency (FHL5) | STXBP2 expression by FC not available (no antibody validated). Reduced CD107a expression in NK and CTLs |
STXBP2 (58) | AR |
| Susceptibility to EBV infections RASGRP1 deficiency |
Reduced cell proliferation using fluorescent cell staining dye; impaired T cell activation by measuring CD69 expression; defective CTPS1 expression; reduced intracellular expression of active caspase 3; reduced T cell apoptosis using annexin V/propidium iodide staining, all in response to CD3/TCR activation | RASGRP1 (59–63) | AR |
| CD70 deficiency | CD70 expression on phytohaemagglutinin (PHA)-stimulated T cells; binding of a CD27-Fc fusion protein on T cells | CD70 (64) | AR |
| CTPS1 deficiency | Defective cell proliferation using fluorescent cell staining dye | CTPS1 (65) | AR |
| RLTPR deficiency | RLTPR expression in adaptive (B and T lymphocytes) and innate (monocytes and dendritic cells) immune cells. Reduced phospho-nuclear factor (NF)-κB P65-(pS259) expression and inhibitor (I)κBα degradation in CD4+ and CD8+, specifically after CD28 co-stimulation; CD107a expression after K562 stimulation | RLTPR or CARMIL2 (66) | |
| ITK deficiency | ITK expression by FC not available (no antibody validated). Reduced T cell receptor (TCR)-mediated calcium flux; absence of Natural Killer T (NKT) cells determined as TCR Vβ11 and TCR Vα24 double-positive cells | ITK (67) | AR |
| MAGT1 deficiency | MAGT1 expression by FC not available (no antibody validated). Reduced CD69 expression in CD4+ T cells after anti-CD3 stimulation. Low CD31+ cells in the naïve (CD27+, CD45RO−) CD4+ T cell population. Impaired Mg influx using Mg2+-specific fluorescent probe MagFluo4. Reduced NKG2D expression in NK cells and CTLs | MAGT1 (68) | XL |
| PRKCD deficiency | Increased B cell proliferation after anti-IgM stimulation; resistance to PMA-induced cell death; low CD27 expression on B cells | PRKCD (69–71) | AR |
| XLP1 | SH2D1A expression, low numbers of circulating NKT cells (Vα24TCR+/Vβ11TCR+). Impaired apoptosis. | SH2D1A (72) | XL |
| XLP2 | XIAP expression, low numbers of circulating NKT cells (Vα24TCR+/Vβ11TCR+). Enhanced apoptosis | XIAP (73) | XL |
| CD27 deficiency | CD27 expression on B cells | CD27 (74) | AR |
Diseases are classified as reported by the 2017 IUIS phenotypic classification for PIDs (24). AP3B1, Adaptor Related Protein Complex 3 Beta 1; AP3D1, Adaptor Related Protein Complex 3 Delta 1; AR, Autosomal recessive; CD27, Cluster of Differentiation 27; CD70, Cluster of Differentiation 70; CTPS1, Cytidine triphosphate synthase 1; FHL, familial hemophagocytic lymphohistiocytosis; ITK, IL2 Inducible T Cell Kinase; LYST, Lysosomal Trafficking Regulator; MAGT1, Magnesium Transporter 1; PRF1, Perforin 1; PRKCD, Protein Kinase C Delta; RAB27A, Ras-Related Protein Rab-27A; RASGRP1, RAS guanyl-releasing protein 1; RLTPR, RGD motif, leucine rich repeats, tropomodulin domain and proline-rich containing; sd, syndrome; SH2D1A, SH2 Domain Containing 1A; STX11, Syntaxin 11; STXBP2, Syntaxin Binding Protein 2; UNC13D, Protein unc-13 homolog D; XL, X-linked; XIAP, X-linked inhibitor of apoptosis protein.