Table 2.
Summary of flow cytometry contributions for the immunopathological characterization of Syndromes with autoimmunity.
| Syndromes with autoimmunity | Flow cytometric (FC) application and immunopathological mechanisms identified | Genetic defect (References) | Inheritance |
|---|---|---|---|
| Syndromes associated with increased TCRα/β DN T cells | |||
| ALPS-FAS | FAS expression, reduced T cell apoptosis | TNFRSF6 (75) | AD/AR |
| ALPS-FASLG | FASL expression, reduced T cell apoptosis | TNFSF6 (76) | AD/AR |
| ALPS-Caspase8 | Reduced T cell apoptosis | CASP8 (77) | AR |
| ALPS-Caspase 10 | Reduced T cell apoptosis | CASP10 (78) | AD |
| FADD deficiency | Reduced T cell apoptosis | FADD (79) | AR |
| LRBA deficiency | Reduced T regulatory (T reg) cells, low CTLA4 and Helios; Increased B cell apoptosis and low levels of IgG+/IgA+ CD27+ switched-memory B cells; reduced B proliferative capacity, and impaired activation (using CD138 staining) | LRBA (80) | AR |
| STAT3 gain-of-function (GOF) mutation | Delayed de-phosphorylation of STAT3; diminished STAT5 and STAT1 phosphorylation; which is in line with the role in the negative regulation of several STATs162. High levels of Th17 cells; reduced FOXP3+CD25+ Treg population; decreased FASL-induced apoptosis | STAT3 (81) | AD |
| Defective regulatory T cells | |||
| IPEX | Decreased or absent FOXP3 expression by CD4+CD25+ regulatory T cells | FOXP3 (82) | XL |
| CD25 deficiency | Impaired CD25 expression; defective proliferative responses following anti-CD3 or PH; defective NK cell maturation increased (CD56brightCD16hi and reduced CD56dimCD16hi NK cells in peripheral blood); increased degranulation by elevated CD107a expression and higher perforin and granzyme B expression in NK cells; | CD25 or IL2RA (83) | AR |
| CTLA4 haploinsufficiency | CTLA4 expression, trafficking, binding to its ligand, and CTLA4-mediated trans-endocytosis | CTLA4 (84) | AD |
| BACH2 deficiency | Reduced BACH2 expression in T and B lymphocytes, decreased FOXP3 expression by CD4+CD25+ regulatory T cells, reduced total and class-switched memory B cells, increased T-bet expression | BACH2 (85) | AD |
| Normal regulatory T cell function | |||
| APECED | Expression of IL-17A, IL-17F, and IL-22 by PBMCs. AIRE expression by FC is not available (no antibody validated) | AIRE (86) | AR |
| Tripeptidyl-Peptidase II deficiency | Lymphocytes expressing high levels of major histocompatibility complex (MHC) class I molecules, a predominant T CD8+CD27−CD28−CD127− phenotype; increased percentage of IFN-γ and IL-17 positive T cells; high expression of T-bet and perforin. Defective proliferation lymphoproliferation and increased susceptibility to apoptosis; increased levels of CD21low B cells | TPP2 (87) | AR |
| JAK1 GOF | Increased JAK1, STAT1, and STAT3 phosphorylation | JAK1 (88) | AD |
| Immune dysregulation with early onset Colitis | |||
| IL-10 deficiency | No FC assay available. Normal STAT3 phosphorylation in response to IL-10 | IL-10(89) | AR |
| IL-10RA deficiency | IL-10RA expression; defective STAT3 phosphorylation in response to IL-10. Normal STAT3 phosphorylation in response to IL-23 | IL-10Ra (90) | AR |
| IL-10RB deficiency | IL-10RB expression; defective STAT3 phosphorylation in response to IL-10. Normal STAT3 phosphorylation in response to IL-23 | IL-10Rb (90) | AR |
Diseases are classified as reported by the 2017 IUIS phenotypic classification for PIDs (24). AD, Autosomal dominant; ALPS-FAS, Autoimmune lymphoproliferative syndrome-Fas cell surface death receptor; ALPS-FASLG, Autoimmune lymphoproliferative syndrome FAS ligand gene; APECED, Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; AR, Autosomal recessive; BACH2, BTB Domain And CNC Homolog 2; CASP8, cysteine-aspartic acid protease 8;CASP10, cysteine-aspartic acid protease 10; CD25 or IL2RA, Interleukin 2 Receptor A; CTLA4, cytotoxic T-lymphocyte-associated Protein 4; DN, double negative; FADD, Fas Associated Via Death Domain; IL-10, Interleukin-10; IL-10Ra, Interleukin-10 Receptor alpha; IL-10Rb, Interleukin-10 Receptor beta; IPEX, Immune dysregulation; polyendocrinopathy; enteropathy; XL, X-linked; JAK1, Janus Kinase 1; LRBA, LPS Responsive Beige-Like Anchor Protein; NFAT5, Nuclear Factor Of Activated T Cells 5; STAT3, signal transducer and activator of transcription 3; TPP2, Tripeptidyl Peptidase 2.