Table 1.
Clinical and laboratory features of ALPS-like patients.
| EBV susceptibility | ||||||||
|---|---|---|---|---|---|---|---|---|
| PRKCD | MAGT1 | XIAP | SH2D1A | RASGRP1 | TNFRSF9 | PIK3CD | PIK3R1 | |
| IUIS classification | Immune dysregulation | Immune dysregulation | Immune dysregulation | Immune dysregulation | Immune dysregulation | Immune dysregulation | Antibody deficiencies | Antibody deficiencies |
| Inheritance | AD LOF | XL | XL | XL | AR | AR | AD GOF | AD GOF |
| Clinical features | ||||||||
| Lymphoproliferation | S, H, L | S, H, L | S, H, L | S, H, L | S, H, L | S, H, L | S, H, L | S, H, L |
| Autoimmunity | Cytopenia, SLE, APS, vasculitis | Cytopenia | Cytopenia, AIE | Cytopenia | Cytopenia | Cytopenia | Cytopenia, SLE | Cytopenia, AIT, vasculitis |
| Malignancy | NR | HL and NHL | NR | NHL | HL | HL | HL | HL, NHL |
| Associated features | RI, skin lesions, diarrhea | RI, neurological affection | RI, HLH, IBD, skin lesions, JIA, GLILD | RI, HLH, neurological affection, skin lesions, diarrhea | RI, skin lesions, diarrhea, HLH | RI, HLH | RI, skin lesions, diarrhea, HLH | RI, skin lesions, diarrhea |
| ALPS parameters | ||||||||
| DNT | Normal | Normal | NR | NR | Normal | NR | Normal/moderate high | NR |
| Vitamin B12 | NR | Normal | NR | NR | NR | NR | NR | NR |
| sFASL | NR | Normal | NR | NR | NR | NR | NR | NR |
| IL-10 | NR | Normal | NR | NR | NR | NR | NR | NR |
| IgG level | Low/Normal/High | Low/Normal | Low / normal | Low | Low/Normal/High | Low | Low/Normal | Low |
| IgA level | Normal | Low/Normal | Low / normal | Low | Normal/High | Low | Low/Normal | Low |
| IgM level | Normal/High | Low/Normal | Low / normal | Normal/High | Normal/High | Normal | High | Normal/High |
| Immunophenotype | ||||||||
| T-cell compartment | Normal | CD4 lymphopenia. Inverted CD4:CD8 ratio. | Inverted CD4:CD8 ratio. High T memory | Inverted CD4:CD8 ratio. | CD4 lymphopenia. Inverted CD4:CD8 ratio | Low TFH. Low Treg | CD4 lymphopenia. Inverted CD4:CD8 ratio. Low naïve, senescent CD8 | Inverted CD4:CD8 ratio. Low naïve, senescent CD8 (Figure 4F) |
| B-cell compartment | B lymphocytosis. High CD21low and BT. Low BM | B lymphopenia. Low BSM, normal/high BT | B lymphopenia | Low BM | Normal | Low BM, high BT | Low BM, high BT | Low BM, high BT |
| NK-cell compartment | Low/normal NK | Low NK | Low/ normal NK | Low NK | Normal | Low NK | Normal | Normal |
| Other | NR | NR | Low iNKT | Low iNKT | NR | NR | NR | NR |
| Clinical functional assays | High B proliferation. Low NK activity. Decreased/ normal T proliferation. Poor vaccine response | Low/normal NK degranulation. Low NKG2D expression (Figure 4D). Poor vaccine response | Low XIAP expression (Figure 4C) | Low SAP expression (Figure 4B). Low NK activity. Poor vaccine response | Impaired T proliferation | Impaired T and B proliferation. Poor vaccine response | Impaired/ normal T proliferation. Poor vaccine response | Impaired/ normal T proliferation. Poor vaccine response |
| Research functional assays | – | – | Impaired NOD2 signaling in monocytes | – | Impaired ERK activation | – | High AKT, S6 phosphorylation. Upregulated IGF1, TP53, HIF1A expression | High AKT, S6 and FOXO1/3A phosphorylation (Figure 4E) |
| Treatment | Hydroxychloroquine. TMP/SMX. IVIG. Steroids. Rapamycin. Rituximab. MMF | IVIG. Rituximab. Oral Mg2+.Ganciclovir. | Steroids, immunosuppressive drugs. Adalimumab/ infliximab. HSCT | Steroids, immunosuppressive drugs. IVIG. HSCT | Steroids. IVIG. HSCT | IVIG. Rituximab. HSCT | Steroids. mTOR inhibitors. IVIG. Leniolisib. HSCT | Steroids. mTOR inhibitors. IVIG. Leniolisib. HSCT |
| EBV susceptibility | Tregs defects | |||||||
| ITK | STK4 | STAT3 | CTLA4 | LRBA | CD25 | |||
| IUIS classification | Combined immunodeficiency | Combined immunodeficiency | Immune dysregulation | Immune dysregulation | Immune dysregulation | Immune dysregulation | ||
| Inheritance | AR | AR | AD GOF | AD | AR | AR | ||
| Clinical features | ||||||||
| Lymphoproliferation | S, H, L | S, H, L | S, H, L | S, H, L | S, H, L | S, H, L | ||
| Autoimmunity | Cytopenia, vitiligo | Cytopenia, polyarthritis | Cytopenia, AIT, AIE, CD | Cytopenia, AIE, AIEC | Cytopenia, AIE | Cytopenia | ||
| Malignancy | HL | HL, NHL | HL* | HL, NHL, gastric cancer | HL, NHL | NR | ||
| Associated features | RI, skin lesions, ILD, hearing defect, HLH | RI, CMC, skin lesions, hearing defect, nephropathy, cardiomyopathy | ILD, IBD, skin lesions, liver disease, arthritis | RI, IBD, skin lesions, GLILD, Lymphocytic infiltration of nonlymphoid organs, neurological affection, arthritis, HLH | RI, IBD, skin lesions, GLILD, Lymphocytic infiltration of nonlymphoid organs, neurological affection, arthritis, HLH | RI, skin lesions, diarrhea, polyendocrinopathy | ||
| ALPS parameters | ||||||||
| DNT | High | High | Normal/High | Normal/High | Normal/High | Normal/High | ||
| Vitamin B12 | High | NR | Normal/moderate high | Normal | Normal | NR | ||
| sFASL | NR | NR | High | Normal | Normal/High | NR | ||
| IL-10 | NR | NR | NR | NR | Normal | NR | ||
| IgG level | Low/Normal | Low/Normal/ High | Low/Normal | Low/Normal | Low/Normal | Normal | ||
| IgA level | Low/Normal | Normal/ High | Low/Normal/High | Low/Normal | Low/Normal | Normal/High | ||
| IgM level | Low/Normal/High | Low/Normal/High | Low/Normal/High | Low/Normal | Low/Normal | Normal | ||
| Immunophenotype | ||||||||
| T-cell compartment | CD4 lymphopenia. Low naïve. Low CD8 CM and TEMRA | CD3 lymphopenia. Low T naïve. | CD3 lymphopenia. Low CD4 naïve. High CD4 memory. Low Th17. Low/normal Tregs | CD3 lymphopenia. Low CD4 naïve. Low/normal Tregs. High cTFH | CD3 lymphopenia. Low CD4 naïve. Low/normal Tregs (Figure 5B). High cTFH (Figure 5E) | Inverted CD4:CD8 ratio. Normal Tregs values. Low T naïve, high T memory | ||
| B-cell compartment | Normal | B lymphopenia, Low BM and BSM, high BT | High B naïve, low BSM, high CD21low | B lymphopenia. High B naïve, low BSM, high CD21low | Low BSM, high BT | High B naïve, low BT and BM | ||
| NK-cell compartment | Normal | Low NK | Low NK | Low/normal NK | Low/normal NK | Low NK | ||
| Other | Low iNKT | NR | Low pDC | NR | NR | NR | ||
| Clinical functional assays | Impaired T proliferation. | Low T proliferation, high apoptosis. Poor vaccine response | High sCD25 (Figure 7). Poor vaccine response | Impaired Treg suppression, low CTLA4 expression (Figure 5C). Poor vaccine response | Impaired Treg suppression, low LRBA expression (Figure 5D). High sCD25 (Figure 7). Poor vaccine response | Low CD25 expression/sCD25. Rescue of T proliferation with IL-2. Poor vaccine response | ||
| Research functional assays | Low S6 phosphorylation | Low STK4 and FOXO3a expression. | Normal/high STAT3 and low STAT5 and STAT1 phosphorylation (Figure 5F). High SOCS3 expression | CTLA4 transendocytosis defect | – | Low STAT5 phosphorylation. | ||
| Treatment | Steroids. Rituximab. Foscarnet/ ganciclovir. | Steroids, immunosuppressive drugs. IVIG. Rituximab. HSCT | Steroids. IVIG. Rituximab. Tocilizumab. Ruxolitinib. HSCT | IVIG. MMF. CTLA4 replacement. Abatacept. Sirolimus. Rituximab. HSCT. | Steroids. IVIG. Abatacept. Sirolimus. Rituximab. HSCT | Steroids, immunosuppressive drugs. IVIG. Rituximab. HSCT | ||
| T regs defects | Other ALPS-like related genes | |||||||
| CD122 | DEF6 | TET2 | TPP2 | STAT1 | IL12RB1 | |||
| IUIS classification | Immune dysregulation | Immune dysregulation | Not published | Immune dysregulation | Innate immunity defect | Innate Immunity defect | ||
| Inheritance | AR | AR | AR | AR | AD GOF | AR | ||
| Clinical features | ||||||||
| Lymphoproliferation | S, H, L | EBV-LPD. S, H, L | S, H, L | S, L | S, H, L | S, H, L | ||
| Autoimmunity | Cytopenia, AIE, vasculitis | Cytopenia | Cytopenia, AIT | Cytopenia | Cytopenia, SLE, AIT, hepatitis | Cytopenia | ||
| Malignancy | NR | HL* | HL, NHL | NR | NR | NR | ||
| Associated features | RI, skin lesions, diarrhea, hepatitis | RI, IBD, cardiomyopathy, arthritis | RI, liver dysfunction | RI, skin lesions | CMC, RI, skin lesions, diarrhea, lung disease | Recurrent leishmaniasis, MSMD, adenitis, skin lesions, vasculitis | ||
| ALPS parameters | ||||||||
| DNT | NR | NR | High | Normal | NR | Normal / High | ||
| Vitamin B12 | NR | NR | NR | Normal | NR | High | ||
| sFASL | NR | NR | Moderate high | Normal | NR | Low | ||
| IL-10 | NR | NR | High | NR | NR | High | ||
| IgG level | High | Normal | High | High | Normal/High | High | ||
| IgA level | High | Normal | Low | Normal | Normal/High | Normal/High | ||
| IgM level | High | Normal | Low | High | Low/Normal | Normal/High | ||
| Immunophenotype | ||||||||
| T-cell compartment | Low/Normal CD8. Low Tregs | Inverted CD4:CD8 ratio. Low CD4 naïve. Low/ Normal/high Tregs | Low TFH | Low CD4 naïve. High senescence | Inverted CD4:CD8 ratio. Low T naïve. High Th17 | Normal | ||
| B-cell compartment | Normal | Normal | Low BSM | B lymphopenia. High senescence | Low BSM | B lymphopenia | ||
| NK-cell compartment | High NK | Normal | Normal | Normal | Normal | Normal | ||
| Other | NR | NR | NR | NR | NR | NR | ||
| Clinical functional assays | Impaired T proliferation. Low CD122 cell surface expression. | Low DEF6 expression. CTLA4 cycling defect. | Low TET2 expression and enzymatic activity. Poor vaccine response | Low TPP2 expression. Impaired CD8 proliferation | Decreased IL-17 production. Poor vaccine response | Low IL12RB1, FASL expression and soluble FASL | ||
| Research functional assays | Low STAT3 and STAT5 phosphorylation | Low ERK and AKT phosphorylation | DNA hypermethylation | – | Normal/High STAT1 phosphorylation (Figure 6D). | Low STAT4 phosphorylation | ||
| Treatment | Rituximab. Sirolimus. HSCT | Abatacept | Steroids, IVIG. Rituximab. HSCT | Steroids. IVIG. MMF. Rituximab. Sirolimus. HSCT | Steroids. Ruxolitinib. sulbactam + itraconazole. HSCT | Steroids. Liposomal amphotericin B. Miltefosine. Meglumine antimoniate. | ||
| Other ALPS-like related genes | ||||||||
| ADA2 | TNFAIP3 | NRAS / KRAS (RALD) | CARD11 | |||||
| IUIS classification | Autoinflammation | Autoinflammation | Phenocopy | Antibody deficiencies | ||||
| Inheritance | AR | AD LOF | Somatic | AD GOF | ||||
| Clinical features | ||||||||
| Lymphoproliferation | S, H, L | S, H, L | S, H, L | S, L | ||||
| Autoimmunity | Cytopenia | Cytopenia | Cytopenia | Cytopenia | ||||
| Malignancy | NR | NR | B-cell lymphoma | B-CLL | ||||
| Associated features | RI, skin lesions, neurological affection, stomatitis, arthritis, vasculitis | RI, skin lesions, diarrhea, liver dysfunction, ulcers, arthritis | Arthralgias, pericarditis, IBD, skin lesions | RI, skin lesions, HLH | ||||
| ALPS parameters | ||||||||
| DNT | Normal / High | Normal / High | Normal/High | Normal/ High | ||||
| Vitamin B12 | Moderate High | Normal | NR | NR | ||||
| sFASL | NR | High | Normal/High | NR | ||||
| IL-10 | High | High | Normal/High | NR | ||||
| IgG level | Normal | Normal/ High | Normal/High | Normal/High | ||||
| IgA level | Normal | Low/ High | Normal/High | Low/Normal | ||||
| IgM level | Low/ Normal | Normal/ High | Normal/High | Normal | ||||
| Immunophenotype | ||||||||
| T-cell compartment | High CD4 naïve, low CD4 memory. Low TFH | Low T naïve, high T memory. Low Th1 | Normal | Normal/ Moderate T lymphopenia | ||||
| B-cell compartment | Normal / High B naïve, low BM | Low/normal BSM | B lymphocytosis | B lymphocytosis. Low BM and BSM | ||||
| NK-cell compartment | Normal | Low/normal NK | Normal | Normal | ||||
| Other | NR | NR | Monocytosis | NR | ||||
| Clinical functional assays | – | Low TNFAIP3 expression. | – | Poor vaccine response | ||||
| Research functional assays | Low ADA2 enzymatic activity | High NF-κB signaling | – | Constitutive NF-κB activation | ||||
| Treatment | Steroids. IVIG. MMF. Sirolimus. Etanercept. HSCT | Steroids. IVIG. Anakinra. | Steroids. IVIG. Sirolimus. Rapamycin. Hydroxychloroquine. | Steroids. Sirolimus. IVIG. Rituximab. HSCT | ||||