Comparison of human NFAT1 deficiency, Nfatc2−/− mice, and patients receiving calcineurin inhibitors
| Feature . | NFAT1-deficient patient . | Nfatc2−/− knockout mice . | Use of calcineurin inhibitors . |
|---|---|---|---|
| Skeletal abnormalities and cartilage/chondrocyte defects | Joint contractures, difficulty in ambulation. Decreased range of motion in joints | Joint contractures, difficulty in ambulation; decreased range of motion in joints18 | – |
| Increased cell cycling, resistance to apoptosis in osteochondroma chondrocytes | Invasive cartilage cells in vivo and contact-induced growth inhibition in vitro, chondrosarcoma18 | Proliferation of chondrocytes from articular cartilage69 | |
| Increased MMP9 and increased IL6/IL-6-STAT3 pathway in patient chondrocytes | Susceptible to osteoarthritis, increased catabolic and decreased anabolic activity in articular cartilage, increased IL620 | – | |
| Low total body bone mineral density with vertebral compression fractures | Decreased bone volume19 | Posttransplant osteoporosis in organ recipients,55 reduced bone mass and osteoporosis in FK506-treated mice in mice19 and rats70 | |
| B cell lymphoma and malignancies | B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and cHL at age 18 y; Burkitt lymphoma at age 21 y | Effaced lymph node architecture, increased incidence of B cell malignancies, features of anaplastic and/or plasmablastic plasmacytomas, and none in Nfatc2+/−53 | Posttransplant lymphoproliferative disorder mostly in EBV+ B cells,71,72 anti-apoptotic effects in Burkitt’s lymphoma cell line,73 increased incidence of lymphoma with topical calcineurin inhibitors74,75 |
| CD4+ T cell impairments | Higher activated (CD69+) T cells, accumulation of CD4+ central memory that exhibit high PD-1 expression | Age-related increase in accumulation of activated CD69+ T cells and memory T cells in secondary lymphoid organs53 | Increase in CD4+ T cell exhaustion post-kidney and post-liver transplants but not CD8+76-78 |
| T follicular helper cell impairment | TFH cells activation is impaired and there is a lack of B cell class switching | Nfatc1/Nfatc2 double knockout mice: impaired TFH differentiation and function, impaired GC formation15 | Decreased TFH numbers and function, low TFH-mediated B cell differentiation in transplant patients79,80 |
| Feature . | NFAT1-deficient patient . | Nfatc2−/− knockout mice . | Use of calcineurin inhibitors . |
|---|---|---|---|
| Skeletal abnormalities and cartilage/chondrocyte defects | Joint contractures, difficulty in ambulation. Decreased range of motion in joints | Joint contractures, difficulty in ambulation; decreased range of motion in joints18 | – |
| Increased cell cycling, resistance to apoptosis in osteochondroma chondrocytes | Invasive cartilage cells in vivo and contact-induced growth inhibition in vitro, chondrosarcoma18 | Proliferation of chondrocytes from articular cartilage69 | |
| Increased MMP9 and increased IL6/IL-6-STAT3 pathway in patient chondrocytes | Susceptible to osteoarthritis, increased catabolic and decreased anabolic activity in articular cartilage, increased IL620 | – | |
| Low total body bone mineral density with vertebral compression fractures | Decreased bone volume19 | Posttransplant osteoporosis in organ recipients,55 reduced bone mass and osteoporosis in FK506-treated mice in mice19 and rats70 | |
| B cell lymphoma and malignancies | B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and cHL at age 18 y; Burkitt lymphoma at age 21 y | Effaced lymph node architecture, increased incidence of B cell malignancies, features of anaplastic and/or plasmablastic plasmacytomas, and none in Nfatc2+/−53 | Posttransplant lymphoproliferative disorder mostly in EBV+ B cells,71,72 anti-apoptotic effects in Burkitt’s lymphoma cell line,73 increased incidence of lymphoma with topical calcineurin inhibitors74,75 |
| CD4+ T cell impairments | Higher activated (CD69+) T cells, accumulation of CD4+ central memory that exhibit high PD-1 expression | Age-related increase in accumulation of activated CD69+ T cells and memory T cells in secondary lymphoid organs53 | Increase in CD4+ T cell exhaustion post-kidney and post-liver transplants but not CD8+76-78 |
| T follicular helper cell impairment | TFH cells activation is impaired and there is a lack of B cell class switching | Nfatc1/Nfatc2 double knockout mice: impaired TFH differentiation and function, impaired GC formation15 | Decreased TFH numbers and function, low TFH-mediated B cell differentiation in transplant patients79,80 |
cHL, classic Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus.