#615607
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because immunodeficiency-17 (IMD17) is caused by homozygous or compound heterozygous mutation in the CD3G gene (186740) on chromosome 11q23.
Immunodeficiency-17 (IMD17) is an autosomal recessive primary immunodeficiency characterized by highly variable clinical severity. Some patients have onset of severe recurrent infections in early infancy that may be lethal, whereas others may be only mildly affected or essentially asymptomatic into young adulthood. More severely affected patients may have evidence of autoimmune disease or enteropathy. The immunologic pattern is similar among patients, showing partial T-cell lymphopenia, particularly of cytotoxic CD8 (see 186910)-positive cells, decreased amounts of the CD3 complex, and impaired proliferative responses to T-cell receptor (TCR)-dependent stimuli. B cells, natural killer (NK) cells, and immunoglobulins are usually normal. Although thymic output of functional naive T cells early in life is decreased, polyclonal expansion of functional memory T cells is substantial. The phenotype in some patients is reminiscent of severe combined immunodeficiency (SCID) (summary by Timon et al. (1993) and Recio et al. (2007)).
Regueiro et al. (1986) described a Spanish family in which 2 brothers had divergent clinical presentations of a primary immunodeficiency. The older sib was healthy at age 4 years. The younger sib had an intestinal malabsorption syndrome associated with lack of gut villi and serum gut epithelial cell autoantibodies. This child had failure to thrive beginning at age 11 months, recurrent gastrointestinal and respiratory bacterial and viral infections, and bronchiolitis obliterans. Both patients had absent or very low expression of the TCR-CD3 complex on T cells and impaired responses to allogeneic lymphocytes and tetanus toxoid. Lymphocyte numbers were in the normal range. Arnaiz-Villena et al. (1991, 1992) also studied the brothers reported by Regueiro et al. (1986). The younger brother developed autoimmune hemolytic anemia and died at age 31 months after a viral infection. The other brother was healthy at age 10 years.
Alarcon et al. (1988) described studies of the immune cells derived from the 2 Spanish brothers originally reported by Regueiro et al. (1986). There was low expression of antigen receptor on the surface of their T lymphocytes. Functional analyses of their T cells showed impaired immune response to alloantigens, tetanus toxoid, and mitogens. Biochemical studies showed reduced intracellular expression of CD3-zeta (CD3Z, or CD247; 186780) chains; all other components of the TCR-CD3 complex appeared to be expressed normally intracellularly. Alarcon et al. (1988) suggested that the impaired association of the CD3-zeta chain with the other chains of the complex was the primary defect leading to low expression of the TCR-CD3 complex and immunodeficiency in these children. However, studies on patient cells by Arnaiz-Villena et al. (1991) and Perez-Aciego et al. (1991) strongly suggested that the immunodeficiency in these patients was due to decreased or absent levels of the CD3-gamma chain. This TCR-CD3 structural variant was still capable of transducing certain activation signals, since normal proliferation and a low but significant calcium flux were observed in patient cells. These data indicated that a functional TCR-CD3 complex can be expressed in the surface of T cells in the absence of CD3-gamma.
Timon et al. (1993) found that the healthy 10-year-old brother reported by Regueiro et al. (1986) had mild T-cell lymphopenia with a strong reduction of CD8-positive lymphocytes and a smaller reduction of CD4 (186940)-positive/CD45RA (151460)-positive T lymphocytes, corresponding to virgin helper T cells. CD4-positive/CD45R0-positive T lymphocytes, corresponding to memory helper T cells, B cells, and NK cells were normal. These results suggested that the CD3G subunit of the TCR/CD3 complex is required for peripheral development of certain T-cell types.
Recio et al. (2007) reported 2 brothers, born of consanguineous parents, with IMD17. The patients presented in infancy with recurrent infections, and immune work-up showed partial T lymphocytopenia and low CD3, but normal B cells, NK cells, and immunoglobulins. Proliferative responses were low compared with controls. Both patients also had inflammatory bowel disease without evidence of autoimmunity. One boy underwent bone marrow transplantation, but died at age 20 months, whereas the other boy died at age 9 months before transplantation. An unrelated child from the same region of Turkey had a milder phenotype. He was diagnosed at age 4 years and alive at age 15 years. In a comparison of these 3 patients with the 2 Spanish brothers reported by Regueiro et al. (1986), Recio et al. (2007) found that the partial T lymphocytopenia was more intense early in life, and that all had impaired proliferative response to TCR-dependent stimuli. All tested patients had very few peripheral blood thymus emigrants and decreased TCR rearrangement excision circles (TRECs), whereas the mature memory T-cell pool was essentially normal. These findings suggested that lack of CD3G impairs thymus production, but not peripheral expansion or accumulation of mature polyclonal T cells.
The transmission pattern of IMD17 in the family reported by Regueiro et al. (1986) was consistent with autosomal recessive inheritance.
In 2 Spanish brothers with IMD17 with marked differences in severity (Regueiro et al., 1986), Arnaiz-Villena et al. (1992) identified compound heterozygous truncating mutations in the CD3G gene (186740.0001 and 186740.0002).
In 2 Turkish brothers and an unrelated Turkish individual with IMD17, Recio et al. (2007) identified a homozygous truncating mutation in the CD3G gene (K69X; 186740.0003). Haplotype analysis indicated a founder effect. Recio et al. (2007) emphasized the clinical variability of these patients despite similar immunologic findings and noted that lack of the CD3G subunit may be less severe than lack of the CD3E (186830) subunit.
Alarcon, B., Regueiro, J. R., Arnaiz-Villena, A., Terhorst, C. Familial defect in the surface expression of the T-cell receptor-CD3 complex. New Eng. J. Med. 319: 1203-1208, 1988. [PubMed: 3262828, related citations] [Full Text]
Arnaiz-Villena, A., Perez-Aciego, P., Ballestin, C., Sotelo, T., Perez-Seoane, C., Martin-Villa, J. M., Regueiro, J. R. Biochemical basis of a novel T lymphocyte receptor immunodeficiency by immunohistochemistry: a possible CD3-gamma abnormality. Lab. Invest. 64: 675-681, 1991. [PubMed: 1709425, related citations]
Arnaiz-Villena, A., Timon, M., Corell, A., Perez-Aciego, P., Martin-Villa, J. M., Regueiro, J. R. Primary immunodeficiency caused by mutations in the gene encoding the CD3-gamma subunit of the T-lymphocyte receptor. New Eng. J. Med. 327: 529-533, 1992. [PubMed: 1635567, related citations] [Full Text]
Perez-Aciego, P., Alarcon, B., Arnaiz-Villena, A., Terhorst, C., Timon, M., Segurado, O. G., Regueiro, J. R. Expression and function of a variant T cell receptor complex lacking CD3-gamma. J. Exp. Med. 174: 319-326, 1991. [PubMed: 1713248, related citations] [Full Text]
Recio, M. J., Moreno-Pelayo, M. A., Kilic, S. S., Guardo, A. C., Sanal, O., Allende, L. M., Perez-Flores, V., Mencia, A., Modamio-Hoybjor, S., Seoane, E., Regueiro, J. R. Differential biological role of CD3 chains revealed by human immunodeficiencies. J. Immun. 178: 2556-2564, 2007. [PubMed: 17277165, related citations] [Full Text]
Regueiro, J. R., Arnaiz-Villena, A., Ortiz de Landazuri, M., Martin Villa, J. M., Vicario, J. L., Pascual-Ruiz, V., Guerra-Garcia, F., Alcami, J., Lopez-Botet, M., Manzanares, J. Familial defect of CD3 (T3) expression by T cells associated with rare gut epithelial cell autoantibodies. (Letter) Lancet 327: 1274-1275, 1986. Note: Originally Volume I. [PubMed: 2872416, related citations] [Full Text]
Timon, M., Arnaiz-Villena, A., Rodriguez-Gallego, C., Perez-Aciego, P., Pacheco, A., Regueiro, J. R. Selective disbalances of peripheral blood T lymphocyte subsets in human CD3 gamma deficiency. Europ. J. Immun. 23: 1440-1444, 1993. [PubMed: 8325321, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 169082; DO: 0111973;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q23.3 | Immunodeficiency 17, CD3 gamma deficient | 615607 | Autosomal recessive | 3 | CD3G | 186740 |
A number sign (#) is used with this entry because immunodeficiency-17 (IMD17) is caused by homozygous or compound heterozygous mutation in the CD3G gene (186740) on chromosome 11q23.
Immunodeficiency-17 (IMD17) is an autosomal recessive primary immunodeficiency characterized by highly variable clinical severity. Some patients have onset of severe recurrent infections in early infancy that may be lethal, whereas others may be only mildly affected or essentially asymptomatic into young adulthood. More severely affected patients may have evidence of autoimmune disease or enteropathy. The immunologic pattern is similar among patients, showing partial T-cell lymphopenia, particularly of cytotoxic CD8 (see 186910)-positive cells, decreased amounts of the CD3 complex, and impaired proliferative responses to T-cell receptor (TCR)-dependent stimuli. B cells, natural killer (NK) cells, and immunoglobulins are usually normal. Although thymic output of functional naive T cells early in life is decreased, polyclonal expansion of functional memory T cells is substantial. The phenotype in some patients is reminiscent of severe combined immunodeficiency (SCID) (summary by Timon et al. (1993) and Recio et al. (2007)).
Regueiro et al. (1986) described a Spanish family in which 2 brothers had divergent clinical presentations of a primary immunodeficiency. The older sib was healthy at age 4 years. The younger sib had an intestinal malabsorption syndrome associated with lack of gut villi and serum gut epithelial cell autoantibodies. This child had failure to thrive beginning at age 11 months, recurrent gastrointestinal and respiratory bacterial and viral infections, and bronchiolitis obliterans. Both patients had absent or very low expression of the TCR-CD3 complex on T cells and impaired responses to allogeneic lymphocytes and tetanus toxoid. Lymphocyte numbers were in the normal range. Arnaiz-Villena et al. (1991, 1992) also studied the brothers reported by Regueiro et al. (1986). The younger brother developed autoimmune hemolytic anemia and died at age 31 months after a viral infection. The other brother was healthy at age 10 years.
Alarcon et al. (1988) described studies of the immune cells derived from the 2 Spanish brothers originally reported by Regueiro et al. (1986). There was low expression of antigen receptor on the surface of their T lymphocytes. Functional analyses of their T cells showed impaired immune response to alloantigens, tetanus toxoid, and mitogens. Biochemical studies showed reduced intracellular expression of CD3-zeta (CD3Z, or CD247; 186780) chains; all other components of the TCR-CD3 complex appeared to be expressed normally intracellularly. Alarcon et al. (1988) suggested that the impaired association of the CD3-zeta chain with the other chains of the complex was the primary defect leading to low expression of the TCR-CD3 complex and immunodeficiency in these children. However, studies on patient cells by Arnaiz-Villena et al. (1991) and Perez-Aciego et al. (1991) strongly suggested that the immunodeficiency in these patients was due to decreased or absent levels of the CD3-gamma chain. This TCR-CD3 structural variant was still capable of transducing certain activation signals, since normal proliferation and a low but significant calcium flux were observed in patient cells. These data indicated that a functional TCR-CD3 complex can be expressed in the surface of T cells in the absence of CD3-gamma.
Timon et al. (1993) found that the healthy 10-year-old brother reported by Regueiro et al. (1986) had mild T-cell lymphopenia with a strong reduction of CD8-positive lymphocytes and a smaller reduction of CD4 (186940)-positive/CD45RA (151460)-positive T lymphocytes, corresponding to virgin helper T cells. CD4-positive/CD45R0-positive T lymphocytes, corresponding to memory helper T cells, B cells, and NK cells were normal. These results suggested that the CD3G subunit of the TCR/CD3 complex is required for peripheral development of certain T-cell types.
Recio et al. (2007) reported 2 brothers, born of consanguineous parents, with IMD17. The patients presented in infancy with recurrent infections, and immune work-up showed partial T lymphocytopenia and low CD3, but normal B cells, NK cells, and immunoglobulins. Proliferative responses were low compared with controls. Both patients also had inflammatory bowel disease without evidence of autoimmunity. One boy underwent bone marrow transplantation, but died at age 20 months, whereas the other boy died at age 9 months before transplantation. An unrelated child from the same region of Turkey had a milder phenotype. He was diagnosed at age 4 years and alive at age 15 years. In a comparison of these 3 patients with the 2 Spanish brothers reported by Regueiro et al. (1986), Recio et al. (2007) found that the partial T lymphocytopenia was more intense early in life, and that all had impaired proliferative response to TCR-dependent stimuli. All tested patients had very few peripheral blood thymus emigrants and decreased TCR rearrangement excision circles (TRECs), whereas the mature memory T-cell pool was essentially normal. These findings suggested that lack of CD3G impairs thymus production, but not peripheral expansion or accumulation of mature polyclonal T cells.
The transmission pattern of IMD17 in the family reported by Regueiro et al. (1986) was consistent with autosomal recessive inheritance.
In 2 Spanish brothers with IMD17 with marked differences in severity (Regueiro et al., 1986), Arnaiz-Villena et al. (1992) identified compound heterozygous truncating mutations in the CD3G gene (186740.0001 and 186740.0002).
In 2 Turkish brothers and an unrelated Turkish individual with IMD17, Recio et al. (2007) identified a homozygous truncating mutation in the CD3G gene (K69X; 186740.0003). Haplotype analysis indicated a founder effect. Recio et al. (2007) emphasized the clinical variability of these patients despite similar immunologic findings and noted that lack of the CD3G subunit may be less severe than lack of the CD3E (186830) subunit.
Alarcon, B., Regueiro, J. R., Arnaiz-Villena, A., Terhorst, C. Familial defect in the surface expression of the T-cell receptor-CD3 complex. New Eng. J. Med. 319: 1203-1208, 1988. [PubMed: 3262828] [Full Text: https://doi.org/10.1056/NEJM198811033191806]
Arnaiz-Villena, A., Perez-Aciego, P., Ballestin, C., Sotelo, T., Perez-Seoane, C., Martin-Villa, J. M., Regueiro, J. R. Biochemical basis of a novel T lymphocyte receptor immunodeficiency by immunohistochemistry: a possible CD3-gamma abnormality. Lab. Invest. 64: 675-681, 1991. [PubMed: 1709425]
Arnaiz-Villena, A., Timon, M., Corell, A., Perez-Aciego, P., Martin-Villa, J. M., Regueiro, J. R. Primary immunodeficiency caused by mutations in the gene encoding the CD3-gamma subunit of the T-lymphocyte receptor. New Eng. J. Med. 327: 529-533, 1992. [PubMed: 1635567] [Full Text: https://doi.org/10.1056/NEJM199208203270805]
Perez-Aciego, P., Alarcon, B., Arnaiz-Villena, A., Terhorst, C., Timon, M., Segurado, O. G., Regueiro, J. R. Expression and function of a variant T cell receptor complex lacking CD3-gamma. J. Exp. Med. 174: 319-326, 1991. [PubMed: 1713248] [Full Text: https://doi.org/10.1084/jem.174.2.319]
Recio, M. J., Moreno-Pelayo, M. A., Kilic, S. S., Guardo, A. C., Sanal, O., Allende, L. M., Perez-Flores, V., Mencia, A., Modamio-Hoybjor, S., Seoane, E., Regueiro, J. R. Differential biological role of CD3 chains revealed by human immunodeficiencies. J. Immun. 178: 2556-2564, 2007. [PubMed: 17277165] [Full Text: https://doi.org/10.4049/jimmunol.178.4.2556]
Regueiro, J. R., Arnaiz-Villena, A., Ortiz de Landazuri, M., Martin Villa, J. M., Vicario, J. L., Pascual-Ruiz, V., Guerra-Garcia, F., Alcami, J., Lopez-Botet, M., Manzanares, J. Familial defect of CD3 (T3) expression by T cells associated with rare gut epithelial cell autoantibodies. (Letter) Lancet 327: 1274-1275, 1986. Note: Originally Volume I. [PubMed: 2872416] [Full Text: https://doi.org/10.1016/s0140-6736(86)91413-3]
Timon, M., Arnaiz-Villena, A., Rodriguez-Gallego, C., Perez-Aciego, P., Pacheco, A., Regueiro, J. R. Selective disbalances of peripheral blood T lymphocyte subsets in human CD3 gamma deficiency. Europ. J. Immun. 23: 1440-1444, 1993. [PubMed: 8325321] [Full Text: https://doi.org/10.1002/eji.1830230706]
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