A familial defect of T-cell receptor (TCR)/CD3 complex expression by T lymphocytes, due to a selective deficiency of the CD3γ subunit, was reported in 1986.1,2 Two brothers (V and D) had inherited mutations in both the paternal and maternal CD3γ genes that severely truncated the protein.3 V had very low counts of peripheral blood CD3+ cells and a low density of TCR/CD3 molecules per cell and a severe combined immunodeficiency and autoimmune enteropathy with gut epithelial cell autoantibodies (GECA, cytoplasm 1/16, and brush border greater than 1/64). He died at 32 months of age after severe infections and autoimmunity. Still-living sibling D shared the same genotype regarding CD3γ but had milder laboratory immunological and clinical parameters.4
D was born in 1981 and began showing clinical symptoms at 12 months of age, including infrequent episodes of repeated Gram-positive and -negative bacterial infections (easily controlled), asthma, diarrhea (which spontaneously disappeared after 6 years), vitiligo, and atopic eczema. A lymphocytary meningitis of probable viral origin (which was quickly overcome) and a mild dilated cardiomyopathy (DCM; probably secondary to unrecorded viral infections) with slight valvular insufficiency were diagnosed at the age of 11 years. Otherwise, D has had a normal development and life (including playing frequent short football matches) and is currently 18 years old.
Table 1 summarizes D's most relevant immunological parameters since 1995. Mean CD3+ cells percentage remains approximately 20% lower in D (ranging from 44% to 57%) than in normal controls (ranging from 60% to 80%), and the surface density of CD3 molecules per cell is 4 times lower in D than in normal controls. Serum autoantibodies were never found before June 1999, when antityroglobulin (185 IU/mL; normal range, 0-89 IU/mL) and antithyroid peroxidase autoantibodies (251 IU/mL; normal range, 0-41 IU/mL) appeared. They were also positive in January 2000 and have been maintained so until this writing.5 Thyroid hormones (T4, free T4, and TSH) are normal,6 and thyroid clinical symptoms are absent. Several D alterations (vitiligo, DCM, specific thyroid autoantibodies) may certainly have an organ-specific autoimmune etiopathogeny.7 These autoimmune anomalies may be directly related to the CD8 cytotoxic/suppressor−CD4 lymphocyte disbalance and to the persistent high numbers of memory T-cell clones (CD4+CD45R0+) (Table 1). Autoantibodies against GECA, intrinsic factor, insulin, gliadin, kidney glomerular membrane, islet cell, antinuclear, double-stranded DNA, RNP, SSb, Sm, Ro, Scl-70, mitochondrial, smooth muscle, epithelial basement membrane, centromere, parietal cell, intercellular substance, striated muscle, and adrenal antibodies have been repeatedly negative.5 8
Previous studies showed that the γ chain is the CD3 component that interacts with the αβ TCR heterodimer. But our data support that a CD3 chain other than γ may also associate to αβ (ie, the highly homologous δ).4 This could explain D's relatively mild clinical course and cellular phenotype (Table 1). Also, redundant and overlapping functions among proteins of the immune system permit the existence of healthy but immunodeficient individuals, the best known being congenital C2, IgA, HLA class I, and adenosine deaminase deficiencies. Immune function is apparently sufficient for the survival of the CD3γ-lacking D patient, but continuing a close follow-up will enable us to determine the real importance of adaptive versus nonadaptive immune mechanisms throughout an individual's life and to study the mechanisms that relate autoimmunity and immunodeficiency.
Supported by grants from the Ministerio de Educación (PM95-57 and PM96-21) and Comunidad de Madrid (06/70/97 and 8.3/14/98).
