Patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) typically exhibit thymic hypoplasia, conotruncal cardiac defects, and hypoparathyroidism. The immunodeficiency that results from the thymic hypoplasia has been extensively described and consists primarily of T-cell lymphopenia. A curious feature of the T-cell lymphopenia is that the age-related rate of decline of T-cell numbers is slower in patients than controls. This leads to T-cell numbers in adulthood that are minimally decreased compared with controls. This suggests that homeostatic mechanisms might be acting to preserve the peripheral blood T-cell numbers in patients. We characterized changes in CD4/ CD45RA and CD4/CD45RO T-cell populations in patients and controls of various ages and determined T-cell recombination excision circles and telomere length within the CD4/CD45RA population. Patients had evidence of accelerated conversion of naive to memory cells and had evidence of more extensive replicative history within the CD4/CD45RA compartment compared with controls. Oligoclonal T-cell receptor (TCR) V␤ families and missing V␤ families were seen more often in patients than controls. These data are consistent with homeostatic proliferation of T cells in patients with limited T-cell production due to thymic hypoplasia. ( IntroductionChromosome 22q11.2 deletion syndrome is a disorder that is classically associated with conotruncal cardiac anomalies, thymic hypoplasia, and hypoparathyriodism. 1 DiGeorge syndrome, velocardiofacial syndrome, Opitz/GBBB syndrome, Coloboma, heart defects, atresa of choanae, retardation of growth and development, genital anomalies, ear anomalies (CHARGE) syndrome, and conotruncal anomaly face syndrome have been associated with the deletion. The thymic hypoplasia is seen in more than 80% of the patients with the deletion regardless of the other clinical manifestations of the syndrome. The immunodeficiency arising as a consequence of the thymic hypoplasia in patients with the deletion syndrome has been studied for nearly 50 years, and it is now known to be extremely variable. [2][3][4][5] The spectrum of immunodeficiency ranges from absent T cells due to thymic aplasia to normal T-cell numbers. 2,6 T-cell function is typically preserved, although standard mitogen proliferation assays are usually diminished when the T-cell count is very low, corresponding to the diminished numbers of cells competent to respond to the stimulus. 4 Immunoglobulin A (IgA) deficiency, hypogammaglobulinemia, and defects in functional antibody production have been occasionally described and are thought to be secondary to the T-cell defect. [7][8][9] The clinical picture for patients with chromosome 22q11.2 deletion syndrome is similarly diverse. Early descriptions of the syndrome emphasized life-threatening infections; however, most of these patients were ascertained due to absent or nearly absent T cells. 3,10 Recent descriptions of populations with the deletion have noted that the very severe immunodeficiency...

Quantitation of cytokine production is a valuable adjunct to standard immunologic assays in defining several pathologic processes. Nevertheless, there is little agreement about which tissues should be assayed, which type of assay should be performed, and which stimulation protocol should be used. As these types of assays enter the clinical arena, there is need for standardization. There is also a need to maximize the amount of information which may be derived from a single sample. We compared secreted interleukin 4 (IL-4), IL-2, IL-6, tumor necrosis factor alpha (TNF-␣), and gamma interferon proteins as measured by enzyme-linked immunosorbent assay with intracellular cytokine production (IL-2 and gamma interferon) as detected by flow cytometry and quantitative competitive PCR for IL-2, IL-4, TNF-␣, and gamma interferon mRNA and cDNA. Results from unstimulated cells and cells stimulated with phorbol myristate acetate, phytohemagglutinin, and phorbol myristate acetate plus phytohemagglutin were compared. All three methodologies detected significant stimulation of cytokine production. The combination of phytohemagglutinin and phorbol myristate acetate was overall the most-potent stimulus.

A microsatellite repeat polymorphism was identified in the 3' flanking region of the human ETS1 gene. Sequencing revealed two CA repeat segments in close proximity. Seven different alleles comprising various combinations of CA repeat units were identified in a healthy control population. Because ETS1 plays a role in lymphocyte development and function, apoptosis, and inflammation, we examined whether any of these polymorphisms were associated with a systemic inflammatory condition, systemic lupus erythematosus (SLE). Inheritance of this disease is polygenic and a recent genome-wide screen for SLE susceptibility loci revealed linkage with chromosome 11q14-23, the region in which the ETS1 gene lies. This region has also been identified as a general autoimmune susceptibility region. None of the seven distinct ETS1 alleles appeared statistically more frequently in SLE patients than controls, however, two alleles were associated with particular clinical manifestations. Allele 1 is associated with discoid lesions and allele 7 is associated with vasculitis. While this polymorphism does not directly affect the coding region of ETS1, it may be a marker for overexpression of a particular isoform or inheritance of another polymorphism which does affect function. These data suggest that ETS1 may be involved in the phenotypic expression of systemic lupus erythematosus.