Immunodeficiency and Autoimmunity in 22q11.2 Deletion Syndrome

Abstract

22q11.2 deletion syndrome is the commonest chromosome deletion syndrome. 22q11.2 deletion may result in variable clinical phenotypes which may differ even between patients with identical deletions. Abnormal pharyngeal arch development results in defects in the development of the parathyroid glands, thymus and conotruncal region of the heart. Defective thymic development is associated with impaired immune function. ‘Complete’ DiGeorge syndrome with total absence of the thymus and a severe T‐cell immunodeficiency accounts for <0.5% of patients. The majority of patients with 22q11.2 deletion syndromes have ‘partial’ defects with impaired thymic development rather than complete absence with variable defects in T‐cell numbers. Immunodeficiency in these patients is not solely due to T‐cell deficiency and abnormalities of T‐cell clonality or impairment of proliferative responses may play a role. Humoral deficiencies including defects in the B‐cell compartment have also been identified in these patients. 22q11.2 deletion syndrome patients are at increased risk of a variety of autoimmune diseases. A number of immune defects may predispose to the development of autoimmunity in these patients including increased infection, impaired development of natural T‐regulatory cells and impaired thymic central tolerance.

CHARGE syndrome: a review of the immunological aspects

“…An explanation of the autoimmune predisposition in 22q11.2 deletion syndrome might be a reduced level of natural regulatory T-cells (nTreg). 47 These nTregs are important in the maintenance of self-tolerance, that is, suppression of the immune response against self-antigens. In our collected cohort of CHARGE patients, nTreg levels were mentioned in only two patients: one patient had few nTregs (no value was mentioned) 23 and the other patient had higher proportions of nTregs compared with two adult controls.…”

“…These self-antigens are important for the deletion of autoreactive T-cells. 61 McLean-Tooke et al 47 suggested that the reduced number of nTregs seen in 22q11.2 deletion syndrome is related to thymic function and structure. So the autoimmune predisposition in 22q11.2 deletion syndrome might be explained by both impaired thymic and T-cell development.…”

Two Cases of 22Q11.2 Deletion Syndrome and Type 1 Diabetes

“…1. Bracket shows the most common area of deletion in 22q11.2 deletion syndrome, with 85% of patients missing the genes in this region (7). A smaller subset of patients is missing a smaller area, which may not include the autoimmunity locus identified.…”

“…Autoimmune disease occurs about 10-times more commonly in patients with 22q11.2DS compared with the general population (7,10). Polyarticular juvenile rheumatoid arthritis is estimated to occur up to 150-times more frequently (11), autoimmune cytopenias affect 20-to 200-times more patients (varies by source and type of cytopenia) (12), and autoimmune thyroid disease is found in almost 10% of patients, 1.8% with hyperthyroidism and 7.7% with hypothyroidism (13).…”

“…Patients with 22q11.2DS also have an increased risk of autoimmune disorders, which may be due to a reduction in CD25+ T-regulatory cells from the thymus and therefore a reduced ability to suppress autoimmune reactions (6,7).…”