Thymic Hypoplasia (DIgeorge Syndrome)

Thymic hypoplasia results from dysmorphogenesis of the 3rd and 4th pharyngeal pouches during early embryogenesis, leading to hypoplasia or aplasia of the thymus and parathyroid glands. Other structures forming at the same age are also frequently affected, resulting in anomalies of the great vessels (right-sided aortic arch), esophageal atresia, bifid uvula, congenital heart disease (conotruncal, atrial, and ventricular septal defects), a short philtrum of the upper lip, hypertelorism, an antimongoloid slant to the eyes, mandibular hypoplasia, and low-set, often notched ears (Chapters 76 and 102). The diagnosis is often first suggested by hypocalcemic seizures during the neonatal period.

Defective Expression of the T-Cell Receptor–CD3 Complex (Ti-CD3)

The first type of this disorder was found in two brothers in a Spanish family. The proband presented with severe infections and died at 31 mo of age with autoimmune hemolytic anemia and viral pneumonia. His lymphocytes had responded poorly to mitogens and to anti-CD3 in vitro and could not be stimulated to develop cytotoxic T cells. His antibody responses to protein antigens had been normal, indicating normal T-helper-cell function. His 12 yr old brother was healthy but had almost no CD3-bearing T cells and had IgG2 deficiency similar to his sibling. The defect in this family was due to mutations in the gene encoding the CD3γ chain (Fig. 119-1).

Figure 119-1 Locations of mutant proteins (X) in activated CD4 T cells identified in primary immunodeficiency diseases. ZAP-70, zeta-associated protein 70; SLAM, signaling lymphocyte activation molecule; SH2D1A, SLAM-associated protein; ATM, ataxia telangiectasia mutation; NFAT, nuclear factor of activated T cells; Jak3, Janus kinase 3; WASP, Wiskott-Aldrich syndrome protein.

(From Buckley RH: Primary immunodeficiency diseases due to defects in lymphocytes, N Engl J Med 343:1313–1324, 2000.)

The second type of this disorder was diagnosed in a 4 yr old French boy who had recurrent Haemophilus influenzae pneumonia and otitis media in early life but is now healthy. He had a partial defect in expression of Ti-CD3, and thus the percentage of CD3 cells was about half-normal, but the level of expression is markedly decreased. The defect was shown to be due to two independent CD3ε gene mutations, leading to defective CD3ε chain synthesis. There was a splice site mutation on one allele that did not totally abrogate the normal intron 7 splicing, thus there was partial expression of CD3 on the T cells. His T cells did not proliferate normally in response to anti-CD3 or anti-CD2, but did respond normally to stimulation with anti-CD28 or antigens, such as tetanus toxoid. Thus, this mutation did not result in failure of T-cell development, whereas mutations in the portions of the gene that encode the extracellular component of CD3ε result in a profound deficiency of circulating mature CD3 T cells (Chapter 120).

Defective Cytokine Production

IL-12, which is produced by activated antigen-presenting cells, promotes the development of Th1 responses and is a powerful inducer of IFN-γ production by T and natural killer (NK) cells. A child with bacille Calmette-Guérin (BCG) and Salmonella enteritidis infections had a large homozygous deletion within the IL-12 p40 subunit gene precluding expression of functional IL-12 p70 cytokine by activated dendritic cells and phagocytes. IFN-γ production by the child’s lymphocytes was therefore markedly impaired. IL-12 may be essential for protective immunity to intracellular bacteria such as Mycobacterium and Salmonella.

T-Cell Activation Defects

T-cell activation defects are characterized by the presence of normal or elevated numbers of blood T cells that appear phenotypically normal but fail to proliferate or produce cytokines in response to stimulation with mitogens, antigens, or other signals delivered to the T-cell antigen receptor (TCR), owing to defective signal transduction from the TCR to intracellular metabolic pathways. These patients have problems similar to those of other T-cell–deficient individuals, and some with severe T-cell activation defects may clinically resemble SCID patients.

CD8 Lymphocytopenia Due to Mutations in the Gene Encoding Zeta-Associated Protein 70 (ZAP-70)

Patients with this T-cell activation defect present during infancy with severe, recurrent, and often fatal infections. The majority of cases are reported among Mennonites. These patients have normal or elevated numbers of blood B cells and low to elevated serum immunoglobulin concentrations. Their blood lymphocytes exhibit normal expression of the T-cell surface antigens CD3 and CD4, but CD8 cells are almost totally absent. These cells fail to respond to mitogens or to allogeneic cells in vitro or to generate cytotoxic T lymphocytes. NK cell activity is normal. The thymus of one patient exhibited normal architecture with normal numbers of CD4:CD8 double-positive thymocytes but an absence of CD8 single-positive thymocytes. This condition is due to mutations in the gene encoding zeta-associated protein 70 (ZAP-70), a non-src family protein tyrosine kinase important in T-cell signaling that is localized to chromosome 2q12 (see Fig. 119-1). The normal number of CD4:CD8 double-positive T cells results because the thymocytes can use the other member of the same tyrosine kinase family, Syk, to facilitate positive selection. Syk is present at fourfold higher levels in thymocytes than in peripheral T cells, possibly accounting for the lack of normal responses by the CD4 blood T cells.

Another condition that can result in CD8 deficiency is a mutation in the gene that encodes CD8α. There is a deficiency of cytotoxic T cells in that condition, but the functional immune defect is mild compared to that of ZAP-70 deficiency.

P56 Lck Deficiency

A 2 mo old male infant who presented with bacterial, viral, and fungal infections was found to be lymphopenic and hypogammaglobulinemic. B and NK cells were present, but there was a low number of CD4 T cells. Mitogen responses were variable. The T cells failed to express the activation marker CD69 when stimulated through the T-cell receptor but did when stimulated with phorbol myristate acetate and a calcium ionophore, suggesting a proximal signaling defect. Molecular studies revealed an alternatively spliced transcript for p56 lck that lacked the kinase domain.

Autoimmune Polyendocrinopathy-Candidiasis Ectodermal Dysplasia (Apeced)

Patients with this syndrome present with chronic mucocutaneous candidiasis and autoimmune polyendocrinopathy, usually producing hypoparathyroidism and Addison disease. Additional features include hypogonadism, chronic active hepatitis, alopecia, vitiligo, pernicious anemia, and Sjögren syndrome. APECED, or autoimmune polyendocrinopathy syndrome type I (APS1), is due to a mutation in the autoimmune regulator (AIRE) gene. The gene product, AIRE, is expressed at high levels in purified human thymic medullary stromal cells and is thought to regulate the cell surface expression of tissue-specific proteins such as insulin and thyroglobulin. Expression of these self-proteins allows for the negative selection of autoreactive T cells during their development. Failure of negative selection results in organ-specific autoimmune destruction. The overall significance of AIRE in the establishment and maintenance of T-cell self-tolerance is not well understood.

Most pediatric patients are identified by the presence of mucocutaneous candidiasis and hypoparathyroidsim and later develop insidious signs of Addison disease (Chapter 565).