Primary Defects of Cellular Immunity

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Chapter 119 Primary Defects of Cellular Immunity

In general, patients with defects in T-cell function have infections or other clinical problems that are more severe than in patients with antibody deficiency disorders (see Table 116-4). The defective gene products for some primary T-cell diseases are identified (Table 119-1). These individuals rarely survive beyond infancy or childhood. Transplantation of thymic tissue, or of major histocompatibility complex (MHC)-compatible sibling or haploidentical (half-matched) parental hematopoietic stem cell, is the treatment of choice for patients with primary T-cell defects (Chapter 129).

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.

Genetics and Pathogenesis

DiGeorge syndrome occurs in both males and females. Microdeletions of specific DNA sequences from chromosome 22q11.2, the DiGeorge chromosomal region (DGCR), are found in a majority of cases. Several candidate genes have been identified in this region. A T-box transcription family member, TBX1, has been implicated as an etiology for most of the major signs of DGS. There appears to be an excess of 22q11.2 deletions of maternal origin. Polymerase chain reaction (PCR)-based genotyping using microsatellite DNA markers located within the commonly deleted region permits rapid detection of such microdeletions. Conotruncal heart defects and 22q deletions are observed in DiGeorge syndrome, velocardiofacial syndrome (VCFS), and conotruncal anomaly face syndrome (CTAFS). The CATCH 22 syndrome (cardiac, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia) includes the broad clinical spectrum of conditions with 22q11.2 deletions. Other deletions associated with DiGeorge and velocardiofacial syndromes have been identified on chromosome 10p13 (Chapter 76).

Variable hypoplasia of the thymus and parathyroid glands defines partial DiGeorge syndrome, which is more frequent than total aplasia; aplasia is present in <1% of patients with DiGeorge syndrome and defines complete DiGeorge syndrome. Slightly less than half of patients with complete DiGeorge syndrome are hemizygous at chromosome 22q11. Approximately 15% are born to diabetic mothers. Another 15% of infants have no identified risk factors. Approximately one third of infants with complete DiGeorge syndrome have CHARGE association (coloboma, heart defect, choanal atresia, growth or developmental retardation, genital hypoplasia, and ear anomalies including deafness). Mutations in the chromodomain helicase DNA binding protein 7 (CHD7) gene on chromosome 8q12.2 are found in approximately 60-65% of individuals with CHARGE syndrome. Concentrations of serum immunoglobulins in DiGeorge syndrome are usually normal, but IgA may be diminished and IgE elevated. Other laboratory findings vary depending on the degree of thymic dysfunction.

Absolute lymphocyte counts are usually only moderately low for age. The CD3 T-cell counts are variably decreased in number, corresponding to the degree of thymic hypoplasia, resulting in an increased percentage of B cells. Lymphocyte responses to mitogen stimulation are absent, reduced, or normal, depending on the degree of thymic deficiency. Thymic tissue, when found, contains Hassall corpuscles, normal density of thymocytes, and corticomedullary distinction. Lymphoid follicles are usually present, but lymph node paracortical areas and thymus-dependent regions of the spleen show variable degrees of depletion.