The maturation of T lymphocytes

Without T cells life cannot be sustained. In Case 2 we learned that an absence of B cells was compatible with a normal life style so long as infusions of immunolglobulin G were maintained. When children are born without T cells, they appear normal for the first few weeks or months. Then they begin to acquire opportunistic infections and die while still in infancy. An absence of functional T cells causes severe combined immunodeficiency (SCID). It is severe because it is fatal, and combined because, in humans, B cells cannot function without help from T cells, so that even if the B cells are not directly affected by the defect, both humoral and cell-mediated immunity are lost. Unlike X-linked agammaglobulinemia, which results from a monogenic defect, SCID is a single phenotype that can result from any one of several different genetic defects. The incidence of SCID is three times greater in males than in females and this male:female ratio of 3:1 is due to the fact that the most common form of SCID is X-linked. Approximately 55% of cases of SCID have the X-linked form of the disease.

T-cell precursors migrate to the thymus to mature, at first from the yolk sac of the embryo, and subsequently from the fetal liver and bone marrow. The rudimentary thymus is an epithelial anlage derived from the third and fourth pharyngeal pouches. By 6 weeks of human gestation, the invasion of precursor T cells, and of dendritic and macrophage cells, has transformed the gland into a primary lymphoid organ. T-cell precursors undergo rapid maturation in the thymus gland, which becomes the site of the greatest mitotic activity in the developing fetus. By 20 weeks of gestation mature T cells start to emigrate from the thymus to the secondary lymphoid organs. In all common forms of SCID the thymus fails to become a primary lymphoid organ. A small and dysplastic thymus, as revealed by biopsy, used to be the confirming diagnostic indicator of SCID.

The genetic defect responsible for the X-linked form of SCID has been mapped to the long arm of the X chromosomes at Xq11. From this region the gene encoding the ? chain of the interleukin-2 receptor was cloned, and found to be mutated in X-linked SCID.

The case of Martin Causubon: without T cells life cannot be sustained.

Mr. and Mrs. Causubon had a normal daughter 3 years after they were married. Two years later they had a son and named him Martin. He weighed 3.5 kg at birth and appeared to be perfectly normal. At 3 months of age, Martin developed a runny nose and a persistent dry cough. One month later he had a middle ear infection (otitis media) and his pediatrician treated him with amoxicillin. At 5 months of age Martin had a recurrence of otitis media. His cough persisted and a radiological examination of his chest revealed the presence of pneumonia in both lungs. He was treated with another antibiotic, clarithromycin. Mrs. Causubon noticed that Martin had thrush ( Candida spp .) in his mouth and an angry red rash in the diaper area. He was not gaining weight; he had been in the 50th percentile for weight at age 4 months but by 6 months he had fallen to the 15th percentile. His pediatrician had given him oral polio vaccine at ages 4 and 5 months and, at the same time, diphtheria-pertussis-tetanus (DPT) shots.

Martin's pediatrician referred him to the Children's Hospital for further studies. On admission to the hospital, he was found to be an irritable male infant with tachypnea (fast breathing). A red rash was noted in the diaper area as well as white flecks of thrush on his tongue and buccal mucosa. His tonsils were very small. He had a clear discharge from his nose and cultures of his nasal fluid grew Pseudomonas aeruginosa . Coarse, harsh breath sounds were heard in both lungs. His liver was slightly enlarged.

Martin's white blood count was 4800 cells µl- 1 (normal 5000-10,000 cells µl- 1 ) and his absolute lymphocyte count was 760 cells µl- 1 (normal 3000 lymphocytes µl- 1 ). None of his lympohocytes reacted with anti-CD3 and it was concluded that he had no T cells. Ninety-nine percent of his lymphocytes bound antibody against the B-cell molecule CD20 and 1% were natural killer cells reacting with anti-CD16. His serum contained IgG at a concetration of 30 mg dl- 1 , IgA at 27 mg dl- 1 , IgM at 42 mg dl- 1 (IgG levels are normally 400 mg dl- 1 ; the IgA and IgM levels were at the low end of the normal range for Martin's age). His blood mononuclear cells were completely unresponsive to phytohemagglutinin (PHA), concanavalin A (ConA), and pokeweed mitogen (PWM), as well as to specific antigens to which he had been previously exposed by immunization or infection - tenanus and diphtheria toxoids, and Candida antigen. His red cells contained normal amounts of adenosine deaminase and purine nucleoside phosphorylase. His B lymphocytes did not react with an antibody to the ? chain of the interleukin-2 receptor (IL-2R?). Cultures of sputum for bacteria and viruses revealed the abundant presence of respiratory syncytial virus (RSV).

At this point a blood sample was obtained from Martin's mother in order to examine her T cells for random inactivation of the X chromosome. It was found that her T cells exhibited complete nonrandom X-chromosome inactivation. HLA typing showed that Martin's sister had no matching HLA alleles. His parents, as expected, each shared one HLA haplotype with Martin.

Martin was treated with intravenous gamma globulin at a dose of 2 g kg- 1 body weight and his serum IgG level was maintained at 600 mg dl- 1 by subsequent IgG infusions. He was given aerosolized ribavirin to control his RSV infection and trimethoprim-sulfamethoxazole intravenously for prophylaxis against Pneumocystis carinii . Without any further preparation, Martin was given 500x10 6 bone marrow cells from his mother. The bone marrow donation from his mother was depleted of mature T cells by treating with a monoclonal antibody to T cells together with complement. After the transplant of the maternal bone marrow cells Martin was given cyclosporin and prednisone, to suppress any graft-versus-host disease. Sixty days after receiving the maternal bone marrow, Martin's blood contained 1000 maternal CD3 + T cells µl- 1 , which responded to PHA. His immune system was slowly reconstituted over the ensuing 3 months.

Severe Combined Immunodeficiency

Severe combined immunodeficiency, or SCID, presents the physician with a medical emergency. Unless there is known family history, which provides the opportunity to take corrective therapeutic measures before the onset of infections, children with SCID come to medical attention only after they have been infected with a serious opportunistic infection. As these infants die rapidly from such infections, even when treated adequately with antibiotics or anti-viral agents, measures must be taken quickly to reconstitute their immune system. In most cases of SCID, the first symptoms are those of thrush in the mouth and diaper area. A persistent cough usually betrays infection with Pneumocystis carinii . The third most common symptom of SCID is intractable diarrhea, usually due to enteropathic coliform bacilli.

As previously mentioned, SCID has many known genetic causes. The autosomal recessive form of SCID is most commonly caused by mutations in the purine degradation enzyme adenosine deaminase (ADA), and, more rarely, by mutations in another such enzyme, purine nucleoside phosphorylase (PNP). Defects in these enzymes lead to an accumulation of nucleotide substrates that are highly toxic to developing T cells, and to a lesser extent also developing B cells. The X-linked form of SCID differs from these autosomal recessive forms in that males with this form of the disease have normal numbers of B cells, but they fail to function in the absence of T cells.

Other cases of autosomal recessive SCID resemble the phenotype of X-linked SCID and have been ascribed to defects in the protein Jak-3, which transduces the signal from interleukin receptors, and defects in the a aplpha; chain of the IL-7 receptor. SCID can also be caused by defects in the ? and e components of the T-cell receptor, or molecules that transduce signals from the T-cell receptor such as the tyrosine kinase ZAP-70, and the DNA-binding protein NFAT, as well as by mutations in the IL-2 gene itself. In these cases, B cells are normal and at least some T cells are present, but they fail to activate in an adaptive immune response, so that a combined immunodeficiency is seen.

The discovery that mutations in the IL-2 receptor ? chain (IL-2R?) caused X-linked SCID in humans seemed contradictory o the finding that 'knocking-out' the IL-2 gene or genes for other components of the IL-2 receptor did not cause SCID in mice.

This apparent contradiction led to a search for the ? chain in other interleukin receptors. It was found that this chain also forms part of the IL-4, IL-7, IL-9, and IL-15 receptors, and it was renamed the gamma common (?c) chain. Jak-3 transduces the signal from all these receptors by binding the ?c chain.

Most infants with SCID can be rescued by a successful bone marrow transplant. Continued gamma-globulin therapy is usually necessary but with this, and successfully engrafted T cells, SCID infants survive to lead a relatively normal life. Gene therapy has also been tried successfully in some patients with X-linked SCID.

For additional information please visit http://www.geneclinics.org/query?dz=x-scid .

We would like to thank Dr. Fred Rosen and Dr. Raif Geha for their contribution of the above information from their book, "Case Studies in Immunology 3."

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