Implications/Analysis of Family History

Immunodeficiency disorders present as recurrent and persistent infections. Because these disorders may be inherited or acquired, a family history indicating that other members have been affected similarly would indicate a genetic basis for the infections. A history indicating that only male infants have been affected directs the physician toward a defect in a gene encoded on the X chromosome. Genetic defects in which both male and female family members are also affected generally indicate an autosomal recessive mode of inheritance. In this particular case, Mark’s family history indicated that both sexes have been affected and so the cause of these infections is unlikely to be an X-linked disorder.

Implications/Analysis of Clinical History

Mark has presented with viral, fungal, and bacterial infections, suggesting that his problem is not limited solely to a B cell or a T cell defect. Although defects in components of the innate immune system can lead to increased susceptibility to these types of infections, adaptive immune defects that result in increased susceptibility to bacterial infections indicate a B cell defect whereas viral and fungal infections typify a T cell defect. Small tonsils and lymph nodes in the presence of active infection would suggest a B cell defect.

Implications/Analysis of Laboratory Investigation

Although the chest radiograph did indicate that Mark has pneumonia, there is no mention of an anomaly regarding the thymic shadow, suggesting the organ of differentiation for T cells is intact (see Case 2). Laboratory investigations should focus on both T cell and B cell numbers and function.

Additional Laboratory Tests

A total blood cell count and differential indicated a gross deficiency in lymphocyte numbers. Quantification of serum IgG and response to immunization confirmed the B cell deficiency, as did the flow cytometry analysis. Given the B cell defect, it was not surprising that serum IgG was low and tonsils/lymph nodes were barely detectable. The low serum IgG levels, despite immunization, also indicate a B cell defect. Flow cytometry results also indicated that both T cell (CD3+) and NK cell (CD3-, CD56+) numbers were drastically decreased. B cells, T cells, and NK cells are derived from a lymphoid stem cell during hematopoiesis.

Bone Marrow Transplant

SCID is often referred to as the “bubble boy” disease, in reference to David Vetter, a young boy who lived for 12 years in a plastic, sterile bubble but succumbed to infection after a bone marrow transplant from his sister who carried a latent Epstein-Barr virus (human herpesvirus 4) infection.

For both SCID and XSCID (and Omenn syndrome) bone marrow transplantation is the treatment of choice if a matched donor can be identified. Because the graft (bone marrow) is a source of lymphohematopoietic cells capable of recognizing the host as foreign, development of graft versus host disease can potentially occur except for grafts between identical twins (see Introduction, Transplantation Immunology, Section V).

Enzyme Therapy (Depending on Etiology)

For SCID secondary to a deficiency in adenosine deaminase (ADA), regular injections of ADA linked to polyethylene glycol (PEG-ADA) are often effective. PEG is linked to the ADA to delay degradation of the ADA.

Pharmacologic Treatment

In some cases there is a very leaky syndrome (incomplete loss of T cells and B cells); and for these cases, lifelong treatment of infections “as they appear” is possible. However, for more severe cases, other forms of therapy must be considered.

Gene Therapy

Because the gene products absent in all of the aforementioned causes of SCID and XSCID have been identified, a gene therapy approach may be the treatment of choice in the future. Gene therapy for ADA-SCID was introduced in 1990 when three physicians working at the National Institutes of Health infused T cells carrying a normal ADA gene into Ashanthi Desilva, a 4-year-old girl for whom PEG-ADA was not optimally effective. Today, she is alive and well but continues to receive injections of PEG-ADA, albeit at much lower doses.

In the early gene therapy clinical trials, a genetically altered retrovirus carrying a normal ADA gene was allowed to infect the patient’s T cells in vitro and then the T cells were activated to proliferate. When a sufficient number of T cells had been generated, they were infused into the patient at regular intervals for 2 years. Because retroviruses integrate (randomly) into host chromosomes, the normal ADA gene was now an integral part of the DNA in the transfected T cells and was present in all their progeny after T cell activation.

More recently, physicians from the Hospital Necker in Paris have treated children with XSCID by infusing genetically altered stem cells isolated from their bone marrow, instead of using mature T cells to carry the vector. Consequently, all myeloid and lymphoid cells generated during hematopoiesis will carry the normal gene. To date, these patients are doing well and are reported to have developed serum antibodies after pediatric DPT (diphtheria, pertussis, and tetanus toxoid) immunization.

Adenosine Deaminase

One of the earliest defects identified in SCID patients was a deficiency in ADA, an enzyme required for purine metabolism and which is most active in lymphocytes, particularly T lymphocytes. In the absence of this enzyme, toxic metabolites accumulate and inhibit DNA synthesis so proliferation does not occur in response to polyclonal activators.

Deficiency in CD132 (Common γ Chain)

CD132, a signaling molecule in several cytokine receptor complexes, is encoded on the X chromosome and so this immunodeficiency is referred to as XSCID. Receptor complexes, in which CD132 is a component, bind the following interleukins: IL-2, IL-4, IL-7, IL-9, and IL-15 (Fig. 1-2). IL-7 plays an important role in the development of lymphoid progenitors during hematopoiesis; however, knockout mice for IL-7 are grossly deficient in T cells and only moderately deficient in B cells, suggesting that IL-7 is required for T cell maturation in the thymus.

FIGURE 1-2 Defects in CD132 lead to X-linked severe combined immunodeficiency disorder (XSCID). Receptor complexes through which cytokines IL-2, IL-4, IL-7, IL-9, and IL-15 signal all have CD132 as a component of that complex. Defects in this protein, therefore, have a significant impact on immune responses because so many cytokine receptors are affected.

(Modified with permission from Gorczynski R, Stanley J: Clinical Immunology. Austin, Landes, 1999.)

Mutations, ranging from nonsense mutations to deletion of entire exons, in the gene encoding CD132 lead to SCID because multiple cytokine systems are simultaneously affected. One of the diagnostic procedures for identifying these individuals is genomic sequencing of CD132. Because CD132 is encoded on the X chromosome, males are predominantly affected. Mark’s family history indicated that both males and females had presented with this disorder; therefore, it is unlikely that Mark has XSCID. Furthermore, the white blood cell differential indicated a gross deficiency of both B cells and T cells.

Deficiency in JAK 3

CD132 is a transmembrane protein whose cytoplasmic domain interacts with JAK 3 (Janus tyrosine kinase 3) after cytokine binding (Table 1-1). JAK 3 activates, by phosphorylation, the latent transcription factor, STAT 5 (signal transducer and activator of transcription), which then translocates to the nucleus. Stable T cell lines derived from patients with a deficiency in JAK 3 do not proliferate in response to IL-2, a T cell growth factor that signals via a receptor complex that includes CD132. An in vitro reconstitution study, in which a retroviral vector encoding JAK 3 was introduced into these cell lines, restored JAK 3 expression and proliferation of T cells in response to IL-2. Not surprisingly, JAK 3–deficient patients have a clinical phenotype virtually identical to that of XSCID, even though JAK 3 is encoded on chromosome 19 and not on the X chromosome.

Defect in Recombinase Activation Gene

Theoretically, in any given individual, it is possible to generate 10¹² different T cell (or B cell) clones each bearing antigen specific receptors that consist of a unique variable and a constant region. This uniqueness is made possible because the variable regions are made up of sections of DNA referred to as variable (V), diversity (D), and joining (J) segments. Multiple versions of each segment are present in the germline genes (see Case 2). In the construction of a gene encoding any variable region, the gene segments are recombined in a different sequence from that present in germline DNA. This process, termed somatic recombination, requires the activation of recombinases, nucleoprotein products of the RAG1 and RAG2 genes (recombination-activating genes).

Mutations in RAG1 and RAG2 have been identified. Although many of the mutations are missense mutations, deletional or splice mutations have also been identified. Patients with a total defect in these recombinase activation genes are unable to construct variable regions for the B cell and T cell antigen receptors, which results in an SCID phenotype. However, some mutations impair but do not totally abolish the recombination activity such that a very restricted repertoire of T cells is generated. Patients with this rare form of SCID, called Omenn syndrome, present with symptoms of graft versus host disease. In the absence of an allograft, this clinical presentation can be explained by the generation of an autoreactive T cell population that was not negatively selected during development in the thymus. In essence, the presence of a rash, lymphadenopathy, diarrhea, and a high lymphocyte (activated T cell) count distinguishes Omenn syndrome from the traditional SCID patients. Although not typical, there are reports of patients with RAG1 mutations who have B cells and circulating antibodies but no T cells.