March 2001
CHICAGO - Despite their rarity, primary immunodeficiency diseases provide important clinical lessons in cell function and antibody response.
"I consider immunodeficiency disorders the watershed of immunology," said Thomas A. Fleisher, MD, chief of the department of laboratory medicine at the National Institutes of Health in Bethesda, Md. "Much of what we have learned about immunodeficiencies has crossed the boundary and is applicable to a variety of other diseases. I think their impact on clinical medicine far outweighs the frequency of these disorders."
| The 10 Warning Signs of Primary Immune Deficiency |
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Primary immune deficiency causes children to have infections that come back frequently or are unusually hard to cure. In America alone, up to 500,000 people suffer from one or more of the 70 known primary immune deficiency diseases. Here are 10 warning signs. 1.
Eight or more new ear infections within 1 year |
The three general categories of these disorders are combined immunodeficiencies, immunodeficiencies involving primarily defective antibody production and other immunodeficiencies.
A patient with severe combined immunodeficiency (SCID), such as the famous "Bubble Boy" in Texas, represents the most serious of these conditions. "These infants present with recurrent lung, gastrointestinal and mucosal infections, along with failure to thrive and chronic diarrhea," Fleisher said. They lack a thymus and tonsils. "If a child in your care is suspected of having SCID and needs a transfusion, the blood must be irradiated. This is an absolute requirement," he said.
Fortunately, "the past seven years have been remarkable in identifying the underlying genetic basis of SCID," Fleisher said. The three major groupings are patients who lack both T cells and B cells (T-/B-); patients who lack T cells but have B cells (T-/B+); and disease based on an enzyme defect (adenosine deaminase).
Patients classified as T-/B- SCID have difficulty with their T-cell antigen receptor or with their HLA molecule. "It doesn't matter which end of the equation is impacted," Fleisher said. "These patients cannot generate T cells, and they also often tend not to generate B cells." On the other hand, the T-/B+ SCIDs have a problem with a cytokine receptor or the intracellular signaling by this cytokine receptor. "Cytokines not only signal an immune response, but they also are critical in the thymus and in the bone marrow for the development of T cells and B cells," he said. In contrast, the immune deficiency with the adenosine deaminase (ADA) deficiency results from the accumulation of toxic products that kill the lymphocytes.
Bone marrow transplantation, which can cure SCID, opened the door for cellular reconstitution for many diseases. "It is clear now that cytokine pathways are critical for lymphoid development and function," he said. In addition, the evolution of nucleoside analogs to treat selected lymphoid malignancy and autoimmune disorders have been based on ADA-deficient SCID. "We took an immune disorder and developed an approach to immune suppression through drugs that mimic the disorder," Fleisher said. The first gene therapy trials were also initiated in patients with ADA-deficient SCID.
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The antibody deficiency known as X-linked agammaglobulinemia (XLA) is characterized by recurrent sinopulmonary infections, absence of specific antibody response, absence of circulating B cells and a defective tyrosine kinase. "Consequently, these patients have no cells circulating that can't make antibody," he said. These patients also have a higher incidence of enteroviral infections. Moreover, "the B cell absence may be an additional confounding factor beyond the absence of antibody, which increases susceptibility to serious infection with enterovirus," he said.
Enteroviral infections normally are more common in children than adults. "It may well be that if antibody deficiency does not start until age 35, your susceptibility to enteroviral infection is not substantially increased," he said.
The X-linked hyper-IgM syndrome, which presents with recurrent bacterial infections. This disorder identifies the important role of direct B cell/T cell interaction for immunoglobulin class switching. "However, it is not simply a defect between the T cell/B cell talk. There is more going on," he said. "The T cell monocyte interaction is a critical step in responding to Pneumocystis and certain other opportunistic infections. A protein on the T cell that can bind to both a B cell and a monocyte appears to be the root cause for an inability to switch from IgM to IgG or IgA or IgE."
Experimental models suggest that by blocking the CD40 ligand, "you probably can induce tolerance to certain antigens," he said.
For more information:
- Fleisher TA. Basic immunology (traditional). Presented at the American Academy of Pediatrics annual meeting. S554. Oct. 28-Nov. 1, 2000. Chicago.
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