Immune Deficiencies
Immune deficiencies may be due to genetic or acquired defects, and these defects lead to increased risks to certain infectious diseases depending upon the specific immune defects. Much of the basic information concerning the development and function of the immune system has been learned from investigations of inherited, congenital, and acquired defects of the system. Examples of the principal defects that have lead to an elucidation of the immune system are as follows.
The principal genetic defects in the immune system are summarized in Table 1-4. They are as follows.
Patients with these diseases display few T lymphocytes, decreased T cell functions, poor antibody formation, and variable numbers of B cells and serum concentrations of immunoglobulins. As a consequence of the deficiencies in T cells, these patients are very susceptible to opportunistic pathogens, including Candida albicans, Salmonellae, Pneumocystis carinii, Cytomegalovirus, and Varicella zoster virus. Patients with SCID usually die before the age of two years, unless definitive immunologic interventions are instituted.
Specific treatments have been devised for patients with SCID. Many patients have been treated successfully with bone marrow transplants to supply normal stem cells. Patients with adenosine deaminase deficiency may also be managed by infusing the enzyme packaged with polyethylene glycol. Recently, some patients with adenosine deaminase deficiency have been successfully treated with gene therapy. Although the beneficial effects have not been permanent, nevertheless, they are encouraging.
Two major intrinsic defects in the function of phagocytic cells have been recognized. The first one is an autosomal recessive defect in the formation of the common β-subunit of the family of adherence glycoproteins (integrins). The deficiency interferes with the ability of these leukocytes to adhere to the surface of endothelial cells. Consequently, the motility of these cells on two-dimensional surfaces is impaired. Thus, this defect results in bacterial infections in interstitial sites, such as in the skin and periodontium.
The second disorder, chronic granulomatous disease, was the first recognized genetic defect of the function of phagocytic cells. The disease is X-linked in ~ 70% of affected patients. In those cases, the gene for the gp90 protein subunit of cytochrome b558 is abnormal. Consequently, the protein is not produced, the cytochrome does not persist, and intracellular killing is impaired. Less frequently (~ 3% of cases), the disease is due to a defect in the autosomal gene for the lower molecular weight subunit of the heterodimer, p22phox. Autosomal defects in genes for cytoplasmic proteins that stabilize the cytochrome have also been recognized.
In these disorders, phagocytes are unable to mount a respiratory burst and therefore are unable to produce toxic oxygen compounds, such as hydrogen peroxide, which are required for intracellular killing of catalase-positive microorganisms such as Candida albicans, Escherichia coli, and Serratia species. The failure to kill catalase-positive microorganisms occurs because the microbial agents do not supply the oxygen substrates required for intracellular killing. In contrast, these dysfunctional neutrophils kill catalase-negative microorganisms such as the streptococci since those microorganisms bring hydrogen peroxide into the phagolysosome.
Genetic Defects
Table 1-4
X-Linked Agammaglobulinemia
In this immunoglobulin deficiency disease, there is a genetic defect in the development of B cells from pre-B cells in the bone marrow. The defect is due to mutations in the gene that encodes for B cell tyrosine kinase. Consequently, the B cells are not produced. Because of the block in the development of B cells, germinal centers, plasma cells, and specific antibodies are profoundly reduced. The rest of the immune system is normal. Affected individuals are unusually susceptible to infection by virulent encapsulated respiratory bacteria and enteroviruses. These patients benefit greatly from intravenous infusions of human IgG.Hyper-IGM Antibody Deficiency
A second X-linked defect in antibody formation, the hyper-IgM antibody deficiency, is characterized by a block in immunoglobulin class switching. Consequently, IgM (and IgD) antibodies are produced, but IgA and IgG antibodies are not. These patients are also unusually susceptible to infection by virulent encapsulated respiratory bacteria. The disease is due to mutation in the gene that encodes for CD40 ligand (CD39) on T cells. Because of the defect, T and B cell interactions are insufficient for immunoglobulin class switching. These patients also benefit greatly from intravenous infusions of human IgG.Severe Combined Immunodeficiency (SCID)
The most common type of SCID is due to stop codon defects in the X-chromosome gene that encodes for the γ-chain that is common to IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. A more moderate combined immunodeficiency disease has been reported and is due to a missense point mutation in a part of the gene that encodes for the cytoplasmic region of that gene. In addition, other defects reported to cause SCID involve an autosomal recessive defect in the formation of adenosine deaminase, a defect in the formation of CD3, a defect in the post TcR-CD3 receptors' signalling, and deficiency in the formation of IL-2.Patients with these diseases display few T lymphocytes, decreased T cell functions, poor antibody formation, and variable numbers of B cells and serum concentrations of immunoglobulins. As a consequence of the deficiencies in T cells, these patients are very susceptible to opportunistic pathogens, including Candida albicans, Salmonellae, Pneumocystis carinii, Cytomegalovirus, and Varicella zoster virus. Patients with SCID usually die before the age of two years, unless definitive immunologic interventions are instituted.
Specific treatments have been devised for patients with SCID. Many patients have been treated successfully with bone marrow transplants to supply normal stem cells. Patients with adenosine deaminase deficiency may also be managed by infusing the enzyme packaged with polyethylene glycol. Recently, some patients with adenosine deaminase deficiency have been successfully treated with gene therapy. Although the beneficial effects have not been permanent, nevertheless, they are encouraging.
Two major intrinsic defects in the function of phagocytic cells have been recognized. The first one is an autosomal recessive defect in the formation of the common β-subunit of the family of adherence glycoproteins (integrins). The deficiency interferes with the ability of these leukocytes to adhere to the surface of endothelial cells. Consequently, the motility of these cells on two-dimensional surfaces is impaired. Thus, this defect results in bacterial infections in interstitial sites, such as in the skin and periodontium.
The second disorder, chronic granulomatous disease, was the first recognized genetic defect of the function of phagocytic cells. The disease is X-linked in ~ 70% of affected patients. In those cases, the gene for the gp90 protein subunit of cytochrome b558 is abnormal. Consequently, the protein is not produced, the cytochrome does not persist, and intracellular killing is impaired. Less frequently (~ 3% of cases), the disease is due to a defect in the autosomal gene for the lower molecular weight subunit of the heterodimer, p22phox. Autosomal defects in genes for cytoplasmic proteins that stabilize the cytochrome have also been recognized.
In these disorders, phagocytes are unable to mount a respiratory burst and therefore are unable to produce toxic oxygen compounds, such as hydrogen peroxide, which are required for intracellular killing of catalase-positive microorganisms such as Candida albicans, Escherichia coli, and Serratia species. The failure to kill catalase-positive microorganisms occurs because the microbial agents do not supply the oxygen substrates required for intracellular killing. In contrast, these dysfunctional neutrophils kill catalase-negative microorganisms such as the streptococci since those microorganisms bring hydrogen peroxide into the phagolysosome.