AIDs and other Immunodeficiencies chaPter 19 437 in life than other deficiencies and is sometimes called late- subject to severe infection by agents such as meningococcus, onset hypogammaglobulinemia or, incorrectly, acquired which causes fatal disease. IgM deficiency may be accompa- hypogammaglobulinemia. However, CVI has a genetic nied by various malignancies or by autoimmune disease. IgG component and is considered a primary immunodeficiency, deficiencies are also rare. These are often not noticed until although the exact pattern of inheritance is not known. Be- adulthood and can be effectively treated by administration of cause the manifestations are very similar to those of acquired immunoglobulin hypogammaglobulinemia, there is some confusion between the two forms(see below). Infections in CVI sufferers ATAXIA TELANGIECTASIA most frequently bacterial and can be controlled by adminis tration of immunoglobulin In CVI patients, B cells fail to Although not classified primarily as an immunodeficiency. mature into plasma cells; however in vitro studies show that ataxia telangiectasia is a disease syndrome that includes defi- ate differentiation signals. The underlying defect in Cvl is the appearance of broken capillaries(telangiectasia)in the not known, but must involve either an in vivo blockage of the maturation of B cells to the plasma-cell stage or their inabil- eyes. The primary defect appears to be in a kinase involved in ity to produce the secreted form of immunoglobulins regulation of the cell cycle. The relationship between the im- mune deficiency and the other defects in ataxia telangiectasia remains obscure HYPER-IgE SYNDROME (OB SYNDROME) A primary immunodeficiency characterized by skin abcesses, IMMUNE DISORDERS INVOLVING THE THYMUS recurrent pneumonia, eczema, and elevated levels of IgE ac- Several immunodeficiency syndromes are grounded in fail companies facial abnormalities and bone fragility. This multi-system disorder is autosomal dominant and has vari- ure of the thymus to undergo normal development. Thymic able expressivity. The gene for hyper Ige syndrome, or hIes malfunction has a profound effect on T-cell function; all maps to chromosome 4 HIES immunologic signs include re- populations ofT cells, including helper, cytolytic, and regula current infection and eosinophilia in addition to elevated Ige tory varieties, are affected. Immunity to viruses and fungi levels is especially compromised in those suffering from these conditions DiGeorge syndrome, or congenital thymic aplasia, in its SELECTIVE DEFICIENCIES OF IMMUNOGLOBULIN CLASSES most severe form is the complete absence of a thymus. This A number of immunodeficiency states are characterized by developmental defect, which is associated with the dele- ignificantly lowered amounts of specific immunoglobulin tion in the embryo of a region on chromosome 22, causes isotypes. Of these, iga deficiency is by far the most common. immunodeficiency along with characteristic facial abnor- There are family-association data showing that Iga defi- malities, hypoparathyroidism, and congenital heart disease ciency prevails in the same families as CVl, suggesting a rela-( Figure 19-4). The stage at which the causative developmen tionship between these conditions. The spectrum of clinical tal defect occurs has been determined, and the syndrome is symptoms of igA deficiency is broad; many of those affected sometimes called the third and fourth pharyngeal pouch syn are asymptomatic, while others suffer from an assortment of drome to reflect its precise embryonic origin. The immune serious problems. Recurrent respiratory and genitourinary defect includes a profound depression of T-cell numbers and tract infections resulting from lack of secreted igA on mu- absence of T-cell responses. Although B cells are present in cosal surfaces are common. In addition, problems such as in- normal numbers, affected individuals do not produce anti- testinal malabsorption, allergic disease, and autoimmune body in response to immunization with specific antigens disorders may also be associated with low IgA levels. The rea- Thymic transplantation is of some value for correcting the sons for this variability in the clinical profile of IgA deficiency T-cell defects, but many DiGeorge patients have such severe not clear but may relate to the ability of some, but not all, heart disease that their chances for long-term survival are patients to substitute IgM for igA as a mucosal antibody. The poor, even if the immune defects are corrected. defect in igA deficiency is related to the inability of igA B cells Whereas the DiGeorge syndrome results from an in- to undergo normal differentiation to the plasma-cell stage. trauterine or developmental anomaly, thymic hypoplasia, or IgG2 and Ig G4 may also be deficient in IgA-deficient pa- the Nezelof syndrome, is an inherited disorder. The mode of tients. No causative defect in iga genes has been identified, inheritance for this rare disease is not known and its presen- and the surface igA molecules on these patients' B cells ap- tation varies, making it somewhat difficult to diagnose. As pear to be expressed normally. a gene outside of the im- the name implies, thymic hypoplasia is a defect in which a munoglobulin gene complex is suspected to be responsible vestigial thymus is unable to serve its function in T-cell de- for this fairly common syndrome velopment. In some patients, B cells are normal, whereas in Other immunoglobulin deficiencies have been reported, others a B-cell deficiency is secondary to the T-cell defect Af but these are rarer. An igm deficiency has been identified as fected individuals suffer from chronic diarrhea, viral and an autosomal recessive trait. victims of this condition are fungal infections, and a general failure to thrivein life than other deficiencies and is sometimes called late￾onset hypogammaglobulinemia or, incorrectly, acquired hypogammaglobulinemia. However, CVI has a genetic component and is considered a primary immunodeficiency, although the exact pattern of inheritance is not known. Be￾cause the manifestations are very similar to those of acquired hypogammaglobulinemia, there is some confusion between the two forms (see below). Infections in CVI sufferers are most frequently bacterial and can be controlled by adminis￾tration of immunoglobulin. In CVI patients, B cells fail to mature into plasma cells; however in vitro studies show that CVI B cells are capable of maturing in response to appropri￾ate differentiation signals. The underlying defect in CVI is not known, but must involve either an in vivo blockage of the maturation of B cells to the plasma-cell stage or their inabil￾ity to produce the secreted form of immunoglobulins. HYPER-IgE SYNDROME (JOB SYNDROME) A primary immunodeficiency characterized by skin abcesses, recurrent pneumonia, eczema, and elevated levels of IgE ac￾companies facial abnormalities and bone fragility. This multi-system disorder is autosomal dominant and has vari￾able expressivity. The gene for hyper IgE syndrome, or HIES, maps to chromosome 4. HIES immunologic signs include re￾current infection and eosinophilia in addition to elevated IgE levels. SELECTIVE DEFICIENCIES OF IMMUNOGLOBULIN CLASSES A number of immunodeficiency states are characterized by significantly lowered amounts of specific immunoglobulin isotypes. Of these, IgA deficiency is by far the most common. There are family-association data showing that IgA defi￾ciency prevails in the same families as CVI, suggesting a rela￾tionship between these conditions. The spectrum of clinical symptoms of IgA deficiency is broad; many of those affected are asymptomatic, while others suffer from an assortment of serious problems. Recurrent respiratory and genitourinary tract infections resulting from lack of secreted IgA on mu￾cosal surfaces are common. In addition, problems such as in￾testinal malabsorption, allergic disease, and autoimmune disorders may also be associated with low IgA levels. The rea￾sons for this variability in the clinical profile of IgA deficiency are not clear but may relate to the ability of some, but not all, patients to substitute IgM for IgA as a mucosal antibody. The defect in IgA deficiency is related to the inability of IgA B cells to undergo normal differentiation to the plasma-cell stage. IgG2 and IgG4 may also be deficient in IgA-deficient pa￾tients. No causative defect in IgA genes has been identified, and the surface IgA molecules on these patients’ B cells ap￾pear to be expressed normally. A gene outside of the im￾munoglobulin gene complex is suspected to be responsible for this fairly common syndrome. Other immunoglobulin deficiencies have been reported, but these are rarer. An IgM deficiency has been identified as an autosomal recessive trait. Victims of this condition are subject to severe infection by agents such as meningococcus, which causes fatal disease. IgM deficiency may be accompa￾nied by various malignancies or by autoimmune disease. IgG deficiencies are also rare. These are often not noticed until adulthood and can be effectively treated by administration of immunoglobulin. ATAXIA TELANGIECTASIA Although not classified primarily as an immunodeficiency, ataxia telangiectasia is a disease syndrome that includes defi￾ciency of IgA and sometimes of IgE. The syndrome is charac￾terized by difficulty in maintaining balance (ataxia) and by the appearance of broken capillaries (telangiectasia) in the eyes. The primary defect appears to be in a kinase involved in regulation of the cell cycle. The relationship between the im￾mune deficiency and the other defects in ataxia telangiectasia remains obscure. IMMUNE DISORDERS INVOLVING THE THYMUS Several immunodeficiency syndromes are grounded in fail￾ure of the thymus to undergo normal development. Thymic malfunction has a profound effect on T-cell function; all populations of T cells, including helper, cytolytic, and regula￾tory varieties, are affected. Immunity to viruses and fungi is especially compromised in those suffering from these conditions. DiGeorge syndrome, or congenital thymic aplasia, in its most severe form is the complete absence of a thymus. This developmental defect, which is associated with the dele￾tion in the embryo of a region on chromosome 22, causes immunodeficiency along with characteristic facial abnor￾malities, hypoparathyroidism, and congenital heart disease (Figure 19-4). The stage at which the causative developmen￾tal defect occurs has been determined, and the syndrome is sometimes called the third and fourth pharyngeal pouch syn￾drome to reflect its precise embryonic origin. The immune defect includes a profound depression of T-cell numbers and absence of T-cell responses. Although B cells are present in normal numbers, affected individuals do not produce anti￾body in response to immunization with specific antigens. Thymic transplantation is of some value for correcting the T-cell defects, but many DiGeorge patients have such severe heart disease that their chances for long-term survival are poor, even if the immune defects are corrected. Whereas the DiGeorge syndrome results from an in￾trauterine or developmental anomaly, thymic hypoplasia, or the Nezelof syndrome, is an inherited disorder. The mode of inheritance for this rare disease is not known and its presen￾tation varies, making it somewhat difficult to diagnose. As the name implies, thymic hypoplasia is a defect in which a vestigial thymus is unable to serve its function in T-cell de￾velopment. In some patients, B cells are normal, whereas in others a B-cell deficiency is secondary to the T-cell defect. Af￾fected individuals suffer from chronic diarrhea, viral and fungal infections, and a general failure to thrive. AIDS and Other Immunodeficiencies CHAPTER 19 437