8536d_ch08_185-199 8/22/02 11: 49 AM Page 192 mac100 mac 100: 128_tm: 8536d: Goldsby et al./ Immunology 5e- 192 PART II Generation of B-Cell and T-Cell Response CLINICAL FOCUS ells were isolated from biopsied skin Deficiency in Transporters from several patients, supporting this ssibility. Normally, the activity of NK Associated with Antigen cells is limited through the action of killer-cell-inhibitory receptors (KIRs) Presentation(TAP) Leads to a which deliver a negative signal to the NK Diverse Disease Spectrum cell following interaction with class I molecules(see Chapter 14). The defi. ciency of class I molecules in TAP-related blS patients explains the excessive activ- A relatively of the upper respiratory tract, and in the ity of the NK cells. Activation of NK cells econd decade begins to have chronic in. further explains the absence of severe dition known as bare lymphocyte syn. fection of the lungs. It is thought that virus infections, which are limited by NK drome,or BLS, has been recognized for post-nasal-drip syndrome common in and y8 cells more than 22 years. The lymphocytes in younger patients promotes the bacterial The best treatment for the character- BLS patients express MHC molecules at lung infections in later life. Noteworthy is istic lung infections appears to be antibi- below-normal levels and, in some cases, the absence of any severe viral infection, otics and intravenous immunoglobulin not at all. In type 1 BLS, a deficiency in which is common in immunodeficien. Attempts to limit the skin disease by im- MHC class I molecules exists; in type 2 cies with T-cell involvement(see Chapter munosup s. such BLS, expression of class ll molecules is 19). Bronchiectasis (dilation of the steroid treatment or cytotoxic agents, impaired. The pathogenesis of one type bronchial tubes )often occurs and red can lead to exacerbation of lesions and is of BLS underscores the importance of ring infections can lead to lung damage therefore contraindicated. Mutations in the class I family of MHC molecules in that may be fatal. The most characteristic the promoter region of TAP that preclude their dual roles of preventing autoim. mark of the deficiency is the occurrence expression of the gene were found for munity as well as defending against of necrotizing skin lesions on the extrem. several patients, suggesting the possibil- pathogens ities and the midface. These lesions ul- ity of gene therapy, but the cellular distri. Defects in promoter sequences that cerate and may cause disfigurement(see bution of class I is so widespread that it preclude MHc gene transcription were figure). The skin lesions are probably due is not clear what cells would need to be found for some type 2 BLS cases, but in to activated NK cells and y8 T cells; NK corrected to alleviate all symptoms many instances the nature of the under lying defect is not known. A recent stud has identified a group of patients with type 1 BLS due to defects in TAP1 TAP2 genes. Manifestations of the TAP deficiency were consistent in this patient group and define a unique disease. As teins are necessary for the loading of peptides onto class I molecules, a step that is essential for expression of class I MHC molecules on the cell surface. Lym- phocytes in individuals with TAP defi ency express levels of class I molecules an no Other cellular abnormalities include in. creased numbers of NK and y8 T cells and decreased levels of CD8* aB Tcells As we shall see. the disease manifesta Necrotizing granulomatous lesions in the midface of patient with TAP-deficiency syn- tions are reasonably well explained by drome. TaP deficiency leads to a condition with symptoms characteristic of autoimmu these deviations in the levels of certain uch as the skin lesions that on the extremities and the midfau ells involved in immune function immunodeficiency that causes chronic sinusitis, leading to recurrent lung infection g In early life the TAP-deficient individ- (From S.D. Gadola et al., 1999, Lancet 354: 1598, and 2000, Clinical and Experimental al suffers frequent bacterial infections Immunology 121: 173. 1192 PART II Generation of B-Cell and T-Cell Responses of the upper respiratory tract, and in the second decade begins to have chronic in￾fection of the lungs. It is thought that a post-nasal-drip syndrome common in younger patients promotes the bacterial lung infections in later life. Noteworthy is the absence of any severe viral infection, which is common in immunodeficien￾cies with T-cell involvement (see Chapter 19). Bronchiectasis (dilation of the bronchial tubes) often occurs and recur￾ring infections can lead to lung damage that may be fatal. The most characteristic mark of the deficiency is the occurrence of necrotizing skin lesions on the extrem￾ities and the midface. These lesions ul￾cerate and may cause disfigurement (see figure). The skin lesions are probably due to activated NK cells and  T cells; NK cells were isolated from biopsied skin from several patients, supporting this possibility. Normally, the activity of NK cells is limited through the action of killer-cell-inhibitory receptors (KIRs), which deliver a negative signal to the NK cell following interaction with class I molecules (see Chapter 14). The defi￾ciency of class I molecules in TAP-related BLS patients explains the excessive activ￾ity of the NK cells. Activation of NK cells further explains the absence of severe virus infections, which are limited by NK and  cells. The best treatment for the character￾istic lung infections appears to be antibi￾otics and intravenous immunoglobulin. Attempts to limit the skin disease by im￾munosuppressive regimens, such as steroid treatment or cytotoxic agents, can lead to exacerbation of lesions and is therefore contraindicated. Mutations in the promoter region of TAP that preclude expression of the gene were found for several patients, suggesting the possibil￾ity of gene therapy, but the cellular distri￾bution of class I is so widespread that it is not clear what cells would need to be corrected to alleviate all symptoms. A relativelyrare con￾dition known as bare lymphocyte syn￾drome, or BLS, has been recognized for more than 22 years. The lymphocytes in BLS patients express MHC molecules at below-normal levels and, in some cases, not at all. In type 1 BLS, a deficiency in MHC class I molecules exists; in type 2 BLS, expression of class II molecules is impaired. The pathogenesis of one type of BLS underscores the importance of the class I family of MHC molecules in their dual roles of preventing autoim￾munity as well as defending against pathogens. Defects in promoter sequences that preclude MHC gene transcription were found for some type 2 BLS cases, but in many instances the nature of the under￾lying defect is not known. A recent study has identified a group of patients with type 1 BLS due to defects in TAP1 or TAP2 genes. Manifestations of the TAP deficiency were consistent in this patient group and define a unique disease. As described earlier in this chapter, TAP pro￾teins are necessary for the loading of peptides onto class I molecules, a step that is essential for expression of class I MHC molecules on the cell surface. Lym￾phocytes in individuals with TAP defi￾ciency express levels of class I molecules significantly lower than normal controls. Other cellular abnormalities include in￾creased numbers of NK and  T cells, and decreased levels of CD8  T cells. As we shall see, the disease manifesta￾tions are reasonably well explained by these deviations in the levels of certain cells involved in immune function. In early life the TAP-deficient individ￾ual suffers frequent bacterial infections CLINICAL FOCUS Deficiency in Transporters Associated with Antigen Presentation (TAP) Leads to a Diverse Disease Spectrum Necrotizing granulomatous lesions in the midface of patient with TAP-deficiency syn￾drome. TAP deficiency leads to a condition with symptoms characteristic of autoimmu￾nity, such as the skin lesions that appear on the extremities and the midface, as well as immunodeficiency that causes chronic sinusitis, leading to recurrent lung infection. [From S. D. Gadola et al., 1999, Lancet 354:1598, and 2000, Clinical and Experimental Immunology 121:173.] 8536d_ch08_185-199 8/22/02 11:49 AM Page 192 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-: