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Chapter 23 : Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders

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Abstract:

This chapter talks about molecular basis of congenital immunodeficiencies; immune consequences of defects in hematopoiesis and clinical features of various immunodeficient states. During the past two decades, the identification and detailed investigation of the acquired immunodeficiency syndrome (AIDS) have not only heightened one's awareness of immunodeficiency, but have expanded the understanding of the relationship between specific immune defects, opportunistic pathogens, and clinical syndromes. For many years the discussion of immunodeficiency diseases was primarily limited to clinical descriptions of disease courses. Immunodeficiency disorders may manifest solely as recurrent infection of a given tissue or anatomic site or may be encountered as part of a syndrome with many other features. Manifestations of immune dysfunction frequently target the respiratory tract, skin, and gastrointestinal tract or are associated with invasive (systemic) infectious disease. Invasive bacterial disease is common among children because of their frequent environmental exposure to respiratory pathogens, as in day care facilities; their naive immune systems, which lack immunologic memory; and the diminished barrier protection afforded by their skin (especially in premature infants). Periodontitis and gingivitis are common in individuals with genetic, developmental, or acquired disorders involving either phagocyte deficiencies or functional abnormalities of neutrophils. Severe gingivitis also is seen in patients infected with HIV and patients with severe malnutrition, viral illnesses, or unusually severe complications of vaccination with live virus vaccines.

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23

Key Concept Ranking

Immune Systems
0.63354564
White Blood Cells
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MHC Class I
0.5152846
Major Histocompatibility Complex
0.5079127
0.63354564
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Figures

Image of Figure 23.1
Figure 23.1

Diagram of leukopoiesis, indicating the locations of developmental or functional defects associated with immunodeficiency. The names of some immunodeficiency syndromes are given in pink boxes (for developmental defects) or orange boxes (for functional defects). Note that some defects (for example, LAD) affect the function of more than one cell lineage. Also note that some classes of immunodeficiency (for example, SCID) can result from either developmental defects or functional defects.

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Image of Figure 23.2
Figure 23.2

Flow chart of lymphocyte development and function, indicating the locations of developmental or functional defects that result in SCID. Some of the defects that are shown (yellow boxes) only affect T cells directly, but result in a SCID phenotype due to an inability of helper T cells to help B cells.

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Image of Figure 23.3
Figure 23.3

Bare lymphocyte syndrome (BLS). Diagram of trafficking and peptide loading by MHC class I (MHC I) and class II (MHC II) in a normal antigen-presenting cell. The more common type of BLS, BLS (MHC II), usually results from a failure to synthesize MHC class II due to a defect in the transcription factor CIITA. MHC class I is still produced and loaded with peptide normally. A less common form of BLS, BLS (MHC I), is characterized by normal synthesis of MHC class I but greatly reduced membrane expression of MHC class I due to a defect in TAP. TAP deficiency results in an inability to load antigenic peptides onto MHC class I, causing the class I proteins to be retained in the endoplasmic reticulum (ER). Ii, invariant chain.

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Image of Figure 23.4
Figure 23.4

Defects in phagocytic killing. In a normal phagocyte, phagocytosis of a bacterium is followed by a fusion of the phagosome with a lysosome (large black circles) to form a phagolysosome. In the phagolysosome, hydrolytic enzymes (small black circles) damage ingested bacteria. Simultaneously, a family of NADPH oxidases (p22, p67, and p91) and myeloperoxidase (MPO) enzymes become activated to produce the oxidative burst, resulting in the production of toxic oxygen intermediates such as superoxide (O ), peroxynitrite (ONOO), hydrogen peroxide (HO), and hypochlorous acid (HOCl), which also participate in microbial killing. Some phagocytic defects, such as CGD and myeloperoxidase deficiency, result from defects in the enzymes needed for the oxidative burst. Without the oxidative burst, hydrolytic enzymes in the phagolysosome are insufficient for microbial killing. Chediak-Higashi syndrome results from a defect in the regulation of lysosome trafficking and fusion. As a result, most lysosomes in a Chediak-Higashi syndrome phagocyte prematurely fuse with each other, resulting in giant, nonfunctional lysosomes. In these phagocytes, the oxidative burst occurs normally, though it alone is insufficient for microbial killing in the absence of phagosome-lysosome fusion.

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Image of Figure 23.5
Figure 23.5

LAD. In a normal individual, leukocytes are able to leave the circulation and enter solid tissues by a multistep process of extravasation. This involves the following steps: low-affinity rolling adhesion mediates by mucin-selectin interactions; signaling via chemokines such as IL-8; conversion of leukocyte integrin proteins to their high-affinity form via a G protein-dependent signal upon binding to IL-8; high-affinity binding of leukocyte to vascular endothelium, leading to leukocyte arrest; and diapedesis. In an individual with LAD, rolling () and signaling via IL-8 () still occur normally, but a defect in leukocyte integrin proteins () prevents high-affinity leukocyte-endothelium interactions. Therefore, leukocytes never arrest on the endothelium and detach from the latter ().

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Image of Figure 23.6
Figure 23.6

DiGeorge syndrome. A thymic shadow is absent in the anterior-posterior chest radiograph.

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Image of Figure 23.7
Figure 23.7

Bronchiectasis. A computed tomographic scan confirms chronic pneumonia/bronchiectasis in the right lower lobe. A chest radiograph of 12-year-old boy showing chronic right lower lobe infiltrate (arrowheads) consistent with bronchiectasis.

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Image of Figure 23.8
Figure 23.8

PCP. Diffuse interstitial disease with nodularity suggests PCP.

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Image of Figure 23.9
Figure 23.9

Lung abscess. A chest radiograph shows early abscess cavities (arrowheads).

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Image of Figure 23.10
Figure 23.10

Mucocutaneous candidiasis. Fungal plaques are seen on the inner lining of the cheek and coating the tongue.

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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References

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1. Buckley, R. H. 2001. The hyper-IgE syndrome. Clin. Rev. Allergy Immunol. 20:139154.
2. Buckley, R. H. 2002. Primary cellular immunodeficiencies. J. Allergy Clin. Immunol. 109:747757.
3. Bunting, M.,, E. S. Harris,, T. M. McIntyre,, S. M. Prescott,, and G. A. Zimmerman. 2002. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands. Curr. Opin. Hematol. 9:3035.
4. Cunningham-Rundles, C. 2001. Physiology of IgA and IgA deficiency. J. Clin. Immunol. 21:303309.
5. Etzioni, A. 2002. Novel aspects of hypogammaglobulinemic states. Isr. Med. Assoc. J. 4:294297.
6. Fischer, A. 2002. Primary immunodeficiency diseases: natural mutant models for the study of the immune system. Scand. J. Immunol. 55:238241.
7. Khan, W. N. 2001. Regulation of B lymphocyte development and activation by Bruton’s tyrosine kinase. Immunol. Res. 23:147156.
8. Kirkpatrick, C. H. 2001. Chronic mucocutaneous candidiasis. Pediatr. Infect. Dis. J. 20:197206.
9. Kokron, C. M.,, F. A. Bonilla,, H. C. Oettgen,, N. Ramesh,, R. S. Geha,, and F. Pandolfi. 1997. Searching for genes involved in the pathogenesis of primary immunodeficiency syndromes: lessons from mouse knockouts. J. Clin. Immunol. 17:109126.
10. Lekstrom-Himes, J. A.,, and J. I. Gallin. 2000. Immunodeficiency disease caused by defects in phagocytes. N. Engl. J. Med. 343:17031714.
11. Leonard, W. J. 2001. Cytokines and immunodeficiency diseases. Nat. Rev. Immunol. 1:200208.
12. Puck, J. M. 1999. Prenatal diagnosis of primary immunodeficiency diseases, p. 563580. In A. Milunsky (ed.), Genetic Disorders and the Fetus, 4th ed. Johns Hopkins University Press, Baltimore, Md..
13. Reith, W.,, and B. Mach. 2001. The bare lymphocyte syndrome and the regulation of MHC expression. Annu. Rev. Immunol. 19:331373.
14. Yang, K. D.,, and H. Hill. 2001. Granulocyte function disorders: aspects of development, genetics and management. Pediatr. Infect. Dis. J. 20:889900.

Tables

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Table 23.1

Molecular defects associated with immunodeficiency

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
Generic image for table
Table 23.2

Common clinical manifestations of primary immune deficiency

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
Generic image for table
Table 23.3

Clinical manifestation of granulocyte defects

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Table 23.4

Clinical manifestations of B-cell defects

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
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Table 23.5

Clinical illness in association with complement deficiency

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23
Generic image for table
Table 23.6

Clinical manifestations of T-cell deficiency or dysfunction

Citation: Milunsky J, Pelton S. 2004. Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders, p 553-572. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch23

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