Alt Advances in Immunology

1. Auflage 2005
ISBN: 978-0-08-045853-3
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 86, 336 Seiten

Reihe: Advances in Immunology

Advances in Immunology, a long established and highly respected publication, presents current developments as well as comprehensive reviews in immunology. Articles address the wide range of topics that comprise immunology, including molecular and cellular activation mechanisms, phylogeny and molecular evolution, and clinical modalities. Edited and authored by the foremost scientists in the field, each volume provides up-to-date information and directions for future research. - Now available online! - Highly respected review series with an impact factor in 2003 of of 7.424 and ranked number 8/114 - New Editor, Frederick Alt

Autoren/Hrsg.

Alt, Frederick W.

Inhaltsverzeichnis

1;front cover;1
2;copyright;5
3;table of contents;6
4;Contributors;10
5;Adenosine Deaminase Deficiency: Metabolic Basis of Immune Deficiency and Pulmonary Inflammation;12
6;Mechanism and Control of V(D)J Recombination versus Class Switch Recombination: Similarities and Differences;53
7;Isoforms of Terminal Deoxynucleotidyltransferase: Developmental Aspects and Function;123
8;Innate Autoimmunity;147
9;Formation of Bradykinin: A Major Contributor to the Innate Inflammatory Response;168
10;Interleukin-2, Interleukin-15, and Their Roles in Human Natural Killer Cells;218
11;Regulation of Antigen Presentation and Cross-Presentation in the Dendritic Cell Network: Facts, Hypothesis, and Immunological Implications;249
12;Index;314
13;Contents of Recent Volumes;322

Leseproben

Adenosine Deaminase Deficiency: Metabolic Basis of Immune Deficiency and Pulmonary Inflammation
Michael R. Blackburn; Rodney E. Kellems    Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, Texas 77030 USA Abstract
Genetic deficiencies in the purine catabolic enzyme adenosine deaminase (ADA) in humans results primarily in a severe lymphopenia and immunodeficiency that can lead to the death of affected individuals early in life. The metabolic basis of the immunodeficiency is likely related to the sensitivity of lymphocytes to the accumulation of the ADA substrates adenosine and 2'-deoxyadenosine. Investigations using ADA-deficient mice have provided compelling evidence to support the hypothesis that T and B cells are sensitive to increased concentrations of 2'-deoxyadenosine that kill cells through mechanisms that involve the accumulation of dATP and the induction of apoptosis. In addition to effects on the developing immune system, ADA-deficient humans exhibit phenotypes in other physiological systems including the renal, neural, skeletal, and pulmonary systems. ADA-deficient mice develop similar abnormalities that are dependent on the accumulation of adenosine and 2'-deoxyadenosine. Detailed analysis of the pulmonary insufficiency seen in ADA-deficient mice suggests that the accumulation of adenosine in the lung can directly access cellular signaling pathways that lead to the development and exacerbation of chronic lung disease. The ability of adenosine to regulate aspects of chronic lung disease is likely mediated by specific interactions with adenosine receptor subtypes on key regulatory cells. Thus, the examination of ADA deficiency has identified the importance of purinergic signaling during lymphoid development and in the regulation of aspects of chronic lung disease. 1 Introduction
Adenosine deaminase (ADA) is an essential enzyme of purine metabolism (Fig. 1) and is highly conserved throughout phylogeny. The initial clue revealing the importance of ADA to mammalian organisms came with the chance discovery that a form of severe combined immunodeficiency disease (SCID) in humans was associated with ADA deficiency (Giblett et al., 1972). In this serendipitous way ADA deficiency was the first of the immunodeficiency diseases for which the underlying biochemical defect was discovered. Subsequent investigations indicated that ADA deficiency accounts for approximately 20% of cases of human SCID and that it is the most severe of the immunodeficiency diseases, affecting both cell-mediated and humoral immunity (Buckley et al., 1997; Hershfield and Mitchell, 2001). Soon after their discovery that defects in ADA were associated with immunodeficiency, Giblett and colleagues examined other immunodeficient individuals for deficiencies in purine catabolic enzymes and found that defects in purine nucleoside phosphorylase (Fig. 1) also result in immunodeficiency disease (Giblett et al., 1975). These findings demonstrate the importance of purine metabolism in development of the immune system. Deciphering the mechanisms by which defects in purine metabolism lead to abnormal lymphopoiesis has proved a difficult task, and although significant progress in this arena has been made, many questions remain. However, efforts to understand the metabolic basis of the immunodeficiency associated with ADA deficiency have led to advances in the treatment of certain leukemias, and the treatment of ADA deficiency in humans has advanced aspects of enzyme replacement and gene replacement therapies. Figure 1 Catabolism of adenosine and 2'-deoxyadenosine. Adenosine and 2'-deoxyadenosine are deaminated to inosine and 2'-deoxyinosine by adenosine deaminase (ADA). This is followed by cleavage of the purine base from the ribose or deoxyribose sugar moieties by the enzyme purine nucleoside phosphorylase (PNP) to produce hypoxanthine. Hypoxanthine is salvaged back to inosine monophosphate (IMP) in most tissues by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) or is oxidized first to xanthine and then to uric acid by the enzyme xanthine oxidase (XO). In humans, uric acid is excreted in the urine, whereas in the mouse uric acid can be converted to allantoin by the enzyme uricase before excretion. The generation of ADA-deficient mice (Blackburn et al., 1998; Migchielsen et al., 1995; Wakamiya et al., 1995) provided the opportunity to examine the pathways by which disturbances in purine metabolism influence physiological systems in the whole animal. ADA-deficient mice develop a combined immunodeficiency similar to that seen in ADA-deficient humans, and experiments in these mice have provided novel mechanistic information about how the accumulation of the ADA substrates adenosine and 2'-deoxyadenosine impact components of the immune system. In addition, by removing the major enzyme that controls adenosine levels in tissues and cells, these mice have served as biological screens for physiological processes sensitive to chronic elevations in adenosine (Blackburn, 2003). In particular, ADA-deficient mice have served as a useful model for deciphering the role of adenosine signaling in chronic inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). This review discusses the current understanding of how the accumulation of ADA substrates impacts the immune and pulmonary systems by comparing findings in ADA-deficient humans and mice. 2 ADA Deficiency in Humans
ADA deficiency in humans arises from naturally occurring mutations in the ADA gene that are inherited in an autosomal recessive manner. Most ADA-deficient humans are diagnosed early in life, when they present with marked lymphopenia; failure to thrive; and opportunistic fungal, viral, and bacterial infections (Buckley et al., 1997; Hershfield and Mitchell, 2001). These patients have little to no detectable ADA activity and severe metabolic disturbances associated with the loss of ADA activity. The thymus is absent or small and dysplastic in ADA-deficient individuals (Borzy et al., 1979), and they have severely reduced numbers of peripheral T, B, and natural killer (NK) cells (Buckley et al., 1997). ADA-deficient SCID is the only immunodeficiency in which all three cell types are severely reduced in number. Without intervention, ADA-deficient individuals die from overwhelming infections within the first year of life. A smaller population of ADA-deficient patients presents later in life with a less severe form of immunodeficiency that coincides with less severe loss of ADA enzymatic activity and associated metabolic disturbances (Santisteban et al., 1993). Specific mutations within the ADA gene have been identified for both “early” and “late” onset ADA deficiency (reviewed in Hershfield and Mitchell, 2001), and the severity of the mutations, regarding the loss of ADA enzymatic function, correlates well with the severity of the ensuing disease (Hershfield, 2003). The most successful treatment for ADA deficiency is histocompatible bone marrow transplantation from an HLA-matched sibling. Because this treatment option is seldom available, alternative treatments have been identified, including T cell–depleted haploidentical bone marrow transplantation from a parent. However, these approaches have met with limited success. A successful biochemical approach for the treatment of ADA deficiency involves the use of enzyme replacement therapy wherein a polyethylene glycol–modified form of bovine ADA (PEG–ADA) is provided to patients by twice weekly intramuscular injection (Hershfield et al., 1993). Polyethylene glycol appears to protect the bovine ADA from proteolytic and immunologic attack, hence increasing the circulating half-life of this exogenous enzyme. ADA replacement therapy is effective in reducing the metabolic impact of ADA deficiency and has prolonged the life of individuals who have in some cases been treated for more than 8 years (Hershfield, 1995). Relatively few complications have been reported with respect to allergic reactions or immunogenicity to PEG–ADA, and it appears to be the best option for the prolonged treatment of ADA-deficient patients who lack an HLA-identical marrow donor. ADA deficiency has received considerable attention as the testing ground for the development of gene therapy protocols. Several features of ADA deficiency make it an attractive candidate for gene replacement therapy: bone marrow or cord blood stem cells are relatively accessible cell populations; individuals with as little as 5% normal ADA activity have normal immune function, suggesting a high degree of replacement may not be necessary; and evidence exists to suggest that T cells with ADA activity can be selected for and enriched in an ADA-deficient environment. The latter is supported by observations in ADA-deficient individuals where spontaneous clinical remissions occurred in association with mosaicism for ADA expression (Hirschhorn et al., 1994, 1996), which in one instance was associated with the reversion of a mutation in the ADA allele to normal in lymphoid cells (Hirschhorn et al., 1996). Thus, the hope is that efficient transfer of a recombinant ADA gene into hematopoietic cells will result in the outgrowth of a genetically...