Natural Immunity (eBook)

Lorand Bertok, Donna Chow (Herausgeber)

eBook Download: EPUB

2005 | 1. Auflage
379 Seiten
Elsevier Science (Verlag)
978-0-08-046046-8 (ISBN)

Infos

Natural Immunity is a broadly-based account of the activities of the evolutionarily conserved molecules, cells and processes of the natural immune system. This encompasses the early host protection against microbes (bacteria and viruses) and tumours, prior to the generation of the adaptive immune response, diverse major current pathologies including inflammatory and autoimmune diseases, and key roles in essential physiological processes such as reproduction and wound healing.

* The first comprehensive book on natural immunity
* Reviews new topics, effects of behaviour, aging, and exercise, and diet on natural immunity
* Highlights the physiological role of natural immunity
* Focuses on the relationship of the neuroendocrine system with natural immunity
* Brings together the diversity and complexity of natural immune system activity

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"e;Natural Immunity"e; is a broadly-based account of the activities of the evolutionarily conserved molecules, cells and processes of the natural immune system. This encompasses the early host protection against microbes (bacteria and viruses) and tumours, prior to the generation of the adaptive immune response, diverse major current pathologies including inflammatory and autoimmune diseases, and key roles in essential physiological processes such as reproduction and wound healing. - The first comprehensive book on natural immunity- Reviews new topics, effects of behaviour, aging, and exercise, and diet on natural immunity- Highlights the physiological role of natural immunity- Focuses on the relationship of the neuroendocrine system with natural immunity- Brings together the diversity and complexity of natural immune system activity

Inhalt

Front Cover 1
Natural Immunity 4
Copyright Page 5
Contents 16
Foreword 6
Preface 8
Acknowledgements 10
List of Contributorvs 12
Part I: Host Defense Mechanisms 18
Chapter 1. Host Defense: An Interaction of Neuroendocrine- Metabolic and Immune Mechanisms in the Interest of Survival 20
Part II: Epithelial, Secretory and Endogenous Host Defense 44
Chapter 2. Antimicrobial Peptides – The Defense Never Rests 46
Chapter 3. Endogenous Cytoprotective Mechanisms 66
Chapter 4. The Role of Bile Acids in Natural Resistance: Physico-Chemical Host Defense 84
Part III: The Natural Immune System 96
Chapter 5. A Histrocal Introduction of Natural Killer (NK) Cells and Current Status of Their Role in Host Defenses 98
Chapter 6. The Role of the Reticuloendothelial System in Natural Immunity 112
Chapter 7. Effector Mechanisms of Natural Immunity: an Invertebrate Perspective 120
Chapter 8. Natural Immune Activation: Stimulators/Receptors 140
Chapter 9. Signalling in Natural Immunity: Natural Killer Cells 168
Chapter 10. Pathogen Recognition by Toll-like Receptors 184
Part IV: Regulation of Natural Immunity 200
Chapter 11. Molecular Control of Leukocyte Trafficking – Internal Regulatory Circuits of the Immune System: Leukocyte Circulation and Homing 202
Chapter 12. Neuroendocrine Regulation of Natural Immunity 232
Chapter 13. Natural Immunity – Effect of Exercise 280
Chapter 14. New Prospect for the Enhancement of Natural Immunity 306
Part V: Physiological, Pathological and Behavioral Significance 326
Chapter 15. Physiological Activities of the Natural Immune System 328
Chapter 16. Pathological Relevance of the Natural Immune System 348
Chapter 17. Behavioral Mechanisms for Defense Against Pathogens 368
Keyword Index 386

Textauszug

Antimicrobial Peptides – The Defence Never Rests

Kenneth M. Huttner    Division of Neonatology, Department of Pediatrics, Harvard Medical School and the Mass-General Hospital for Children, Boston, MA 02114 U.S.

ABSTRACT

The era of genomics has arrived bringing with it the promise of novel insights into the molecular basis of human health and disease. True to this promise, the field of innate immunity has seen extraordinary advances in the identification of key molecules for pathogen recognition, cellular signalling and microbicidal activity. Prominent among them in both epithelial tissues and granulocytes are the abundant and evolutionary-ancient defensins and cathelicidins. These molecules, recognized initially for their broad-spectrum antimicrobial properties, are now shown to occupy critical junctions in both the regulatory and effector arms of the innate immune system. This review will focus on these unique peptides, highlighting their structure, function and regulation in epithelial host defence, with an emphasis on clinical implications and a role as therapeutic targets.

1 ANTIMICROBIAL PEPTIDES

1.1 Structures

The two salient features that identify an antimicrobial peptide are an ability to inactivate microorganisms, tested either in vitro or in vivo, and a size less than 100 amino acids. Given these rather broad definitions, over 500 molecules derived from either plant or animal species are now categorised as antimicrobial peptides [1–3]. As a general rule, they are derived from propeptides following constitutive or inducible processing. The active peptides vary in structure from disulfide-bridged circular peptides to amphipathic α-helical sequences enriched for a single amino acid (Fig. 1). A common feature is the formation of a tertiary structure permissive for interaction with the predominantly anionic, cholesterol-poor microbial membrane [4].

Figure 1 Chemical structural classification of some well-studied mammalian antimicrobial peptides (modified from [3] with permission).

Many excellent reviews are available on the numerous classes of antimicrobial peptides, describing in a wealth of detail their gene, mRNA and peptide structures [5,6]. Here we will outline briefly the principle classes of antimicrobial peptides isolated from mammalian tissues, with particular emphasis on those from H. sapiens.

In the 1980’s, investigators at UCLA published seminal work characterising neutrophil defensins, the most abundant class of mammalian antimicrobial peptides [5]. As a general rule, mammalian defensins are cationic, arginine-rich, cysteine-containing peptides 29–47 amino acids in length that are derived from larger, precursor molecules. Most commonly, these precursor molecules are prepropeptides containing a signalling pre- sequence, a neutralizing propeptide and the carboxy-terminal defensin that is liberated following multiple processing steps. Nearly all mammalian defensins contain six cysteine molecules participating in three disulfide bonds. They can be sorted broadly into three groups based on cysteine spacing and disulfide-bond alignment (Fig. 1).

The α-defensins are generally shorter in length and contain disulfide bridges in a {C1-C6, C2-C4, C3-C5} pattern, while the (β-defensins are more variable in length at both termini and contain disulfide bridges in a {C1-C5, C2-C4, C3-C6} pattern. The core tertiary structure of α- and β-defensins is considered to be a triple-stranded antiparallel [β-sheet [7]. The third group of defensins, θ-defensins, has been identified only in rhesus macaques [8], and is unique both in structure (circular) and in mechanism of post-translational assembly (intermolecular disulfide bridging).

As an interesting aside, it was recognised recently that the CXC motif present in the N-terminal of defensins is analogous to the CXC motif present in a class of chemokines [9]. Specific CXC chemokines demonstrate a pattern of broad-spectrum antimicrobial activity similar to that of the defensins [9], perhaps blurring the distinction between antimicrobial and signalling molecules.

The second main class of mammalian antimicrobial peptides is the cathelicidins, all of which are cleaved from precursor proteins containing the highly conserved propeptide sequence termed cathelin [6]. Interestingly, the cathelin propeptide was discovered independently as a porcine inhibitor of cathepsin L [10,11]. Cathelicidin genes consist of 4 exons, with exons 1-3 encoding the tissue-targeting cathelin portion of the molecule, and exon 4 encoding the active peptide. The active cathelicidin peptides vary widely in their primary sequence, and the cathelicidin gene family varies markedly in size among species. To date, only a single human cathelicidin gene has been identified, hCAP18. hCAP18 refers to the 18 kd cathelicidin prepropeptide, while the processed, active moiety is termed LL-37 (N-terminal leu-leu with length 37 a.a.) (Fig. 1).

Peptides of the defensin and cathelicidin families follow the dual paradigm of being processed from a precursor propeptide and having an antimicrobial activity linked to their net cationic charge. However, nature in its abundant diversity is likely to have evolved multiple paradigms for providing molecular protection of the epithelial barrier. The search for additional, novel classes of antimicrobial peptides has required novel insights and novel laboratory approaches. Among the unique peptide classes under investigation are anionic peptides and histone fragments.

The former are zinc-binding small molecules detected in pulmonary tissues of both sheep and humans [12]. In both species, these molecules and their precursors are constitutively expressed in airway tissues [13]. It is interesting to speculate whether they contribute to the proven effectiveness of zinc supplements in ameliorating pulmonary infections.

Many investigators have reported the HPLC purification of histone fragments with antimicrobial activity, and for years this was thought to be of no real consequence. However, it is now better appreciated that cellular apoptosis may be a defence response to microbial invasion. Therefore, it is a reasonable hypothesis that the release of histone fragments from the apoptotic cell chromatin is a highly effective strategy for augmenting host defence [14,15].

1.2 Cellular origin

Each species examined has a unique pattern of antimicrobial peptide expression, perhaps reflective of its unique life cycle and environment. However, a feature common to all species is the presence of abundant antimicrobial peptides in circulating granulocytes (e.g., neutrophils [5] and eosinophils [16]). It has been estimated that the antimicrobial α-defensins stored in human neutrophil granules (termed HNP’s) may constitute up to 50% of the total neutrophil protein [5]. A subset of these granule antimicrobial peptides can be detected in epithelial tissues, with the most prominent examples being the epidermal expression of human cathelicidin LL-37 and the orthologous mouse cathelicidin CRAMP [11,17]. Additionally, cells of both the T and B cell lineages, capable of infiltrating epithelial tissues, demonstrate transcription, translation and release of both defensins and cathelicidins [15].

Defensins and cathelicidins are the principle antimicrobial peptides expressed in the epithelium of every major organ system examined. In human tissues this includes the skin, ear canal, salivary glands, conjunctiva, breast tissue, GI tract from oesophagus to colon, pulmonary tract, and genitourinary tract [6,11,18–20]. In addition to their expression in the epithelial lining cells, antimicrobial peptides may be released locally from tissue monocytes encountering microbes or their products [21]. Their presence in circulating phagocytic cells as well as at sites of host-environment interface has lead investigators to hypothesise that they are the microbicidal effector molecules of the innate immune system. Recent evidence described below (section 1.8–1.10, and section 2) not only is supportive of this role in innate immunity, but also is suggestive of a more central role in regulating host immunity.

1.3 Mechanisms of microbicidal action

In general, defensins and cathelicidins are bactericidal in vitro against both Gram-positive and Gram-negative bacteria in assays using simplified, low ionic strength media. Subsets of these peptides demonstrate antiviral, antifungal and antiprotozoal activity as well. A working model for their mechanism of activity includes an initial interaction of the cationic moiety with the anionic bacterial membrane phospholipids, subsequent weakening of the microbial membrane integrity and a terminal disruption of membrane function [4,22,23]. This model is consistent with the repeated observations that: (1) elevation of salt or divalent cation concentration in the media may shield the charges on the microbial surface and reduce antimicrobial peptide activity; and (2) bacteria may acquire resistance to microbial activity through alterations in their surface lipid properties.

As we attempt to develop a unifying model for the antimicrobial peptide mechanism of action, we should recognise that a number of independent...

Produkt-Details

• Erscheint lt. Verlag: 11.4.2005
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber
• Themenwelt: Medizin / Pharmazie ► Allgemeines / Lexika
• Themenwelt: Medizinische Fachgebiete ► Innere Medizin ► Endokrinologie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Studium ► Querschnittsbereiche ► Infektiologie / Immunologie
• Themenwelt: Naturwissenschaften ► Biologie
• Themenwelt: Technik
• ISBN-10: 0-08-046046-1 / 0080460461
• ISBN-13: 978-0-08-046046-8 / 9780080460468