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  Systemicdiseaseandperiodontitis:manifestationsof neutrophildysfunction D  avid  E. D eas , S cott  A. M  ackey   & H oward  T. McD onnell  It is well accepted that the tissue destruction char-acteristic of periodontal diseases is a result of animbalance between the host inflammatory processand specific pathogenic bacteria residing in the per-iodontal crevicular space. The protective nature of the host response enables the majority of the popu-lation to fend off the bacterial insult that constantly threatens the health of the supporting tissues of thedentition. One of the major players on this inflam-matory and immunologic battleground is the poly-morphonuclear leukocyte (PMN) or neutrophil. Hartet al. in 1994, reviewed evidence placing the neutro-phil in a central host response role against invading periodontal pathogens (83). As stressed in their pub-lication, the importance of this cellular defender inthe pathogenesis of periodontal disease is dramati-cally brought to the forefront in those systemic dis-eases that are characterized by either an innate or aninduced abnormality in the number and/or functionof the neutrophil and a concomitant destruction of the periodontium (Table 1). Although a relatively rare occurrence in clinical practice, the severe peri-odontal destruction associated with these disorderscan be overwhelming for both the patient and theprovider. Despite this, the periodontal manifesta-tions often are of secondary importance given thelife threatening nature of many of these diseases. A general knowledge of these systemic diseases is of benefit in understanding the role the neutrophilholds in the initiation and progression of aggressiveperiodontitis and in coordinating the multidisciplin-ary care that is often required. With this in mind, it isour aim to review the mechanisms by which theneutrophil provides protection against bacterialpathogens, to provide an overview of neutrophilabnormalities and the laboratory tests currently employed to test neutrophil function, and to review those systemic diseases that have a link betweenneutrophil dysfunction and aggressive periodontitis. Neutrophilfunction Neutrophils are short lived, non-mitotic cells gener-ated in large numbers from pluripotential stem cellsresiding in the bone marrow. Undifferentiated stemcells become committed to a myeloid lineagethrough the influence of a combination of stem cellfactors, interleukin (IL)-3, and granulocyte macro-phage colony-stimulating factor (154). Differentia-tion and maturation in the marrow involves theprogression through five cellular precursors beforethe mature neutrophil is released. During this pro-cess of myelopoiesis, the neutrophil acquires thenecessary capabilities to detect infection, migrateto the site of infection, and ingest and kill microor-ganisms. The first three stages comprise the prolif-eration phase of myelopoiesis: the precursor cells aretermed myeloblast, promyelocyte, and myelocyte.The proliferation phase lasts approximately 1 week and involves active mitosis and the development of primary and secondary lysosomal granules. The nextphase, a 1-week maturation process, starts with thedifferentiation of the myelocyte to form the meta-myelocyte and proceeds through the development of the band neutrophil and, finally, the mature segmen-ted neutrophil (88). The three cell types in this finalphase lose their ability to divide. Approximately  82  Periodontology 2000, Vol. 32, 2003, 82–104 Copyright   #  Blackwell Munksgaard 2003Printed in Denmark. All rights reserved   PERIODONTOLOGY 2000 ISSN 0906-6713 Disclaimer: The opinions expressed in this article are those of the authors and are not to be construed as official or as representing theviews of the United States Air Force or the Department of Defense.  10 11 neutrophils are produced daily and this numbermay increase several fold in the face of a systemicinfection (154). Under normal conditions, approxi-mately 90% of the body  ’ s neutrophils are in the bonemarrow. Many of the daily produced neutrophilsundergo apoptosis even before leaving the bone mar-row. For those neutrophils that are released, thehalf-life in circulation is six to nine hours. The tissuehalf-life varies from one to four days (108, 154, 168).Mobilization of unstimulated neutrophils from themarrow into circulation is controlled by a variety of signaling factors such as IL-1, tumor necrosis factor- a  (TNF- a ), colony stimulating factors and comple-ment fragments. In the face of infection, a complex array of vascular and extravascular events press theneutrophil into action as the  fi rst line defender. Che-mokines and other chemotactic substances releasedfrom the site of infection activate cell surface mole-cules on vascular endothelial cells and neutrophilsleading to the movement of neutrophils to the per-iphery of the venule, a process called margination.Neutrophil and endothelial cell surface glycoproteinscalled selectins produce a low af  fi nity cell-to-cellinteraction resulting in  ‘‘ rolling  ’’  of the neutrophilalong the endothelial surface (Table 2). This slowing of the neutrophil increases its exposure to in fl amma-tory mediators such as histamine, IL-1, TNF- a , com-plement fragment C5a, leukotriene B 4 , IL-8, plateletactivating factor and bacterial products. In responseto these chemotactic stimuli, the adhesion of neu-trophils is strengthened through the induction of   b 2 (CD18) and  a  (CD11a,b,c) integrin adhesion mole-cules. This adhesion to endothelial cells is mediatedthrough interactions of neutrophil surface integrincomplexes LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), and perhaps p-150,95 (CD11c/CD18) withendothelial cell surface receptors ICAM-1 and 2,ELAM-1, and GMP-140 (88, 168).Following adhesion to endothelial cells, the neu-trophils  fl atten out and begin to emigrate out of postcapillary venules by pushing pseudopodsthrough intracellular junctions between the endothe-lial cells. This process of migration through theendothelium and into the extravascular tissues iscalled diapedesis. Once into the tissues, chemotacticfactors produced by both the host and bacterialpathogens bind to transmembrane receptors on theneutrophil. The end result is the movement of cellprotoplasm in the direction of the chemoattractantsand locomotion of the cell through mechanismsmediated by intracellular micro fi laments consisting of actin and myosin. Progression through the tissuesmay be directed principally by the integrin CD11b/     T   a    b    l   e    1 .    c   o   n    t    i   n   u   e    d     S   y   s    t   e   m    i   c    d    i   s   e   a   s   e   e   n    t    i    t   y    N   e   u    t   r   o   p    h    i    l    d   e    f    i   c    i    t    L   a    b   o   r   a    t   o   r   y    t   e   s    t    C    l    i   n    i   c   a    l   m   a   n    i    f   e   s    t   a    t    i   o   n   s     A   g   r   a   n   u    l   o   c   y    t   o   s    i   s    N   e   u    t   r   o   p   e   n    i   a    A    b   s   o    l   u    t   e   n   e   u    t   r   o   p    h    i    l   c   o   u   n    t    F   e   v   e   r ,   n   e   c   r   o    t    i   z    i   n   g   g   a   n   g   r   e   n   o   u   s    l   e   s    i   o   n   s   w    i    t    h   o   u    t   p   u   r   u    l   e   n   c   e ,   o   r   a    l   u    l   c   e   r   s ,   s   p   o   n    t   a   n   e   o   u   s    b    l   e   e    d    i   n   g ,   p   e   r    i   o    d   o   n    t    i    t    i   s    S   y   s    t   e   m    i   c    l   u   p   u   s   e   r   y    t    h   e   m   a    t   o   s   u   s    N   e   u    t   r   o   p   e   n    i   a ,    i   m   p   a    i   r   e    d   p    h   a   g   o   c   y    t   o   s    i   s    A    b   s   o    l   u    t   e   n   e   u    t   r   o   p    h    i    l   c   o   u   n    t ,   p    h   a   g   o   c   y    t    i   c    t   e   s    t    F   a    t    i   g   u   e ,   m   a    l   a    i   s   e ,    f   e   v   e   r ,   a   n   o   r   e   x    i   a ,   m   a    l   a   r   r   a   s    h ,   p    h   o    t   o   s   e   n   s    i    t    i   v    i    t   y ,   a   n   e   m    i   a ,   p   o   s   s    i    b    l   e    i   n   v   o    l   v   e   m   e   n    t   o    f   m   u    l    t    i   p    l   e   o   r   g   a   n   s   y   s    t   e   m   s    M   y   e    l   o   p   e   r   o   x    i    d   a   s   e    d   e    f    i   c    i   e   n   c   y    U   n   a    b    l   e    t   o   o   x    i    d    i   z   e    C    l    i   o   n   s ,   u   n   a    b    l   e    t   o   p   r   o    d   u   c   e    H    O    C    l   w    i    t    h    i   m   p   a    i   r   e    d    i   n    t   r   a   c   e    l    l   u    l   a   r    k    i    l    l    i   n   g    P   e   r   o   x    i    d   a   s   e   s    t   a    i   n    i   n   g   o    f    b    l   o   o    d    f    i    l   m   s ,    f    l   o   w   c   y    t   o   m   e    t   r   y ,   e   n   z   y   m   e   a   s   s   a   y    G   e   n   e   r   a    l    l   y    b   e   n    i   g   n ,   w    i    t    h   p   o   s   s    i    b    l   e    i   n   c   r   e   a   s   e    d   s   u   s   c   e   p    t    i    b    i    l    i    t   y    t   o    f   u   n   g   a    l    i   n    f   e   c    t    i   o   n   s    G    l   y   c   o   g   e   n   s    t   o   r   a   g   e    d    i   s   e   a   s   e    t   y   p   e    1    b    N   e   u    t   r   o   p   e   n    i   a ,    d   e    f   e   c    t    i   v   e   m    i   g   r   a    t    i   o   n   a   n    d   c    h   e   m   o    t   a   x    i   s ,   a    l    t   e   r   e    d   r   e   s   p    i   r   a    t   o   r   y    b   u   r   s    t    A    b   s   o    l   u    t   e   n   e   u    t   r   o   p    h    i    l   c   o   u   n    t ,   c    h   e   m   o    t   a   x    i   s    t   e   s    t   s ,   n    i    t   r   o    b    l   u   e    t   e    t   r   a   z   o    l    i   u   m    t   e   s    t                             ‘                            ‘     D   o    l    l  -    l    i    k   e                             ’                            ’     f   a   c    i   a    l    f   e   a    t   u   r   e   s ,   s    t   u   n    t   e    d   g   r   o   w    t    h ,    h   y   p   o   g    l   y   c   e   m    i   a ,    b    l   e   e    d    i   n   g   e   p    i   s   o    d   e   s    A   c   a    t   a    l   a   s    i   a    C   a    t   a    l   a   s   e    d   e    f    i   c    i   e   n   c   y    C   a    t   a    l   a   s   e   a   s   s   a   y    G   e   n   e   r   a    l    l   y    b   e   n    i   g   n   ;   o   r   a    l   u    l   c   e   r   a    t    i   o   n   s    i   n      <     5    0    % ,   p   o   s   s    i    b    l   e    i   n   c   r   e   a   s   e    d   r    i   s    k    f   o   r    t   y   p   e    2    d    i   a    b   e    t   e   s 84 Deas et al.  CD18 on the cell surface (108). It is believed that C5a is involved in the initial recruitment of neutrophilsand IL-8 is responsible for more prolonged recruit-ment over a 6 – 48-hour span.Neutrophils have multiple surface receptors thatenable them to bind to and phagocytize bacteria oncethey reach the site of infection. Serum factors calledopsonins help trigger this process. Various immuno-globulinsand complementfragment iC3bact asopso-nins by binding to the bacteria and providing receptorsites for the neutrophils to attach. The phagocyticprocess is triggered when the immunoglobulin Fcfragment and iC3b receptor on the neutrophil bindtocorrespondingligandsattachedtothebacteria.Thisfacilitates adherence to the microbe and initiates theformation of pseudopods which surround the bac-teria. If antibody or complement are not available,an alternative mode of opsonization involves neutro-phil bound lipopolysaccharide binding proteinattaching to bacterial lipopolysaccharide through a CD14 receptor (99). The process of endocytic invagi-nation encapsulates the bacteria in a membranebound phagolysosome. Once engulfed, the bacteria are exposed to the neutrophil ’ s intracellular killing processes.Bacterial killing within the neutrophil involves twomicrobicidal systems:   an oxygen-dependent respiratory burst resulting in the generation of free radicals, and   an oxygen-independent release of enzymes intothe phagolysosome through degranulation of cytoplasmic primary and secondary granules.If oxygen is available, phagocytosis is accompanied with a burst of oxygen consumption by the neutro-phil. Membrane bound nicotinamide adenine dinu-cleotide phosphate (NADPH) oxidase catalyzes thereduction of oxygen to superoxide anion, which isthen converted to hydrogen peroxide and hydroxylradical. Although these free radical metabolites arebactericidal, the neutrophil ’ s main oxidative attack against bacteria involves the formation of hypo-chlorous acid, hypochlorite, and chlorine. Hydrogenperoxide and chloride, in the presence of myelo-peroxidase, form the powerful oxidant hypochlorousacid, which is a very effective bacterial killer. Although the neutrophil respiratory burst is meantto protect the host from bacterial invasion, whenuncontrolled it may lead to the destruction of hosttissues. Two essential enzymes, superoxide dismu-tase and catalase, catalyze the breakdown of oxygenradicals and hydrogen peroxide to help protect thehost from these toxic oxygen metabolites.The second intracellular killing mechanism in theneutrophil relies on the fusion of cytoplasmic gran-ules with the phagocytic vacuole and the release of enzymes into the phagosome. This process, calleddegranulation, works concomitantly with the activa-tion of the oxidative pathway described above (119).Neutrophils contain several types of granules butmost attention is given to the classic lysosomal gran-ules called primary (azurophilic) granules and sec-ondary (speci fi c) granules. Primary granules areidenti fi ed by their peroxidase content and containacid hydrolases, elastase, cathepsin G, myloper-oxidase, cationic proteins, neutral proteases, bac-tericidal/permeability-increasing protein, and otherdefensins. It is the contents of these primary granulesthat are primarily responsible for the non-oxidativekilling mechanism possessed by the neutrophil. Sec-ondary granules, which are peroxidase negative, con-tain lysozyme, lactoferrin, collagenase, alkalinephosphatase and vitamin B 12  binding proteins andvarious adhesion proteins (88, 99, 171). These gran-ules are more numerous than primary granulesand are primarily involved in extracellular killing (99). It is important to note that although theseproteolytic enzymes in the primary and secondary granules are effective bacterial killers, they also Table 2.  Neutrophil margination: selectins and integrins involved in the rolling and adhesion of neutrophils toendothelium Selectins (PMN Rolling)  Integrins (PMN Adhesion) Neutrophil bound CD15s (sialy-Lewis x) CD18CD62L (L-selectin) CD11a (LFA-1)CD11b (Mac-1, CR-3)CD11c (p150, 95)Endothelium bound CD62P (P-selectin) CD54 (ICAM-1)CD62E (E-selectin) CD102 (ICAM-2)CD34Glycam-1  PMN, polymorphonuclear neutrophil leukocyte. 85  Systemic disease and periodontitis 

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