TY  - CHAP
M1  - Book, Section
TI  - Leukocyte Adhesion Deficiencies
A1  - Anderson, Donald C.
A1  - Wayne Smith, C.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - A  cascade  of  adhesive  events  is  needed  for  efficient  localization  of  leukocytes  at  foci  of  inflammation.  Members  of  the  selectin  family  of  glycoproteins  are  required  for  primary  adhesion  of  flowing  leukocytes  interacting  with  endothelial  cells  at  venular  shear  rates.  L-selectin  (CD62L)  is  expressed  constitutively  on  neutrophils,  monocytes,  eosinophils,  and  subsets  of  lymphocytes  and  binds  to  carbohydrate  ligands  on  endothelial  cells  and  other  leukocytes.  E-selectin  (CD62E)  is  not  constitutively  expressed  by  endothelial  cells  but  is  up-regulated  following  stimulation  with  inflammatory  cytokines  such  as  IL-1.  P-selectin  (CD62P)  is  found  in  α  granules  of  platelets  and  Wiebel-Palade  bodies  of  venular  endothelial  cells,  and  is  rapidly  up-regulated  to  the  luminal  surface  following  stimulation  (e.g.,  with  histamine).  The  selectins  bind  to  sialylated  and  fucosylated  carbohydrate  ligands  on  cell  surface  glycoproteins.  This  interaction  at  venular  shear  rates  results  in  rolling  of  leukocytes  along  the  endothelium.  Stationary  adhesion  and  transendothelial  migration  of  leukocytes  depends  on  the  interaction  of  integrins  on  the  leukocyte  surface  with  ligands  on  the  endothelial  cells.  The  integrins  of  greatest  importance  to  neutrophils  are  Mac-1  (CD11b/CD18)  and  LFA-1  (CD11a/CD18),  members  of  the  β2  integrin  family.  Cell  activation  is  required  for  effective  transition  from  selectin-dependent  rolling  to  stable  integrin-dependent  adhesion.  Chemotactic  substances  on  the  surface  of  endothelial  cells  (e.g.,  IL-8  and  platelet-activating  factor)  stimulate  this  activation.  Intercellular  adhesion  molecule-1  (CD54)  is  the  principal  ligand  on  endothelial  cells  for  these  integrins.  It  is  constitutively  expressed  on  venular  endothelium  and  is  markedly  up-regulated  by  stimulation  of  these  cells  with  inflammatory  cytokines.  Blockade  or  absence  of  individual  components  can  interrupt  this  cascade  of  events.  Failure  of  the  selectin-dependent  step  results  in  failure  of  leukocytes  to  effectively  bind  to  endothelial  cells,  with  consequent  failure  of  effective  emigration.  Failure  of  the  integrin-dependent  step  allows  rolling  of  leukocytes,  but  emigration  is  again  prevented.Aberrations  in  adhesive  mechanisms  account  for  several  clinical  syndromes  that  involve  an  increase  in  susceptibility  to  bacterial  infection.  Leukocyte  adhesion  deficiency  I  (LAD  I)  (MIM  116920)  was  the  first  to  be  defined  at  a  molecular  level;  it  results  from  mutations  in  CD18,  the  β  subunit  of  β2  integrins,  leading  to  partial  or  complete  absence  of  expression,  or  dysfunction  of  these  integrins.  In  addition  to  their  role  in  neutrophil  emigration,  these  integrins  serve  additional  functions  in  host  defense  against  infection.  LFA-1  is  involved  in  costimulation  of  lymphocytes  during  antigen  presentation.  Mac-1  functions  as  a  receptor  for  complement  opsonized  bacteria,  enhancing  phagocytosis  and  bactericidal  mechanisms  (e.g.,  enhanced  reactive  oxygen  production).  Patients  with  LAD  I  appear  to  fall  into  two  phenotypes.  The  severe  phenotype  occurs  when  CD18  expression  is  absent  or  extremely  low.  These  patients  are  subject  to  overwhelming,  life-threatening  bacterial  infections.  The  moderate  phenotype  occurs  when  either  CD18  expression  is  very  low  or  CD18  integrins  are  dysfunctional.  These  patients  exhibit  increased  susceptibility  to  bacterial  infections,  but  most  have  survived  to  adulthood.  Numerous  CD18  mutations  have  been  defined,  and  patients  are  often  compound  heterozygotes,  with  differing  mutations  from  the  maternal  and  paternal  alleles.A  second  type  of  leukocyte  adhesion  deficiency,  called  LAD  II  (MIM  266265),  results  from  dysfunction  of  the  selectin  pathway  of  adhesion.  This  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/18
UR  - ommbid.mhmedical.com/content.aspx?aid=1181458479
ER  -