TY  - CHAP
M1  - Book, Section
TI  - T Cell and Combined Immunodeficiency Disorders
A1  - Belmont, John W.
A1  - Puck, Jennifer M.
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  - Antigen-specific  adaptive  immune  responses  require  the  function  of  both  T  and  B  lymphocytes.  These  cells  express  multichain  cell-surface  receptors,  T  cell  receptor  (TCR)  and  immunoglobulin  (Ig),  respectively,  that  specifically  recognize  antigenic  determinants  or  epitopes.  While  Ig  directly  binds  antigens,  TCR  recognition  requires  presentation  of  short  peptide  antigens  via  interaction  with  the  class  I  or  class  II  molecules  encoded  in  the  major  histocompatibility  complex  (MHC).  Growth  and  activation  of  T  cells  require  a  network  of  potent  extrinsic  regulatory  factors  (cytokines)  acting  through  specific  receptors  and  signal  transduction  pathways.  The  major  role  of  B  cells  is  to  produce  specific  immunoglobulins  or  antibodies.  T  cells  exhibit  diverse  functions,  including  direct  cellular  cytotoxicity  and  production  of  helper  factors  for  B  cells  and  other  immune  cells.  Given  the  central  role  of  T  lymphocytes  in  coordination  of  the  immune  response,  defects  affecting  T  and  B  cells  or  T  cells  alone  cause  severe  combined  immunodeficiency  (SCID).  The  hallmark  of  SCID  is  severe  or  repeated  infections,  especially  with  opportunistic  microorganisms.  Other  features  may  frequently  accompany  immunodeficiency  including  autoimmune  phenomena,  hematologic  abnormalities,  dermatoses,  and  neoplasia,  depending  on  the  specific  genetic  etiology.  SCID  results  from  failure  of  lymphocytes  to  develop  and  mature,  from  defects  in  MHC  expression,  and  from  interruption  of  signals  required  for  growth  and  activation.  Abnormalities  restricted  to  T  cell  activation  and/or  apoptosis  account  for  other  genetic  defects  in  T  cells  with  less  profound  immunodeficiency.DNA  rearrangement  of  the  immunoglobulin  and  T  cell  receptor  loci  to  generate  the  repertoire  of  antigen-specific  receptors  is  a  critical  developmental  checkpoint  in  both  B  cells  and  T  cells.  Rearrangement  occurs  by  a  unique  site-specific  recombination  mechanism  acting  on  signal  sequences  flanking  the  receptor  loci.  The  process  of  receptor  exon  rearrangement  is  called  V(D)J  recombination.  At  least  two  lymphocyte-specific  proteins,  recombination-activating  genes  1  and  2  (RAG1  and  RAG2),  as  well  as  several  proteins  with  broader  functions  in  the  repair  of  double-strand  breaks  (DSB)  in  DNA  mediate  V(D)J  recombination.  Failure  of  V(D)J  recombination  leads  to  developmental  blocks  in  antigen-specific  cell  surface  receptor  expression  and  consequent  failure  of  both  T  cell  and  B  cell  development  (T−B−SCID).  Mutations  in  both  RAG1  and  RAG2  have  been  associated  with  T−B−  SCID.  Allelic  heterogeneity  in  RAG1  and  RAG2  mutations  accounts  for  the  milder  phenotype  of  Omenn  syndrome  (OS).  While  not  directly  impairing  the  process  of  TCR  rearrangement,  disorders  affecting  DSB  repair  or  related  cell-cycle  checkpoints,  ataxia-telangiectasia,  Bloom  syndrome,  and  Nijmegen  breakage  syndrome,  lead  to  T  cell  immune  deficiency  and  multiple  aberrant  chromosomal  rearrangements  of  TCR.  These  disorders  are  accompanied  by  high  risk  of  neoplasia,  especially  lymphoma.Signal  transduction  after  ligand  interaction  by  the  TCR  involves  a  complex  of  proteins,  the  CD3  complex,  that  recruits  other  signal  transduction  components.  CD3  is  composed  of  two  ε,  two  ζ,  and  one  each  of  δ  and  γ  chains.  In  addition,  T  cells  express  either  CD4  or  CD8  as  coreceptors  that  influence  the  interaction  of  TCR  with  MHC  class  II  or  class  I,  respectively.  Mutations  in  zeta-chain-associated  protein  kinase  (ZAP70),  a  protein  tyrosine  kinase  that  interacts  with  the  ζ  chain  of  CD3,  result  in  a  characteristic  deficiency  of  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/19
UR  - ommbid.mhmedical.com/content.aspx?aid=1181457911
ER  -