PMID- 37520549
OWN - NLM
STAT- MEDLINE
DCOM- 20230801
LR  - 20230801
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 14
DP  - 2023
TI  - Role of the mechanisms for antibody repertoire diversification in monoclonal 
      light chain deposition disorders: when a friend becomes foe.
PG  - 1203425
LID - 10.3389/fimmu.2023.1203425 [doi]
LID - 1203425
AB  - The adaptive immune system of jawed vertebrates generates a highly diverse 
      repertoire of antibodies to meet the antigenic challenges of a constantly 
      evolving biological ecosystem. Most of the diversity is generated by two 
      mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM 
      introduces changes in the variable domain of antibodies, mostly in the regions 
      that form the paratope, yielding antibodies with higher antigen binding affinity. 
      However, antigen recognition is only possible if the antibody folds into a stable 
      functional conformation. Therefore, a key force determining the survival of B 
      cell clones undergoing somatic hypermutation is the ability of the mutated heavy 
      and light chains to efficiently fold and assemble into a functional antibody. The 
      antibody is the structural context where the selection of the somatic mutations 
      occurs, and where both the heavy and light chains benefit from protective 
      mechanisms that counteract the potentially deleterious impact of the changes. 
      However, in patients with monoclonal gammopathies, the proliferating plasma cell 
      clone may overproduce the light chain, which is then secreted into the 
      bloodstream. This places the light chain out of the protective context provided 
      by the quaternary structure of the antibody, increasing the risk of misfolding 
      and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) 
      amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma 
      (cast) nephropathy are a diverse group of diseases derived from the pathologic 
      aggregation of light chains, in which somatic mutations are recognized to play a 
      role. In this review, we address the mechanisms by which somatic mutations 
      promote the misfolding and pathological aggregation of the light chains, with an 
      emphasis on AL amyloidosis. We also analyze the contribution of the variable 
      domain (V(L)) gene segments and somatic mutations on light chain cytotoxicity, 
      organ tropism, and structure of the AL fibrils. Finally, we analyze the most 
      recent advances in the development of computational algorithms to predict the 
      role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and 
      discuss the challenges and perspectives that this approach faces.
CI  - Copyright (c) 2023 Del Pozo-Yauner, Herrera, Perez Carreon, Turbat-Herrera, 
      Rodriguez-Alvarez and Ruiz Zamora.
FAU - Del Pozo-Yauner, Luis
AU  - Del Pozo-Yauner L
AD  - Department of Pathology, University of South Alabama-College of Medicine, Mobile, 
      AL, United States.
FAU - Herrera, Guillermo A
AU  - Herrera GA
AD  - Department of Pathology, University of South Alabama-College of Medicine, Mobile, 
      AL, United States.
FAU - Perez Carreon, Julio I
AU  - Perez Carreon JI
AD  - Instituto Nacional de Medicina Genomica (INMEGEN), Ciudad de Mexico, Mexico.
FAU - Turbat-Herrera, Elba A
AU  - Turbat-Herrera EA
AD  - Department of Pathology, University of South Alabama-College of Medicine, Mobile, 
      AL, United States.
AD  - Mitchell Cancer Institute, University of South Alabama-College of Medicine, 
      Mobile, AL, United States.
FAU - Rodriguez-Alvarez, Francisco J
AU  - Rodriguez-Alvarez FJ
AD  - Instituto Nacional de Medicina Genomica (INMEGEN), Ciudad de Mexico, Mexico.
FAU - Ruiz Zamora, Robin A
AU  - Ruiz Zamora RA
AD  - Instituto Nacional de Medicina Genomica (INMEGEN), Ciudad de Mexico, Mexico.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20230713
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
SB  - IM
MH  - Animals
MH  - Humans
MH  - *Multiple Myeloma
MH  - Friends
MH  - Ecosystem
MH  - B-Lymphocytes
MH  - *Paraproteinemias/genetics
PMC - PMC10374031
OTO - NOTNLM
OT  - V(D)J rearrangement
OT  - amyloid
OT  - antibodies
OT  - immune system
OT  - light chain (AL) amyloidosis
OT  - protein aggregation
OT  - somatic hypermutation
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/07/31 06:43
MHDA- 2023/08/01 06:44
PMCR- 2023/01/01
CRDT- 2023/07/31 04:53
PHST- 2023/04/10 00:00 [received]
PHST- 2023/06/20 00:00 [accepted]
PHST- 2023/08/01 06:44 [medline]
PHST- 2023/07/31 06:43 [pubmed]
PHST- 2023/07/31 04:53 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2023.1203425 [doi]
PST - epublish
SO  - Front Immunol. 2023 Jul 13;14:1203425. doi: 10.3389/fimmu.2023.1203425. 
      eCollection 2023.