Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis.
The unwarranted persistence of the immunoinflammatory process turns this critical component of the body's natural defenses into a destructive mechanism, which is involved in a wide range of diseases, including chronic rejection. Performing a comprehensive analysis of human kidney grafts explanted because of terminal chronic rejection, we observed that the inflammatory infiltrate becomes organized into an ectopic lymphoid tissue, which harbors the maturation of a local humoral immune response. Interestingly, intragraft humoral immune response appeared uncoupled from the systemic response because the repertoires of locally produced and circulating alloantibodies only minimally overlapped. The organization of the immune effectors within adult human inflamed tissues recapitulates the biological program recently identified in murine embryos during the ontogeny of secondary lymphoid organs. When this recapitulation was incomplete, intragraft B cell maturation was impeded, limiting the aggressiveness of the local humoral response. Identification of the molecular checkpoints critical for completion of the lymphoid neogenesis program should help develop innovative therapeutic strategies to fight chronic inflammation.
Thaunat
Olivier
O
Institut National de la Santé et de la Recherche Médicale U872, Centre de Recherche des Cordeliers, France. olivier.thaunatpastu@free.fr
Patey
Natacha
N
Caligiuri
Giuseppina
G
Gautreau
Chantal
C
Mamani-Matsuda
Maria
M
Mekki
Yahia
Y
Dieu-Nosjean
Marie-Caroline
MC
Eberl
Gérard
G
Ecochard
René
R
Michel
Jean-Baptiste
JB
Graff-Dubois
Stéphanie
S
Nicoletti
Antonino
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002908:Chronic Disease; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000196:embryology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000196:embryology / Q000276:immunology / Q000473:pathology; D007672:Kidney Cortex / Q000196:embryology / Q000276:immunology / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008221:Lymphoid Tissue / Q000196:embryology* / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D038081:Organogenesis / Q000235:genetics / Q000276:immunology*; D012189:Retrospective Studies; D046509:Tissue Culture Techniques