title: A change in inflammatory footprint precedes plaque instability: a systematic evaluation of cellular aspects of the adaptive immune response in human atherosclerosis.
abstract: BACKGROUND
  Experimental studies characterize adaptive immune response as a critical factor in the progression and complications of atherosclerosis. Yet, it is unclear whether these observations translate to the human situation. This study systematically evaluates cellular components of the adaptive immune response in a biobank of human aortas covering the full spectrum of atherosclerotic disease.
  
  
  RESULTS
  A systematic analysis was performed on 114 well-characterized perirenal aortic specimens with immunostaining for T-cell subsets (CD3/4/8/45RA/45RO/FoxP3) and the Th1/non-Th1/Th17 ratio (CD4(+)T-bet(+)/CD4(+)T-bet(-)/CD4(+)/interleukin-17(+) double staining). CD20 and CD138 were used to identify B cells and plasma cells, while B-cell maturation was evaluated by AID/CD21 staining and expression of lymphoid homeostatic CXCL13. Scattered CD4 and CD8 cells with a T memory subtype were found in normal aorta and early, nonprogressive lesions. The total number of T cells increases in progressive atherosclerotic lesions (≈1:5 CD4/CD8 T-cell ratio). A further increase in medial and adventitial T cells is found upon progression to vulnerable lesions.This critical stage is further hallmarked by de novo formation of adventitial lymphoidlike structures containing B cells and plasma cells, a process accompanied by transient expression of CXCL13. A dramatic reduction of T-cell subsets, disappearance of lymphoid structures, and loss of CXCL13 expression characterize postruptured lesions. FoxP3 and Th17 T cells were minimally present throughout the atherosclerotic process.
  
  
  CONCLUSIONS
  Transient CXCL13 expression, restricted presence of B cells in human atherosclerosis, along with formation of nonfunctional extranodal lymphoid structures in the phase preceding plaque rupture, indicates a "critical" change in the inflammatory footprint before and during plaque destabilization.
authors: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands (D., D., M.S., H., L.).
authors: R A
authors: RA
authors: van Dijk
authors: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands (D., D., M.S., H., L.).
authors: A J F
authors: AJ
authors: Duinisveld
authors: Department of Transplantation Surgery, Leiden University Medical Center, Leiden, The Netherlands (S.).
authors: A F
authors: AF
authors: Schaapherder
authors: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands (D., D., M.S., H., L.).
authors: A
authors: A
authors: Mulder-Stapel
authors: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands (D., D., M.S., H., L.).
authors: J F
authors: JF
authors: Hamming
authors: Gorlaeus Laboratories, Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (K.).
authors: J
authors: J
authors: Kuiper
authors: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands (B., W.).
authors: O J
authors: OJ
authors: de Boer
authors: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands (B., W.).
authors: A C
authors: AC
authors: van der Wal
authors: CVPath Institute Inc., Gaithersburg, MD (K., V.).
authors: F D
authors: FD
authors: Kolodgie
authors: CVPath Institute Inc., Gaithersburg, MD (K., V.).
authors: R
authors: R
authors: Virmani
authors: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands (D., D., M.S., H., L.).
authors: J H N
authors: JH
authors: Lindeman
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology / Q000502:physiology; D000328:Adult; D001011:Aorta / Q000276:immunology / Q000473:pathology; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology*; D001402:B-Lymphocytes / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D054382:Chemokine CXCL13 / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000276:immunology / Q000473:pathology*; D010950:Plasma Cells / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000473:pathology
chemical_list: D054382:Chemokine CXCL13
keywords: adaptive immunity; aorta; atherosclerosis; inflammation; necrotic core; neovessel; vulnerable plaque