B cell proliferation, somatic hypermutation, class switch recombination, and autoantibody production in ectopic lymphoid tissue in murine lupus.
Intraperitoneal exposure of nonautoimmune mice to 2,6,10,14-tetramethylpentadecane (TMPD) causes lupus and the formation of ectopic lymphoid tissue. Although associated with humoral autoimmunity, it is not known whether Ab responses develop within ectopic lymphoid tissue or if B cells only secondarily migrate there. We show that ectopic lymphoid tissue induced by TMPD not only resembles secondary lymphoid tissue morphologically, but it also displays characteristics of germinal center reactions. Proliferating T and B lymphocytes were found within ectopic lymphoid tissue, activation-induced cytidine deaminase was expressed, and class-switched B cells were present. The presence of circular DNA intermediates, a hallmark of active class switch recombination, suggested that class switching occurs within the ectopic lymphoid tissue. Individual collections of ectopic lymphoid tissue ("lipogranulomas") from the same mouse contained different B cell repertoires, consistent with local germinal center-like reactions. Class-switched anti-RNP autoantibody-producing cells were also found in the lipogranulomas. Somatic hypermutation in the lipogranulomas was T cell-dependent, as was the production of isotype-switched anti-Sm/RNP autoantibodies. Thus, ectopic lymphoid tissue induced by TMPD recapitulates many of the functional characteristics of secondary lymphoid tissue and contains autoantibody-secreting cells, which may escape from normal censoring mechanisms in this location.
Nacionales
Dina C
DC
Center for Autoimmune Disease, University of Florida, Gainesville, 32610, USA.
Weinstein
Jason S
JS
Yan
Xiao-Jie
XJ
Albesiano
Emilia
E
Lee
Pui Y
PY
Kelly-Scumpia
Kindra M
KM
Lyons
Robert
R
Satoh
Minoru
M
Chiorazzi
Nicholas
N
Reeves
Westley H
WH
D000273:Adipose Tissue / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002828:Choristoma / Q000276:immunology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D017578:Immunoglobulin Class Switching / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000633:toxicity; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D008221:Lymphoid Tissue; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013729:Terpenes / Q000633:toxicity
D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D017411:Ribonucleoproteins, Small Nuclear; D013729:Terpenes; C009042:pristane