Activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in Sjögren's syndrome.
Demonstration of ectopic germinal center-like structures (GC-LSs) in chronically inflamed tissues in patients with autoimmune disorders is a relatively common finding. However, to what extent ectopic lymphoid structures behave as true GC and are able to support class switch recombination (CSR) and somatic hypermutation (SHM) of the Ig genes is still debated. In addition, no information is available on whether CSR and SHM can take place in the absence of GCs at extrafollicular sites in an ectopic lymphoid tissue. In this study, we show that in salivary glands (SGs) of Sjögren's syndrome (SS) activation-induced cytidine deaminase (AID), the enzyme responsible for CSR and SHM is invariably expressed within follicular dendritic cell (FDC) networks but is not detectable in SGs in the absence of ectopic GC-LSs, suggesting that FDC networks play an essential role in sustaining the Ag-driven B cell proliferation within SS-SGs. We also show that the recently described population of interfollicular large B cells selectively expresses AID outside ectopic GC in the T cell-rich areas of periductal aggregates. Finally, we report that AID retains its exclusive association with numerous, residual GCs in parotid SS-MALT lymphomas, whereas neoplastic marginal zone-like B cells are consistently AID negative. These results strongly support the notion that ectopic lymphoid structures in SS-SGs express the molecular machinery to support local autoantibody production and B cell expansion and may play a crucial role toward lymphomagenesis.
Bombardieri
Michele
M
Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, St. Bartholomew's and Royal London School of Medicine, London, United Kingdom.
Barone
Francesca
F
Humby
Frances
F
Kelly
Stephen
S
McGurk
Mark
M
Morgan
Peter
P
Challacombe
Stephen
S
De Vita
Salvatore
S
Valesini
Guido
G
Spencer
Jo
J
Pitzalis
Costantino
C
D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000201:enzymology / Q000473:pathology; D001402:B-Lymphocytes / Q000201:enzymology*; D002454:Cell Differentiation; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D020566:Dendritic Cells, Follicular / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D004789:Enzyme Activation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D018442:Lymphoma, B-Cell, Marginal Zone / Q000150:complications / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D012793:Sialadenitis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D012859:Sjogren's Syndrome / Q000150:complications / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D001323:Autoantibodies; D012333:RNA, Messenger; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase