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

Abstract

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.

T Cell-Independent IgA Class Switch Recombination Is Restricted to the GALT and Occurs Prior to Manifest Germinal Center Formation

“…Whether GL7 int B cells were located at an extrafollicular or follicular site in the PP is not known. In support of an interfollicular site for IgA CSR in PP, AID mRNA expression accompanied by switch a-CT has been found in secondary lymphoid organs outside the GC, scattered in the T cell zone and within the mantle zone (46)(47)(48). Nevertheless, in this study we provide compelling evidence that T cell-independent gut IgA CSR occurs in the PP at a stage before manifest GC formations and that such IgA cells carry largely unmutated V region sequences.…”

Is minor salivary gland biopsy more than a diagnostic tool in primary Sjo¨gren׳s syndrome? Association between clinical, histopathological, and molecular features: A retrospective study

“…Some of these ectopic lymphoid structures mirror classical germinal centers (GCs) [17,18]. This organization in lymphoid GC-like structures is well documented in pSS and can be detected in one-third of patients [19].…”

Duodenal and nodal follicular lymphomas are distinct: the former lacks activation-induced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations

“…This sounds contradictory; however, Bombardieri et al 25 reported that neoplastic marginal zone-like B cells are AID-negative but have somatic and ongoing mutations. 26 On the other hand, Smit et al, 27 Pasqualucci et al 28 and Lossos et al 9 reported of lack of correlation between AID expression and intraclonal diversity of VH genes in B-cell non-Hodgkin's lymphomas.…”