Hyper-N-glycosylated SAMD14 and neurabin-I as driver autoantigens of primary central nervous system lymphoma

Abstract

<jats:title>Abstract</jats:title> <jats:p>To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper-N-glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated Pseudomonas exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach.</jats:p>

Lymphocyte predominant cells detect Moraxella catarrhalis-derived antigens in nodular lymphocyte-predominant Hodgkin lymphoma

“…The hypobiotinylated pyruvate carboxylase might contribute to its immunogenicity in patient #5. Autoreactive BCRs contributing to lymphomagenesis by chronic stimulation due to alternative secondary modifications have previously been described in MGUS, Waldenström macroglobulinemia, multiple myeloma, and primary central nervous system lymphoma [19][20][21][22] . Pyruvate carboxylase is a highly conserved gene, and has been identified as an antigen recognized by BCRs of CLL 23 .…”

“…To verify specific reactivity of IgD + , NLPHL derived Fabs against M. catarrhalis RpoC, recombinant Fabs derived from 11 cases of PCNSL, 12 cases of DLBCL, 10 cases of MCL, and 12 cases of CLL were screened against M. catarrhalis lysates on dot blots and against recombinant FLAG-tagged M. catarrhalis RpoC by ELISA 22,23,49 .…”

Primary vitreoretinal lymphomas display a remarkably restricted immunoglobulin gene repertoire

“…The nature of the antigens remains elusive, although some hints can be gained from recent studies that tested antigen reactivity of PCNSL BCR immunoglobulin, expressed as recombinant antibodies, against protein microarrays. 77,78 Montesinos-Rongen et al found that these antibodies displayed polyreactivity, although not with common autoantigens but against a range of diverse proteins, including some expressed by CNS neurons. All antibodies using the IGHV4-34 gene recognized galectin-3, a carbohydrate-binding protein expressed by cells from the cerebral microenvironment.…”

“…79 Alternatively, Thurner et al provided evidence that PCNSLs recognize atypically hyper-N-glycosylated forms of SAMD14 and neurabin-I, 2 proteins that are highly expressed in CNS tissue. 78 However, these investigators failed to detect galectin-3 as a target of their recombinant BCRs.…”

Tropism of PCNSL: is it all about autoantigens?

“…J Exp Med.Björn Chapuy | University Medical Center GöttingenIn this issue of Blood, Thurner et al identified that two-thirds of patients with primary central nervous system lymphoma (PCNSL) have B-cell receptors (BCRs) specific for 2 autoantigens, SAMD14 and neurabin-1. These antigens are predominantly expressed in the central nervous system (CNS), induced strong BCR pathway activation, and autorecognition of them is therefore an attractive explanation for the CNS tropism of the disease 1.…”