Chlamydophila psittaci-negative ocular adnexal marginal zone lymphomas express self polyreactive B-cell receptors

Abstract

The pathogenesis of Chlamydophila psittaci-negative ocular adnexal extranodal marginal zone lymphomas (OAEMZLs) is poorly understood. OAEMZLs are monoclonal tumors expressing a biased repertoire of mutated surface immunoglobulins. Antigenic activation of the B-cell receptor (BCR) may have a role in the pathogenesis of these lymphomas. We have analyzed the reactivity of recombinant OAEMZL immunoglobulins. OAEMZL antibodies reacted with self-human antigens, as demonstrated by enzyme-linked immunosorbent assays, HEp-2 immunofluorescence and human protein microarrays. All the analyzed recombinant antibodies (rAbs) exhibited polyreactivity by comprehensive protein array antibody reactivity and some rAbs also demonstrated rheumatoid factor activity. The identity of several reactive antigens was confirmed by microcapillary reverse-phase high-performance liquid chromatography nano-electrospray tandem mass spectrometry. The tested rAbs frequently reacted with shared intracellular and extracellular self-antigens (for example, galectin-3). Furthermore, these self-antigens induced BCR signaling in B cells expressing cognate surface immunoglobulins derived from OAEMZLs. These findings indicate that interactions between self-antigens and cognate OAEMZL tumor-derived BCRs are functional, inducing intracellular signaling. Overall, our findings suggest that self-antigen-induced BCR stimulation may be implicated in the pathogenesis of C. psittaci-negative OAEMZLs.

Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins

“…Nevertheless, the identification of a mean of 35 (median: 36) proteins in PCNSL and a mean of 87 (median: 87) proteins in FL recognized by the recAb still demonstrates that the ProtoArray data are indicative of polyreactivity. Irrespective of the stringency criteria applied for identification of hits on the ProtoArray as proteins bound by the recAb, these data indicate that polyreactivity may be a feature common to mature B cell lymphomas, including PCNSL, FL, and ocular adnexal extranodal marginal zone lymphoma (22).…”

“…Their use of additional selection strategies revealed a mean of 16 proteins identified by a recAb. Although this selection procedure is not a conditio sine qua non for analysis of ProtoArray raw data, application of these criteria (22) to PCNSL and FL reduces the numbers of proteins markedly. Nevertheless, the identification of a mean of 35 (median: 36) proteins in PCNSL and a mean of 87 (median: 87) proteins in FL recognized by the recAb still demonstrates that the ProtoArray data are indicative of polyreactivity.…”

“…For comparison, five recAbs derived from FL recognized a high number of proteins (606 in total), with a mean of 330 proteins/ recAb, indicating polyreactivity of both lymphoma types. Zhu et al (22) studied BCR reactivity in ocular adnexal extranodal marginal zone lymphoma, also taking advantage of the ProtoArray. Their use of additional selection strategies revealed a mean of 16 proteins identified by a recAb.…”

Long-term course of patients with primary ocular adnexal MALT lymphoma: a large single-institution cohort study

“…However, since B-cell receptors of POAML are autoreactive, local immune stimulation even without clinical autoimmune processes likely plays a role in the pathogenesis of these lymphomas. 12 Further, local immune stimulation may also play an important role in patients with C psittaci infection.…”

“…[9][10][11] These studies implicated a role for autoantigen-induced activation of the B-cell receptor in the pathogenesis of POAML. 12 While major advances were achieved, a large gap in knowledge of POAML exists, primarily due to the rarity of this disease. The majority of POAML clinical studies are small and retrospective with limited follow-up, resulting in nonreproducible findings and incomplete understanding of the natural history, incidence of transformation, relapse, and dissemination of this disease.…”