Splenic marginal zone lymphoma with VH1-02 gene rearrangement expresses poly- and self-reactive antibodies with similar reactivity

Abstract

One-third of all splenic marginal zone lymphomas (SMZL) use the IgH VH1-02 gene. These cases are usually not associated with hepatitis C virus infection. Of interest, the rearranged VH1-02 genes display similar complementarity determining regions 3, a finding confirmed by our study. The latter suggests that these SMZL may produce antibodies with similar reactivity. We produced recombinant antibodies from 5 SMZL cases with VH1-02 gene rearrangement to study the binding reactivity of these antibodies. Surprisingly, the recombinant antibodies demonstrated poly-and self-reactivity as demonstrated by their reactivity with nuclear, cytoplasmic, as well as membranous antigens expressed by human cells and by reactivity with human serum. This polyreactivity was specific as demonstrated by ELISA. The antibodies did not react with proteins on the cell surface that are IntroductionMarginal zone lymphomas are believed to arise from B lymphocytes residing in the marginal zone of the B-cell zone in secondary lymphoid tissue. The origin and function of human marginal zone B lymphocytes have not completely been elucidated, but marginal zone B cells likely have a function in the T-independent immune response. 1 Depending mainly on the organ in which marginal zone lymphoma arises, 3 distinct subtypes of marginal zone lymphoma are recognized: nodal, extra-nodal, and splenic marginal zone lymphomas (SMZL), arising from lymph nodes, mucosal sites, and the spleen, respectively. Together, those marginal zone lymphomas represent ϳ 8% of all lymphomas and are the third most-frequent lymphoma type. 2 SMZL as well as the extranodal marginal zone lymphomas are clinically low grade or indolent, whereas nodal marginal zone lymphomas have a more aggressive clinical course. 3 In contrast to nodal and extranodal marginal zone lymphomas, SMZLs are mostly systemic and are diagnosed with BM infiltration. A subset of extranodal marginal zone lymphomas occurring in the stomach and lung are characterized by the translocation t(11;18)(q21;q21) or variant translocation t(14;18)(q32;q21), resulting in overexpression of the MALT1 gene, and a minority of those lymphomas can show either a translocation t(3;14)(p14;q32), t(1;14)(p22;q32), or BCL10 mutation. Primary genetic alterations have not been demonstrated for nodal or SMZL. However, frequent deletion of the long arm of chromosome 7(del 7q31-32) as well as trisomy 3 have been documented in SMZL. 4 The importance of these genetic findings for the pathogenesis of SMZL is not clear. 5 Extranodal marginal zone lymphomas may occur secondary to chronic infection or chronic inflammation. 6 Extranodal marginal zone lymphoma arising in the stomach may occur secondarily to Helicobacter pylori-associated gastritis. 7 This led to the successful use of antibiotics for its treatment. 8 Similarly, marginal zone lymphoma arising in the thyroid gland and salivary gland can be secondary to chronic inflammation associated with autoimmune disease, such as Hashimoto thyroiditis or Sjö gren syndrome, respectively. 9,10 Othe...

Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation

“…13,17,32,33 This claim is also supported by the remarkably skewed IG heavy and light chain gene repertoire, 20 as well as the antigen reactivity profile of SMZL BcR IG. 10 Prompted by these observations, we explored the precise role of TLR triggering in SMZL, especially since published evidence on this issue is scarce and essentially derives from the analysis of archival material, thus hindering firm conclusions. In order to obtain a more comprehensive insight into the role of TLR signaling in SMZL immunopathogenesis, we performed ex vivo studies in a sizable series of well-characterized patients with SMZL, consolidated within the context of an international collaboration.…”

“…This claim is also supported by the particularly skewed immunoglobulin heavy variable (IGHV) gene repertoire in SMZL, where a substantial proportion of cases (from 20% to more than 30%, depending on the series) express a single IGHV gene allele, namely IGHV1-2*04, suggesting (super)antigenic pressure on the malignant clone involving inflammatory/infectious agents. [10][11][12] Indeed, existing evidence shows that SMZL is associated with viral infections, e.g. with the hepatitis C virus (HCV), as suggested by a number of complete remissions after viral eradication.…”

“…They bind to nuclear, cytoplasmic and membrane antigens expressed by human cells and also react against human serum, implying derivation from natural antibody-producing B cells of MZ origin. 10 Therefore, SMZL can be considered a prototypic infection/inflammation associated tumor. Nevertheless, while several studies focused on the role of the BcR in SMZL, information is still lacking on the potential role played by TLR in disease onset and progression, which is relevant to investigate given that TLRs are implicated in the immune recognition of inflammatory/infectious elements in both normal and malignant B-cell clones.…”

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

“…Moreover, signs of lymphoid clone selection driven by autoantigens can be recognized in the B-cell receptor (BCR) confi guration of chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL), none of which has been causally related to any specifi c infective, infl ammatory, or autoimmune disease (7)(8)(9). Despite the numerous associations described above, the key factors driving the transition from an infl ammatory/autoimmune background to malignant lymphoproliferation have not been identifi ed (10)(11)(12).…”

Mouse marginal zone B cells harbor specificities similar to human broadly neutralizing HIV antibodies

“…Evidence to support this idea includes the much shorter CDRH3 of many IGHV1-2*02-encoded broadly neutralizing antibodies compared with other broadly neutralizing antibodies (12,13), a characteristic of human and rodent MZ B cells (37,42). In addition, the IGHV1-2*02 segment has been viewed clinically as a feature of MZ lymphomas (43,44), indicating that human MZ B cells naturally express this IGHV gene segment. Molecular analyses of a human spleen sample showed no preferential expression for IGHV1-2*02 in MZ B cells, as has been detected in mouse MZ B cells (Fig.…”