Analysis of immunoglobulin V_H genes suggests cutaneous marginal zone B‐cell lymphomas recognise similar antigens

Abstract

Summary Extranodal marginal zone B‐cell lymphomas (EMZL) are thought to develop from reactive infiltrates that represent immune responses to external or auto‐antigens. Except for gastric EMZL, the antigenic triggers of EMZL development are mostly unknown, although a subset of cutaneous EMZL have been associated with Borrelia burgdorferi infections. To further evaluate whether a common antigen may be promoting the development of cutaneous EMZL, the immunoglobulin heavy chain variable (VH) genes from eight USA cases were sequenced and analysed. All used VH3 family gene segments, with 2/8 using the same V3–30 segment, 2/8 using the closely related V3–30·3 or V3–33 segments, 6/8 containing mutations and 2/7 showing evidence of ongoing mutation. Many of the complimentarity‐determining region 3s (CDR3s) also showed similarities in length and displayed conserved amino acid motifs in the non‐templated areas between the diversity and joining segments. The use of similar VH gene segments and conserved CDR3 amino acid motifs suggests that some of these cutaneous EMZL may bind the same or similar antigen via their surface immunoglobulin receptor. Analysis of the somatic mutations present in many of the VH genes was also consistent with antigen directly stimulating the growth of cutaneous EMZL.

T(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas are heterogeneous with respect to the VHgene mutation status

“…Our results also show that t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas predominantly rearrange VH3 family and to a lesser extent VH4 and VH1 family genes, in cases 4, 2 and 1 respectively. This is similar to what was previously observed in several studies on MALT lymphoma [27,30,[32][33][34][35]39] and one study on nodal marginal zone lymphoma [28] . In addition, it was found that the two t(11;18)(q21;q21)-negative gastric MALT lymphomas rearranged VH3 and VH1 family genes respectively (data not shown).…”

“…gastrointestinal MALT lymphomas is consistent with that reported in similar studies on both gastric and non-gastric MALT lymphomas in which data on the presence of t(11;18)(q21;q21) was not available [26,27,30,[32][33][34][35][36][38][39][40] . In addition, analysis of the VH mutation status in 2 t(11;18)(q21;q21)-negative MALT lymphomas (data not shown) revealed a mutation frequency of 0% and 4.5% respectively, indicating that, similar to what is observed in t(11;18)(q21;q21)-positive MALT lymphomas, t(11;18)(q21;q21)-negative MALT lymphomas can be derived from both naïve and memory B cells.…”

“…Lymphomas arising from the marginal zone (e.g. extranodal, nodal and splenic marginal zone lymphomas) seem to carry either unmutated, slightly mutated or highly mutated VH genes, either with or without evidence of antigen selection [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] . These findings indicate that MALT lymphomas are heterogeneous with respect to the B cell differentiation stage at which clonal expansion occurs (being either a naive, early or late memory cell) and that direct antigen stimulation may be involved in the development or growth of the lymphoma.…”

The Role of Molecular Pathology in the Diagnosis of Cutaneous Lymphomas

“…Rather, family-specific primers are used so that, for example, 6 or 7 IGH@ V primers are used instead of ~45 individual V primers. However, several lymphomas have been demonstrated to have a nonrandom utilization of gene segments, so rational design of primer sets can optimize detection rates [29, 30]. …”

Analysis of immunoglobulin variable kappa gene mutations in cutaneous B-cell lymphoma

“…The finding of continuing accumulation of somatic mutations in Letter to the Editor 249 the clone may indicate that PCMZL is derived not from marginal zone B-cells, but from germinal center B-cells. However, some cases of MALT-type lymphoma showed intraclonal diversity in their V genes and MALT-type lymphoma is hypothesized to be derived from marginal zone B-cells, which are thought to be post germinal memory B-cells [9,10]. In these cases, it has been suggested that the neoplastic clones are probably derived from marginal zone-lymphocytes affected by a germinal center B-cell reaction [10].…”