IGHV1-2*04 Heavy Chain Dominance Drives Autoreactivity in SMZL

Splenic marginal zone lymphoma (SMZL) shows distinct immunogenetic features involving the B-cell receptor immunoglobulin (BcR IG), particularly its heavy chain. About 30% of SMZL cases utilize the IGHV1-204 gene, characterized by a unique tryptophan (W) residue at position VH FR3-75 instead of the more common arginine (R). This subgroup exhibits diverse complementarity-determining region 3 (CDR3) characteristics, pronounced intraclonal diversification, and heavy chain dominance. However, the functional and structural relevance of IGHV1-204 remains unclear.

To address this gap, researchers performed immunologic, biochemical, and crystallographic studies using recombinant monoclonal antibodies (rmAbs) from SMZL cases, including 14 IGHV1-204–derived antibodies. Testing against autoantigens revealed significant poly/autoreactivity, regardless of the IGHV gene used or somatic hypermutation status. SMZL rmAbs demonstrated stronger binding to autoantigens compared with similar antibodies from chronic lymphocytic leukemia cases. Flow cytometry and immunohistochemistry confirmed binding to various human cells and tissues, with IGHV1-204–derived antibodies showing distinct profiles.

Site-directed mutagenesis of the IGHV1-204 W75 residue to R (W75R) revealed significant changes in antigen reactivity, highlighting the critical role of W75 in functional properties. Additional experiments combining IGHV1-204 heavy chains with random light chains showed no differences in reactivity, reinforcing heavy chain dominance in this subgroup. Structural studies of IGHV1-2*04–derived BcR fragments (antigen-binding fragments) identified unique homotypic interactions mediated by the W75 residue and R95 side chain, forming stable homodimers with high energetic contribution, as confirmed through in silico analysis.

This study suggests that SMZL likely originates from a B-cell population with restricted BcR IG structures and strong autoreactive potential. The findings highlight heavy chain dominance in the IGHV1-204 subgroup and propose the IGHV1-204 heavy chain as a potential immunotherapeutic target for a significant portion of patients with SMZL.

REFERENCE:

Iatrou A, Patrone M, Sarrigeogiou I, et al. Structural and functional analysis of the clonotypic B cell receptor immunoglobulin in splenic marginal zone lymphoma: ontogenetic and therapeutic implications. Abstract #975. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.