Self-antigen recognition by follicular lymphoma B-cell receptors

Abstract

IntroductionFollicular lymphoma (FL) is a slowly progressive and largely incurable human B-cell malignancy. Transformation to a more aggressive lymphoma, such as diffuse large B-cell lymphoma, is common and strongly associated with an increase in morbidity and mortality. A chromosomal translocation t(14:18) is the hallmark of this disease, and it is found in 85%-90% of cases. It results in the juxtaposition of the BCL2 proto-oncogene with the immunoglobulin (Ig) heavy chain gene, IGH, leading to deregulated overexpression of Bcl-2 protein, a major inhibitor of apoptosis. However, the t(14:18) translocation is insufficient to cause malignancy as it is detectable in rare B cells from healthy persons. 1-3 Thus, FL pathogenesis requires additional signals beyond that imparted by the deregulation of BCL2. The observation that FL cells isolated from patients fail to survive in vitro and undergo spontaneous apoptosis supports the hypothesis that extrinsic microenvironmental factors are required for maintenance and expansion of FL. 4 Phenotypically, FL tumor cells resemble antigen-experienced germinal center B cells. Their Ig genes, which are rearranged to produce a functional B-cell receptor (BCR), have numerous point mutations compared with their germline counterparts, and this process of somatic hypermutation (SHM) is ongoing as the malignant clone expands and diversifies. Thus, individual tumor cells can each have slightly different Ig variable region sequences. 5 Random mutations should eventually result in stop codons and loss of BCR protein expression. However, FL tumors maintain a surface BCR, indicating a selective force favoring retention of a functional BCR. Furthermore, therapy with anti-idiotype antibodies directed against the BCR did not select for the outgrowth of BCR-negative variants. Rather, this therapy selected for the outgrowth of cells that had amino acid substitutions in the targeted V region sequence, making them unrecognizable by the anti-idiotype antibody. 6 Other in vitro studies with malignant B-cell lines have shown that experimental knockdowns of the BCR and members of its signaling pathway result in growth arrest, implicating their importance in tumor cell survival. 7 The BCR can transmit a tonic survival signal, but this is greatly augmented on its binding to a cognate antigen. 8 There is indirect evidence to suggest that antigen recognition plays a role in the pathogenesis of FL. SHM can introduce silent or replacement mutations, the latter leading to an amino acid substitution. In a normal immune response, B cells with mutations resulting in higher binding affinity for the inciting antigen preferentially survive. This selective pressure leads to enrichment of replacement mutations in the complementarity determining regions (CDRs) of the BCR, and an under representation of replacement mutations in the framework regions (FWRs). 9 This same distribution of replacement and silent mutations has been reported for the BCRs of FL cells, 5 and the intraclonal diversity resulting from ongoing SHM...

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

“…Microenvironmental factors serving as self-Ags also were identified for FL, in which 19% of tumor Igs recognized vimentin expressed in the lymph node and one tumor in which myoferlin served as self-Ag (10,18). However, for the immunologically privileged CNS, microenvironmental proteins serving as potential Ags for B cells have not been described before.…”

“…In this regard, PCNSL apparently differs from other types of lymphoma. Reactivity with HEp-2 cells [in a frequency similar to normal memory B cells (24,25)] identified 26% of FLs, which recognized self-Ags (18). Moreover, IgG FL exhibited a higher frequency of self-reactivity than did IgM FL (20.4% versus 3.4%) (10).…”

“…In addition to recAbs derived from PCNSL, five recAbs derived from FL (513, 526, 684, 1081, 1102) were included (18). They were kindly provided by Dr. Ronald Levy and Dr. Debra K. Czerwinski (Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA).…”

The Emerging Importance of IgG Fab Glycosylation in Immunity

“…B cell malignancies are sometimes characterized by aberrant Fab glycosylation. Increased frequencies of N-linked Fab-glycosylation sites in IgG and/or BCR were described for follicular lymphoma, diffuse large B cell lymphoma, and Burkitt's lymphoma B cells, whereas mutated chronic lymphocytic leukemia, multiple myeloma, and MALT lymphoma B cells were comparable with normal B cells (5,45,46). These tumor-associated Fab glycans are highmannose structures, whereas the corresponding Fc glycans are complex-type biantennary glycans, confirming that the normal N-linked glycan-processing pathway is intact (6,47).…”

“…In another study, following immunizations in mice, N-linked glycosylation sites were introduced in the variable domains of the BCR of anergic B cells that presumably allowed these cells to move away from autoreactivity, while allowing them to react against cross-reacting foreign Ags (25). However, in another study, autoantigen binding of follicular lymphomaderived Abs was unaffected upon expression in the presence of tunicamycin to suppress N-linked (Fab) glycosylation (46). Potential role for Fab glycosylation in IVIg therapy.…”