Comparison of B Cell Variable Region Gene Segment Characteristics in Neuro-autoantibodies

Abstract

Autoimmune pediatric neurologic diseases have variable phenotypes and presentations, making diagnosis challenging. The pathologic mechanisms are also distinct, including cell-mediated and Ab-mediated autoimmunity, paraneoplastic syndromes, and postinfectious processes. In recent years a number of studies have described the characteristics of the autoantibodies involved in a number of these diseases. Some of the described Abs use a restricted set of variable gene segments. We sought to compare the Ab characteristics of autoantibodies related to some of the more common disorders to discover whether specific Ab signatures are universally associated with neuroautoimmune diseases. We initially performed a literature review to summarize the Ab characteristics of autoantibodies related to some of the more common disorders, including N-methyl-d-aspartate receptor (NMDAR) and leucine-rich, glioma-inactivated 1 (LGI-1). Next, we performed data analysis from selected studies that sequenced Ig genes to further characterize NMDAR and LGI-1 autoantibodies including CDR3 length distribution, variable gene sequence usage, and isotype use. We found that CDR3 length of NMDAR autoantibodies was normally distributed whereas the CDR3 length distribution of LGI-1 autoantibodies was skewed, suggesting that there is no global structural restriction on types of autoantibodies that can cause encephalitis. We also found that IgG1-IgG3 were the main NMDAR autoantibody isotypes detected, while IgG4 was the major isotype used in autoantibodies from LGI-1 encephalitis. These findings are useful for our understanding of autoimmune encephalitis and will help facilitate better diagnosis and treatment of these conditions in the future.

FIGURE 1.

NMDA autoantibodies H chain CDR3 length distribution. NR-1–reactive clones (black) and nonreactive clones (gray) are presented as a portion of the total clones identified.

FIGURE 2.

NMDA autoantibodies IGHV clonal gene family use. V gene sequence of clones was performed and sequences counts were graphed by predicted V usage as percentile of total sequences within each subgroup, nonreactive (gray) and NR-1 reactive (black).

FIGURE 3.

NMDA autoantibody Ig isotypes delineated by NR-1 reactivity. NR-1–reactive Abs (left side) and NR-1 nonreactive Abs (right side) are shown. Few of the described NR-1–reactive clones had specified isotypes identified. Of those identified, all were IgG (dark gray), with 67% being IgG1. IgG Abs were the most abundant in the NR-1 nonreactive group (68%), with most of these being IgG1, followed by IgA (20%; light gray) and IgM (12%; black).

FIGURE 4.

Comparison of LGI-1 reactive and non-reactive autoantibodies by CDR3 Length. Total Abs by CDR3 amino acid length are shown, with each subgroup, nonreactive (gray) and LGI-1 reactive (black), delineated.

FIGURE 5.

IGHV gene family use: LGI-1 reactive versus LGI-1 nonreactive. Percentages of total Abs utilizing the specific H chain variable segment genes are shown. Gene usage of LGI-1–reactive autoantibodies (black bars) and LGI-1 nonreactive autoantibodies (gray bars) paired comparisons for each gene segment are shown.

FIGURE 6.

LGI-1 autoantibody isotypes. IgG (dark gray) with IgG4 (striped), IgA (light gray), and IgM (black) are shown. IgG4 was the most abundant among the reactive group, whereas IgM was the most abundant among the nonreactive clones. Series 1, LGI-1 reactive; series 2, LGI-1 nonreactive.