Patient Sera Screening Confirms Dihydrolipoamide S-Acetyltransferase Antibodies in Immune-Mediated Neuropathies

Findings from a newly published cross-sectional study in Neurology confirmed the presence of dihydrolipoamide S-acetyltransferase (DLAT) antibodies in the serum of patients with immune-mediated neuropathies, significantly in those with chronic inflammatory demyelinating polyneuropathy (CIDP).¹ These results suggest that the anti-DLAT antibody, which was highly expressed in dorsal root ganglion (DRG), may serve as a diagnostic biomarker for sensory-predominant neuropathies including a subset of patients with CIDP.²

Among 78 sera from patients with CIDP screened, findings demonstrated a positive band around 60-70 kDa identified as DLAT, also known as PDC-E2. Investigators observed a relatively high reactivity in 29 of 160 (18%) patients with CIDP, followed by in 6 of 58 patients with sensory neuropathy (10%) and in 2 of 47 patients with multiple sclerosis (MS)(4%). High reactivity was not observed in patients with Guillain-Barré syndrome (n = 27), patients with hereditary neuropathy (n = 40), and healthy controls (n = 26). Notably, authors noted that both the cell-based and tissue-based assays confirmed reactivity in 26 of 33 (78%) patients with CIDP.

“The immunochemical staining of mouse and human tissues confirmed a strong expression of DLAT in DRG sensory neurons, indicating that patient serum reacts to these neurons,” senior author Masahisa Katsuno, MD, PhD, professor of neurology at Nagoya University Graduate School of Medicine, and colleagues wrote.¹ “Our results also showed that the reactivity was diminished in immunosorbent assays, confirming the antibody's specificity. These findings suggest that antibodies act on DRGs with weak blood-nerve barriers, thereby inducing sensory ataxia.”

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In this study, investigators had proteins extracted from mouse brain tissue and used them to react with sera from patients with CIDP by western blotting to determine the presence of common bands. The bands reported as positive were then characterized by mass spectrometry and confirmed for reactivity with the patient sera utilizing using enzyme-linked immunosorbent assay and western blotting. In further testing, the serum immunoglobulin G (IgG) and IgM antibodies' reactivity to recombinant DLAT was then confirmed by cell-based and tissue-based indirect immunofluorescence assays. Authors also analyzed the clinical characteristics of patients with candidate autoantibody-positive CIDP and their association with other neurologic diseases.

In the comparison of clinical characteristics in patients with CIDP who had anti-DLAT antibodies (n = 29) and those of negative cases (n = 131), investigators observed a higher number of patients who had comorbid sensory ataxia (69% vs 37%), cranial nerve disorders (24% vs 9%), and malignancy (20% vs 5%). Additionally, authors observed a high DLAT expression in human autopsy DRG, which confirmed the reactivity of patient serum with mouse DRG cells.

“The results of neurophysiologic examination revealed prolonged median nerve distal latencies and decreased sensory nerve conduction velocities in these patients, as compared with the antibody-negative cases. However, sural nerve biopsy showed no significant differences in the parameters, such as myelinated fiber density, between the 2 groups,” Katsuno et al noted.¹ “These findings suggest that a disturbance in the central DRG may be responsible for the sensory ataxia, as evidenced by the presence of anti-DLAT antibodies in patients with sensory ataxic neuropathy.”

The design of the study did not allow the investigators to determine the cause and effect of the anti-DLAT antibodies in patients with CIDP and other sensory neuropathies. In addition, authors did not identify the epitope of DLAT in where the antibodies in the patients' sera are recognized and did not perform quantitative assay of cell-based assay. The researchers also were unable to adequately evaluate the presence of DLAT antibody in patients with neuropathy who later develop malignancy because of the study design.

“Cytotoxicity assays with DRG neurons did not detect the cytotoxic effects of anti-DLAT antibodies, suggesting that T-cell–mediated mechanisms or other factors may underlie these results. Additional experimental studies using animal models are needed to clarify the role of the antibodies in the pathogenesis of CIDP,” Katsuno et al wrote.¹ “Further research focusing on the clinical characteristics of patients with anti-DLAT antibodies will aid in better defining this disorder.”

REFERENCES
1. Fukami Y, Iijima M, Koike HH, et al. Autoantibodies Against Dihydrolipoamide S-Acetyltransferase in Immune-Mediated Neuropathies [published correction appears in Neurol Neuroimmunol Neuroinflamm. 2024 Mar;11(2):e200224]. Neurol Neuroimmunol Neuroinflamm. 2024;11(2):e200199. doi:10.1212/NXI.0000000000200199
2. Autoantibodies against dihydrolipoamide S-acetyltransferase (DLAT) in immune-mediated neuropathies. News Release. Nagoya University. Published January 5, 2024. Accessed February 21, 2024. https://www.med.nagoya-u.ac.jp/medical_E/research/pdf/Neu_240110en.pdf