By Dr Felix Kleefeld

Publication

Yamashita S, Tawara N, Zhang Z, Nakane S, Sugie K, Suzuki N, Nishino I, Aoki M. Pathogenic role of anti-cN1A autoantibodies in sporadic inclusion body myositis. J Neurol Neurosurg Psychiatry. 2023 Jul 14:jnnp-2023-331474.

doi: 10.1136/jnnp-2023-331474.

PMID: 37451693.

https://pubmed.ncbi.nlm.nih.gov/37451693/

Summary

Inclusion Body Myositis (IBM) is an inflammatory muscle disease affecting elderly individuals and presenting with a unique clinical phenotype. IBM is currently incurable and associated with significant morbidity. In around 40-60% of patients, autoantibodies targeting cytosolic 5'-nucleotidase 1A (cN1A) can be detected in the serum. However, the exact role of these autoantibodies in the development and progression of the disease is not well understood. Of note, previous studies have established a link between cN1A-positivity and disease severity (e.g. dysphagia). Conversely, while testing for anti-cN1A antibodies showed high specificity and a moderate sensitivity, the antibody was not linked to age of onset, histomorphology or clinical severity in other studies. To investigate the pathogenic properties of these, Yamashita et al. conducted an experimental study using active cN1A peptide immunisation in mice.

This study involved injecting three different mouse cN1A peptides, which corresponded to the previously identified epitope sequences of human cN1A, into wild-type C57BL6 mice. The researchers confirmed the production of autoantibodies targeting the specific cN1A peptides in each group of mice. They then assessed various parameters, including changes in body weight, exercise capacity using a treadmill test, and histological changes in the muscles of the mice injected with cN1A peptides, compared to control mice.

The results of the study demonstrated that the mice injected with cN1A peptides developed autoantibodies against cN1A in their serum. Additionally, certain groups of mice injected with cN1A peptides exhibited significant weight loss and decreased motor activity compared to the control group. Histological analysis revealed an increase in the number of myofibers with internal nuclei in all peptide-injected groups, along with the presence of CD8-positive T cells invading the myofibers, abnormal protein aggregates, and overexpression of p62 and LC3 (autophagy markers). Of note, no mitochondrial abnormalities – a hallmark feature of IBM – were evident.

Based on these findings, the study concluded that active cN1A peptide immunisation in wild-type mice partially replicated the clinical and histological features of IBM. The murine model provided evidence for the pathogenic properties of anti-cN1A autoantibodies in inducing IBM-like histological changes. This study contributes to a better understanding of the mechanisms underlying IBM and highlights the potential pathogenic role of autoantibodies targeting cN1A in the development of the disease.

About the author:

Satoshi Yamashita, MD, PhD: Dr. Satoshi Yamashita is a Professor of Department of Neurology at International University of Health and Welfare, Narita Hospital, Japan. He has a special interest in the development of disease models and therapeutics for myopathies with rimmed vacuoles and motor neuron diseases. He is particularly active in elucidating the etiological significance of anti-cytosol 5'-nucleotidase 1A antibodies in inclusion body myositis. As a clinician, he is also involved in international clinical trials of inclusion body myositis.

Reviewer

Dr Felix Kleefeld is a clinical neurologist working at Charité-Universitätsmedizin Berlin, Germany, specialising in neuromuscular disorders and muscle histopathology.

Dr Kleefeld’s research interests are in understanding the pathophysiology of inflammatory and hereditary muscle diseases with a focus on IBM and associated diseases (e.g., Polymyositis with mitochondrial pathology) and Myotonic Dystrophy Type 2.

He has received research grants from both national and international funders with ongoing projects focusing on biomarker discovery and mitochondrial dysfunction in Myotonic Dystrophy Type 2 and the link between inflammation and mitochondrial abnormalities in IBM.