polyvalent human immunoglobulin (liquid) (Clairyg)

Co-option of retrotransposons promotes antibody diversification.

Lauring Max C MC, Yang Ming M, Sarode Aditya A, Wang Jianhua J et al.

Activation-induced cytidine deaminase (AID) accomplishes somatic hypermutation (SHM) of VH(D)JH genes in germinal center B cells for antibody diversification and affinity maturation. How AID specifically targets VH(D)JH remains unclear. We report the discovery of LINE-1 (L1) retrotransposons upstream to many VH genes in the immunoglobulin locus. These L1s are evolutionarily old, truncated, and retrotransposition dead. Recombined VH promoters generate long, strong antisense RNAs encoding upstream L1s, triggering the human silencing hub (HUSH) complex and AID recruitment, which we term L1-driven SHM. We show that L1-driven SHM occurs in vivo using HUSH conditional knockout mice and engineered mice with VH genes devoid of upstream L1s. Insertion of transcriptionally active L1s at non-immunoglobulin loci endogenously lacking upstream L1s promotes off-target SHM. We demonstrate that old retrotransposons serve physiological roles, and our findings reveal how B cells co-opted an anti-retrotransposon silencing mechanism to promote antibody diversity. In doing so, we established a new link between cell-intrinsic innate and adaptive immunity.

Comparative Elimination Analysis of Lipid Nanoparticle-Encapsulated Human Erythropoietin mRNA by Multimodal Approaches Suggests an Effective Doping Control Strategy for mRNA-Based Agents.

Wong Kin-Sing KS, Yuen Bruce P N BPN, Kwok Coco H Y CHY, Lin Venus Y C VYC et al.

Illicit use of messenger ribonucleic acid (mRNA) agents represents an imminent threat to gene doping control in equine sports. The effectiveness and safety of lipid nanoparticle-encapsulated mRNA agents (LNP-mRNA), which have been well-proven during COVID-19 pandemic, have resulted in prominent growth of the interest on LNP-mRNA agents for expressing desired proteins in vivo. The vast number of potential performance-enhancing mRNAs has demanded cost-effective and reliable methods for their detections. This study employed a multimodal analysis approach to detect an LNP-mRNA product ("LNP-epo" hereafter) arising from encapsulation of a black-market product of human erythropoietin (hEPO) mRNA. Lipid nanoparticle (LNP) components were detected by liquid chromatography/high-resolution tandem mass spectrometry after supported liquid extraction; hEPO mRNA was detected by reverse transcription quantitative polymerase chain reaction after RNA extraction; hEPO protein was detected by sandwich enzyme-linked immunosorbent assay. Comparative elimination analysis of LNP-epo in blood samples collected from an administered horse showed the longest detection time achieved by LNP monitoring (at least 34-day postadministration), followed by hEPO mRNA detection (up to 30 days in whole blood; up to 17 days in plasma), and shortest by hEPO protein detection (up to 3 days). Together with its low analysis cost, broad coverage of LNP components, expandable scope and independence from mRNA sequence modifications and the need for specific reagents (e.g., primers, antibodies), the detection of LNP can be a fit-for-purpose screening method for monitoring the misuse of LNP-mRNA in equine sports. The other two approaches could provide insight on the intentional effect elicited by LNP-mRNA.

Case Report: Overlapping multiple sclerosis and neuropsychiatric systemic lupus erythematosus with positive MOG-IgG: a case initially misdiagnosed as depression.

Wei Wan W, Jin Tao T, Zhang Liuhai L, Sun Yumeng Y et al.

We present a 69-year-old female patient who initially manifested with depression and anhedonia, initially misdiagnosed as primary psychiatric illness. She subsequently developed progressive gait instability and cognitive decline. After comprehensive clinical and laboratory evaluation, she was finally diagnosed with multiple sclerosis (MS) complicated by neuropsychiatric systemic lupus erythematosus (NPSLE). Brain magnetic resonance imaging (MRI) revealed multifocal white matter lesions consistent with demyelination. Serologic testing demonstrated positivity for antinuclear antibody (ANA), anti-double-stranded DNA (dsDNA), anti-SS-A/Ro, anti-histone, anti-nucleosome, and anti-centromere antibodies. Cerebrospinal fluid (CSF) examination confirmed intrathecal synthesis of immunoglobulin G (IgG), as evidenced by CSF-restricted oligoclonal bands (OCBs). Serum myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) was positive at a titer of 1:32, whereas aquaporin-4 (AQP4) antibodies were negative. Based on the clinical manifestations, laboratory results and disease progression, the final diagnosis was established as coexisting MS and NPSLE. The patient achieved clinical improvement after treatment with glucocorticoids and hydroxychloroquine. This case highlights the diagnostic challenges posed by overlapping autoimmune central nervous system (CNS) disorders and underscores the importance of longitudinal assessment in differentiating MS from MOG-IgG-associated disorder (MOGAD) and NPSLE.

Widefield En Face OCT Visualization of Subretinal Perfluorocarbon Liquid.

Ishida Yuichiro Y, Kamei Motohiro M, Tsuboi Kotaro K