Zhihui Deng

The American Society for Histocompatibility and Immunogenetics HLA common and well-documented (CWD) catalog, CWD 2.0.0 catalog and European Federation for Immunogenetics (EFI) CWD catalog have been published, which are useful for improving the accuracy of HLA genotyping in laboratories. Here, we studied the Chinese HLA CWD catalog. A total of 812 211 unrelated volunteer donors from the China Marrow Donor Program (CMDP) were analyzed. Six hundred seventy-six alleles at the HLA-A, -B, -C, -DRB1, and -DQB1 loci were defined as CWD alleles in the Chinese population, including 159 common and 517 well-documented alleles. The distribution of HLA alleles in the Chinese CWD catalog is different from that in the EFI CWD catalog. Thirty-two percent (215/676) of CWD alleles in the Chinese CWD catalog are shared with those in the EFI CWD catalog. Fifty-six percent (380/676) of alleles in the Chinese CWD catalog are not found in the EFI CWD catalog, while 655 alleles in the EFI CWD catalog are neither common nor well-documented alleles in the Chinese CWD catalog. The Chinese CWD catalog described in this study may help to improve high-resolution histocompatibility testing for CMDP-accredited laboratories in China. However, to accommodate an increasing number of HLA alleles, this Chinese CWD catalog should be regularly updated.

Key points Spinal cord α‐motoneurons display strong membrane immunoreactivity (IR) against small‐conductance calcium‐activated potassium channel (SK) isoform SK2, and a specific subpopulation of motoneurons also express SK3‐IR. Rat α‐motoneurons expressing SK3‐IR are significantly smaller, have significantly longer after‐hyperpolarization half‐decay time, significantly larger after‐hyperpolarization amplitude and significantly slower axon conduction velocity than α‐motoneurons that lack SK3‐IR. Motoneuron pools innervating slow‐twitch muscles have a higher percentage of SK3‐IR α‐motoneurons than those innervating fast‐twitch muscles. Expression of SK3 may contribute to variability in after‐hyperpolarization duration and amplitude across different types of rat α‐motoneurons and may be a molecular factor differentiating between slow‐ and fast‐type motoneurons. In the soma and proximal dendrites of α‐motoneurons, large clusters of SK2 and SK3 channel subunits appose cholinergic C‐boutons and colocalize with muscarinic type 2 receptors and Kv2.1 channels, which suggests a novel cellular mechanism for state‐dependent regulation of neuronal excitability. Abstract Small‐conductance calcium‐activated potassium (SK) channels mediate medium after‐hyperpolarization (AHP) conductances in neurons throughout the central nervous system. However, the expression profile and subcellular localization of different SK channel isoforms in lumbar spinal α‐motoneurons (α‐MNs) is unknown. Using immunohistochemical labelling of rat, mouse and cat spinal cord, we reveal a differential and overlapping expression of SK2 and SK3 isoforms across specific types of α‐MNs. In rodents, SK2 is expressed in all α‐MNs, whereas SK3 is expressed preferentially in small‐diameter α‐MNs; in cats, SK3 is expressed in all α‐MNs. Function‐specific expression of SK3 was explored using post hoc immunostaining of electrophysiologically characterized rat α‐MNs in vivo . These studies revealed strong relationships between SK3 expression and medium AHP properties. Motoneurons with SK3‐immunoreactivity exhibit significantly longer AHP half‐decay times (24.67 vs . 11.02 ms) and greater AHP amplitudes (3.27 vs . 1.56 mV) than MNs lacking SK3‐immunoreactivity. We conclude that the differential expression of SK isoforms in rat and mouse spinal cord may contribute to the range of medium AHP durations across specific MN functional types and may be a molecular factor distinguishing between slow‐ and fast‐type α‐MNs in rodents. Furthermore, our results show that SK2‐ and SK3‐immunoreactivity is enriched in distinct postsynaptic domains that contain Kv2.1 channel clusters associated with cholinergic C‐boutons on the soma and proximal dendrites of α‐MNs. We suggest that this remarkably specific subcellular membrane localization of SK channels is likely to represent the basis for a cholinergic mechanism for effective regulation of channel function and cell excitability.

Background and objective Aetiology and pathogenesis of anti- N -methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the most common autoimmune encephalitis, is largely unknown. Since an association of the disease with the human leucocyte antigen (HLA) has not been shown so far, we here investigated whether anti-NMDAR encephalitis is associated with the HLA locus. Methods HLA loci of 61 patients with anti-NMDAR encephalitis and 571 healthy controls from the Chinese Han population were genotyped and analysed for this study. Results Our results show that the DRB1*16:02 allele is associated with anti-NMDAR encephalitis (OR 3.416, 95% CI 1.817 to 6.174, p=8.9×10 −5 , p adj =0.021), with a higher allele frequency in patients (14.75%) than in controls (4.82%). This association was found to be independent of tumour formation. Besides disease susceptibility, DRB1*16:02 is also related to the clinical outcome of patients during treatment, where patients with DRB1*16:02 showed a lower therapeutic response to the treatment than patients with other HLA alleles (p=0.033). Bioinformatic analysis using HLA peptide-binding prediction algorithms and computational docking suggested a close relationship between the NR1 subunit of NMDAR and the DRB1*16:02 . Conclusions This study for the first time demonstrates an association between specific HLA class II alleles and anti-NMDAR encephalitis, providing novel insights into the pathomechanism of the disease.