Ilya Kister

The formation of a stable antigenic peptide-HLA II (p-HLA class II) complex is a critical early step in the adaptive immune response. In this work, we identify the residue-residue contacts that ‘anchor’ the peptide between the alpha and beta chains of HLA II and examine whether the anchoring residue-residue contacts are shared among different p-HLA II complexes. We hypothesize that there are similarities between the contact map of the alpha and beta chains of HLA II with CLIP (the fragment of the invariant gamma chain that binds to newly synthesized HLA II molecules) and the contact maps between the different alpha and beta chains of HLA II molecules with various antigenic peptides. To test the hypothesis, 81 diverse peptide-HLA II DR and DQ complexes, including CLIP-HLA II complex, were selected from the PDB database, and ‘Unified Residue Numbering’ was introduced for all complexes. The Unified Residue Numbering enables us to compare residue contacts across complexes for each position, e.g., to identify the position in peptides occupied by residues with the highest number of contacts with HLA II similar to CLIP position with the highest number of contacts in all structures, and to define characteristics of residues for each position. We also identified all ‘similar contacts’ in the analyzed structures. ‘Similar contacts’ are defined as contacts between same-numbered residues in the peptide and HLA II and CLIP with HLA II structure independent of physicochemical properties of residues involved in the contact. We found that in the 81 analyzed structures, 90% of contacts between peptide and the alpha chains were ‘similar contacts’, as were 80% of contacts between peptides and the beta chains. Thus, our approach to sequence alignment, which is based on alignment of similar contacts rather than similar residues, allows one to define the common network of residues that underlies the interactions between peptide and HLA II. We also consider several criteria for the specificity of antigen peptide loading into HLA II based on the structural and physicochemical characteristics of the residues involved in the ‘anchoring’ contacts. These data may be useful for refining existing computational algorithms that predict peptide interactions with HLA II complexes.

Double seronegative NMOSD (DS-NMOSD) lacks approved disease-modifying treatments, and limited data exist on optimal relapse-prevention strategies. In this multicenter, international, retrospective cohort study, we sought to compare the real-world effectiveness of anti-CD20 agents vs nonspecific immunosuppressants as disease-modifying strategies for relapse prevention in DS-NMOSD. A retrospective cohort database was constructed using standardized data collection from medical records across collaborating centers in the United States, Brazil, the United Kingdom, Thailand, Turkiye, and China. Patients meeting IPND-2015 NMOSD criteria with negative serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibody testing via cell-based assays and at least 12 months of follow-up were reviewed. The primary outcome was the incidence rate ratio (IRR) of relapses; secondary outcomes included the annualized relapse rate (ARR) and time to relapse. A total of 103 patients with DS-NMOSD met study criteria, with a median follow-up of 6 years. Anti-CD20 therapy was associated with a significantly lower IRR (0.02, 95% CI 0.01-0.04) and ARR (0.17, 95% CI 0.07-0.40) compared with nonspecific immunosuppressants (0.76, 95% CI 0.40-1.43) after adjusting for covariates. Survival analysis demonstrated a prolonged relapse-free interval with anti-CD20 agents. Our findings support the use of B-cell depletion as a potentially superior relapse-prevention strategy in DS-NMOSD, highlighting its potential as a first-line therapy. This study provides Class IV evidence that, in patients with DS-NMOSD, treatment with a DMT reduces relapse incidence rate ratio compared with no treatment and anti-CD20 DMTs are associated with a lower relapse incidence rate ratio compared with nonspecific immunosuppressants.

Background and Objectives: Multiple sclerosis (MS) is characterized by lesions and atrophy on conventional MRI, yet these often fail to explain disability. Diffusion MRI (dMRI) detects microstructural injury with diffusion tensor (DTI) and kurtosis imaging (DKI) offering sensitivity, and Standard Model Imaging (SMI) providing biologically interpretable parameters. We evaluated whether these clinically feasible dMRI metrics are associated with disability beyond volumetric and lesion measures, and whether effects arise from normal-appearing white matter (NAWM). Methods: This cross-sectional study included MS patients who underwent 3T MRI including T1- and T2-weighted and a ∼7-minute multi-shell dMRI protocol. Brain volumes (gray matter, white matter, thalamus) and lesion load were derived using FreeSurfer and Icobrain. Diffusion metrics included radial diffusivity (RD) from DTI, radial kurtosis (RK) from DKI, intra-axonal water fraction ( f ) and fiber dispersion ( p ₂ ) from SMI. Clinical outcomes were the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), 9-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), and disease duration. Voxelwise and tract-based regions of interest analyses were adjusted for sex and age at onset and repeated after excluding lesions. Results: Ninety-two patients (68 women; mean age 48, range 24–73; median disease duration 14 years; EDSS 3.0, range 0-8.5) were included. dMRI revealed widespread associations with all clinical measures that persisted after lesion exclusion, implicating NAWM. Functional outcomes were tract-specific: 9HPT correlated with corticospinal tract and optic radiations (RD ρ=0.45; RK ρ=–0.44; f ρ=–0.42); MSFC with brainstem and optic radiations (RD ρ=–0.52; RK ρ=0.40; f ρ=0.39). SDMT showed widespread correlation with diffusion and atrophy (white matter ρ=0.49; thalamus ρ=0.47). EDSS showed weaker diffusion highlighting commissural disorganization (forceps major/minor ρ ≈– 0.30 to –0.32) and was most strongly associated to infratentorial lesion load (ρ=0.42). Disease duration was dominated by gray-matter atrophy (ρ=–0.54) with commissural p ₂ reductions (≈–0.45). Discussion: dMRI detects NAWM injury underlying functional impairment beyond atrophy and lesions. SMI adds specificity ( f for axonal loss/demyelination; p ₂ for inflammation). Structural measures capture the effect of cumulative burden in terms of disease duration and EDSS. Together, diffusion, volumetric, and lesion metrics offer complementary insights, supporting multimodal imaging for MS monitoring and stratification.

Purpose of Review To outline a practical and comprehensive approach to evaluating transient neurologic dysfunction (TND) in adults. Recent Findings TNDs are a common reason for neurologic consultation. Diagnosis relies largely on history, as neurologic examination is usually normal in the post-ictal stage. The differential of TNDs is extensive, and testing should be targeted to the more likely etiologies and ones that may portend permanent loss of neurologic function. In addition to the more common causes - transient ischemic attack (TIA), seizures, migraine auras, drug-induced adverse events, hypoglycemia, blood pressure fluctuations, hyperventilation, panic attacks, and paroxysmal vestibular disorders, there are some distinctive TND presentations and special circumstances that may point to the less common etiologies. The article outlines the key features of the common presentations and presents a comprehensive differential diagnosis that includes many rare causes of TNDs in adults and adolescents. Summary The proposed approach relies on carefully elucidating the nature, timeline, and circumstances of the symptoms, gathering examination clues, and seeking to determine whether the event is likely due to neuro-vascular, non-vascular neurologic (paroxysmal or chronic), non-neurologic, or rare neurologic etiologies. Specific diagnoses are listed for each of these categories.

The formation of a stable peptide-MHC class II complex is a critical step in the adaptive immune response. In this work, we investigate the residue-residue contacts that ’anchor’ the peptide between the alpha and beta chains of MHC II and examine whether such anchoring residue-residue contacts are shared among different peptide-MHC II complexes. We hypothesize that there is a similarity between the map of contacts of antigenic peptides with the alpha and beta chains of MHC II and the map of contacts of the “natural” complex of MHC II with the CLIP - the fragment of the gamma chain. Thus, the CLIP-MHC II complex – specifically, PDB structure 3PDO - was taken as the prototype for peptide-MHC II interaction. To compare the contact maps between the prototype structure and antigenic peptides/MHC II in 14 crystal structures, we developed a ‘unified numbering system’ for residues in peptide-MHC II complexes. Using this unified residue numbering system, we show that approximately half of the CLIP-MHC II residue-residue contacts have analogs in structures that involve different antigenic peptides and different MHC II (HLA-DR, HLA-DQ, and mouse A/B) alpha and beta chains. We present here this common network of contacts that underlies peptide/MHC class II interactions, as well as the structural and physicochemical characteristics of these contacts. Based on these shared characteristics, we propose criteria for the specificity of antigenic peptide loading into MHC II, whereby one can predict whether a particular peptide fragment will bind to MHC II as well as the likely localization of the fragment within the peptide binding groove of MHC II.