Predicted high affinity binding of prion PRPC protein to Human Leukocyte Antigen (HLA)
Apostolos P. Georgopoulos1,2,3*, Lisa M. James1,2,4, Matthew Sanders1,2,3
1The HLA and Chronic Diseases Research Groups, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, Minnesota, USA.
2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
3Institute for Health Informatics, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
4Department of Psychiatry, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Misfolding of the cellular prion protein (PRPC) is associated with fatal neurodegenerative prion diseases for which no treatments are currently available. Although the immune system is generally non-responsive (tolerant) to self-proteins such as PRPC, evidence of anti-prion antibodies suggests escape from self-tolerance in some individuals and supports the potential for the human immune system to be leveraged against prion disease. Human leukocyte antigen (HLA) plays a central role in rejecting endogenous non-self proteins (e.g. cancer neoantigens) by activating CD8+ cytolytic T cells via the Class I system (HLA-I) and CD4+ helper T cells via the Class II (HLA-II) system. Here we investigated the predicted binding affinity of 334 HLA molecules with all possible linear 9-mer (for HLA-I) and 15-, 18- and 22-mer (for HLA-II) PRPC peptides to identify peptide-HLA (pHLA) complexes with strong predicted binding (IC50 < 50 nM). We found that 12.4% of all prion peptides tested showed strong binding affinity to HLA molecules and that 20.2% of HLA alleles were able to bind strongly with PRPC peptides. These findings suggest that carriers of certain HLA alleles that are capable of binding strongly to PRPC peptides may have enhanced protection against prion disease, through reduction in the overall amount of PRPC available for conversion to the misfolded, infectious scrapie isoform (PRPSc) of PRPC and, potentially, by destroying it. These findings have implications for other disorders including common neurodegenerative diseases characterized by protein misfolding (e.g. α-synuclein, huntingtin, amyloid, tau, etc.).
DOI: 10.29245/2578-3009/2026/1.1266 View / Download PdfImmune Thrombocytopenia, Chronic Myeloid Leukemia, and Tyrosine Kinase Inhibitor Therapy
Yuichi Nakamura*
Department of Hematology, Saitama Medical University Hospital, Japan
Immune thrombocytopenia (ITP) and chronic myeloid leukemia (CML) are rarely observed concurrently. We recently reported a case of ITP in which CML developed over the course of the disease. Although the patient exhibited resistance and intolerance to corticosteroid therapy for ITP, thrombocytopenia improved following treatment with a tyrosine kinase inhibitor (TKI), imatinib, as a CML-directed therapy. We postulate that the off-target effects of TKI improve ITP by suppressing autoimmune responses. TKIs exert significant off-target multi-kinase inhibitory effects, including stimulatory and suppressive effects on the immune system. In addition to the immunomodulatory effects of T and natural killer cells, which elicit cytotoxicity against leukemic cells, TKIs also impair B cell-mediated humoral immunity. Notably, Bruton’s tyrosine kinase, which has recently emerged as a therapeutic target in immunosuppressive treatment for ITP, has been demonstrated to be suppressed by the off-target effects of TKIs. Drawing on our clinical observations, this mini-review summarizes the association between ITP and CML, the immunological off-target effects of TKIs, and their potential therapeutic applications in autoimmune diseases, including ITP.
DOI: 10.29245/2578-3009/2026/1.1265 View / Download PdfUpdates in the Treatment of Chronic Lymphocytic Leukemia with Targeted and Immunotherapies
Priya Hays
Hays Documentation Specialists, LLC, San Mateo, CA USA
Chronic lymphocytic leukemia is a B cell malignancy characterized by proliferation of B cells and is most prevalent in elderly populations that has poor prognosis in advanced stages. Bruton tyrosine kinase inhibitors such as ibrutinib and BCL-2 inhibitors such as venetoclax are considered one of the standard front-line treatments as shown by several clinical trials. However, several targeted and immunotherapies are emerging. Sonrotoclax is a BH3 mimetic BCL2i has been tested in combination with Zanubrutinib in phase I dose escalation/dose expansion study and resulted in a uMRD4 rates of 78% at a 320mg dose in the peripheral blood. No disease progression at a median follow-up of 10 months resulted with no atrial fibrillation and grade 3 infections at 8% of patients. Two clinical studies describe the construction of CAR T cell therapies for the treatment of CLL. CAR T cell therapies in two clinical studies describe constructions which are definite options, and combinations of BCL-2 and BTK inhibitors have been evaluated especially for double refractory disease. One study provided a protocol to recapitulate the TME of CLL to further precision medicine approaches for the disease with the aim of understanding resistance targeted therapies. Another agent, VIP152, is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy that phosphorylates RNA POLII by positive transcription elongation factor complex (P-TEFb). It is a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, producing dysregulated transcripts in CLL.
DOI: 10.29245/2578-3009/2026/1.1263 View / Download PdfCOVID-19 in Autoimmune Rheumatic Diseases: Lessons Learned and Emerging Risk Stratification Approaches
Vasiliki E. Georgakopoulou1, Clio P. Mavragani1,2,3
1Department of Pathophysiology, Laiko General Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
2 Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, 11527, Athens, Greece
3Joint Academic Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, 11527, Athens, Greece
The coronavirus disease (COVID-19) pandemic has posed unique challenges for individuals with autoimmune and autoinflammatory rheumatic diseases (AARDs), raising critical concerns about susceptibility, disease severity, treatment outcomes, and vaccine response. This mini-review draws on data from a national Greek cohort and global studies. It summarizes current evidence on disease course and risk stratification in AARD patients with COVID-19.Most patients experienced mild disease; however, those with advanced age, interstitial lung disease (ILD), and treatment with rituximab, mycophenolate mofetil, or corticosteroids demonstrated increased risk for hospitalization and mortality. In contrast, biologics targeting pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin 6 (IL-6) were not associated with worse outcomes and, in some analyses, correlated with reduced hospitalization rates. Notably, long-term sequelae, particularly persistent fatigue, emerged as a common burden, underscoring the overlap between post-viral symptoms and underlying autoimmune dysfunction. The serologic response to SARS-CoV-2 infection and vaccination was attenuated in some AARD subgroups, especially in patients receiving B-cell depleting therapies, emphasizing the need for tailored immunization and preventive strategies. Additionally, anosmia was inversely associated with hospitalization and may represent a biomarker of milder disease and more effective early immune responses. This review highlights key predictors of adverse outcomes and discusses implications for immunosuppression management, vaccination timing, and long-term care. As the pandemic evolves, identifying high-risk AARD patients and implementing precision prevention and treatment strategies remain vital priorities.
DOI: 10.29245/2578-3009/2025/4.1262 View / Download PdfA Novel Point-of-Care Method for Measuring Human Salivary Immunoglobulin A
Kelsi Irvine*, David Vollmer and Xuesheng Han
4Life Research, LLC, Sandy, UT;
Purpose: The purpose of this study was to examine the potential of a novel method for quantifying salivary immunoglobulin A (sIgA) using a point of care device.
Method: This novel method included the use of a non-invasive oral fluid collector, lateral flow strips, and a cube reader device to collect and evaluate sIgA. Volunteers were recruited to collect saliva for analysis over three separate evaluations. These evaluations examined the precision, accuracy, and robustness of the method.
Result: Results indicated that this novel method could provide a reasonably reliable and fast option to monitor sIgA levels at an accessible price point.
Conclusion: This method could be a useful tool to improve individuals' ability to self-monitor important health biomarkers and gain insight into the status of their oral immunity with minimal effort and at a low cost compared to current standard methods.
DOI: 10.29245/2578-3009/2025/3.1260 View / Download PdfChimeric Antigen receptor-T cell Therapy for Solid Tumors with Antigen Heterogeneity.
Xing-Ning Li1, Chunfeng Qu1*
1Immunology Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Chimeric antigen receptor-T (CAR-T) cell therapy in the treatment of solid tumors remains limited, though it has demonstrated remarkable success for hematological malignancies. One of the major restrictions is immune escape from the attack mediated by primary targeted CAR-T cells, driven by the heterogeneous cell components of solid tumors, including heterogeneous expression of tumor antigens. Here, we reviewed the specified challenges and corresponding strategies which are being developed, including the use of multi-targeted CAR-T cells and the activation of endogenous immune responses.
DOI: 10.29245/2578-3009/2025/2.1261 View / Download PdfAdvancing Brain Tumor Immunotherapy: The Role of Nanomedicine in Primary and Metastatic Brain Tumor
Sandbhor Puja1*, Mathur Ishita1, John Geofrey2, and Goda Jayant2
1Translational Nanomedicine and Bioengineering Lab, Department of Radiation Oncology, Advanced Centre for Treatment, Research, and Education in Cancer-Tata Memorial Centre (ACTREC-TMC), Navi-Mumbai 410210, India
2Radiobiology Lab, Department of Radiation Oncology & Homi Bhabha National Institute, Tata Memorial Hospital (TMH), Mumbai, 400012, India
The present mini-review explore the therapeutic potential of nanomedicine in advancing immunotherapy for primary and metastatic brain tumors, addressing existing challenges and paving the way for transformative precision therapy. Primary brain tumors including glioblastoma and metastases from other cancers like breast, lung etc., experiences limitation in treatment outcomes due to the tumor heterogeneity, immunosuppressive tumor microenvironment (TME), the blood-brain-barrier (BBB), and therapy resistance. Although, immunotherapies have shown promising benefits, however are hindered by immune escape, organ toxicities, and variable patient responses. Major unresolved challenges include insufficient therapeutic penetration across the BBB, the inability to reprogram the immunosuppressive TME, limited strategies to counteract dynamic tumor antigen escape, and systemic toxicities associated with conventional therapies. To address these challenges, multifunctional nanomedicines offer promising solutions through precise and controlled delivery, immunosuppressive TME modulation, and/or recalibration of immune system. Advanced nanomaterials including lipid/polymer-based system, dendrimers, and quantum dots, can co-deliver immunomodulators and chemotherapeutic/radiosensitizers, enhances BBB permeability, and activate favorable immune responses. Nanomedicines with multimodality such as localized hyperthermia (e.g. photothermal ablation), and immunogenic cell death stimulate immunological memory and improve therapeutic benefits. Furthermore, innovation in gene therapy (e.g. CRISPR-Cas9) and personalized cancer vaccines enhance targeted anti-tumor immune responses. Despite these groundbreaking advancements challenges persist, including nanoparticles-biological interactions (protein corona effects), stability, scalability, and regulatory hurdles. However, emerging trends such as 3D organoids, organ-on-a-chip system, patient-derived xenografts, and integration of AI/ML platforms, offer physiologically relevant platforms to optimize nanotherapy with better response predictions. Moreover, surface functionalization such as solid-lipid nanoparticles targeting programmed death–ligand 1 (PD-L1)-epidermal growth factor receptor (PD-L1/EGFR), have demonstrated success in augmenting the abscopal effect of radiotherapy. Radiotherapy enhances tumor antigen cross-presentation by inducing immunogenic cell death (ICD), leading to the release of tumor-associated antigens (TAAs). This process is accompanied by the release of damage-associated molecular patterns (DAMPs), such as calreticulin, HMGB1, and ATP. These signals recruit and activate dendritic cells (DCs), which engulf tumor antigens and process them via the major histocompatibility complex (MHC) class I, facilitating the activation of cytotoxic T lymphocytes (CTLs) against the tumor (S. Zhu et al., 2022). Nanoparticles (NPs) can improve antigen delivery by encapsulating tumor antigens and immune-modulatory agents, ensuring prolonged antigen presentation. Furthermore, radio-enhancing NPs, such as gold or hafnium oxide nanoparticles, intensify the effects of radiation by increasing DNA damage and reactive oxygen species (ROS) production, which strengthens the ICD response and improves antigen release (He et al., 2025). In order to further enhance immune activation, some NPs are also designed to modulate the tumor microenvironment by promoting pro-inflammatory signaling.
DOI: 10.29245/2578-3009/2025/1.1259 View / Download PdfHot to Cold Tumors: Regulations of MEX-3 Family Proteins
DOI: 10.29245/2578-3009/2025/1.1258 View / Download PdfKanglong Yang1#*, Lulu Zhu1#, Liang Zhang1*
1Center for Advanced Interdisciplinary Science and Biomedicine of IHM; Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics; Hefei National Research Center for Cross-disciplinary Science; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China
Human Leukocyte Antigen (HLA) at the Root of Persistent Antigens and Long COVID
Apostolos P. Georgopoulos1,2*, Lisa M. James1,2,3 and Phillip K. Peterson4
1Brain Sciences Center, Minneapolis Veterans Affairs Health Care System, Minneapolis, MN, USA
2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA
4Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA
Here we offer a perspective on recent findings of persistent SARS-CoV-2 antigens in Long COVID1 through the lens of immunogenetic risk and protection, namely in the context of the fundamental role of Human Leukocyte Antigen (HLA) in eliminating viral infections. Specifically, we attribute the persistence of viral antigens to the lack or weak protection conferred by HLA against SARS-CoV-2 in individuals carrying HLA alleles with low binding affinities to the virus. We suggest that determining the HLA Class I and II makeup of Long COVID patients will provide valuable new information in elucidating the cause for antigen persistence underlying the development of Long COVID and pave the way for successful interventions.
DOI: 10.29245/2578-3009/2025/1.1257 View / Download Pdf