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 Pdf