Transmembrane Helices Are an Over-Presented and Evolutionarily Conserved Source of Major Histocompatibility Complex Class I and II Epitopes

Cytolytic T cell responses are predicted to be biased towards membrane proteins. The peptide-binding grooves of most alleles of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefore peptide fragments derived from human transmembrane helices (TMHs) are predicted to be presented more often as would be expected based on their abundance in the proteome. However, the physiological reason of why membrane proteins might be over-presented is unclear. In this study, we show that the predicted over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II, and confirmed by re-analysis of epitope databases. Moreover, we show that TMHs are evolutionarily more conserved, because single nucleotide polymorphisms (SNPs) are present relatively less frequently in TMH-coding chromosomal regions compared to regions coding for extracellular and cytoplasmic protein regions. Thus, our findings suggest that both cytolytic and helper T cells are more tuned to respond to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs are less prone to mutations that enable pathogens to evade T cell responses.

Effect of Ethyl Acetate Fraction of Marsilea crenata Presl. Leaf Extract on Major Histocompatibility Complex Class II Expression in Microglial HMC3 Cell Lines

Phytoestrogens are plant-derived chemical substances that have estrogen-like structures or estrogenic functions. Deficiency of estrogen in human brain causes neuroinflammation characterized by increase of major histocompatibility complex class II (MHC II) expression as a marker of M1 phenotype in microglia. Recent research found phytoestrogen compounds in Marsilea crenata Presl. The aim of this study was to investigate the effect of ethyl acetate fraction of Marsilea crenata Presl. leaf extract in MHC II expression of microglial HMC3 cell lines, for resolution of inflammation and tissue repair. The fractions were given at concentrations of 62.5, 125, and 250 ppm to microglia, that had been previously induced by IFNγ 10 ng for 24 hours to stimulate the cells into M1 phenotype. Genistein as phytoestrogen was given at a concentration of 50 μM as positive control. Expression of MHC II was analyzed using immunocytochemistry method. Result showed reduction in MHC II expression of microglial cells, which indicated the activity of all extracts and, showed that 250 ppm of the fraction showed the strongest effect with MHC II value expression of 148.632 AU, and ED50 of 1,590 ppm. It was concluded from the study, that ethyl acetate fraction of Marsilea crenata Presl. leaves has antineuroinflammation effect.

Overview on Diagnosis and Management of Polymyositis

Polymyositis (PM) is an autoimmune disorder; result from abnormal activation of cytotoxic T lymphocytes (CD8 cells) and macrophages against muscular antigens as well as the strong extrafusal muscular expression of major histocompatibility complex class 1 causing damage to the endomysium of the skeletal muscles. Polymyositis develops over the months as compared to inclusion body myositis (IBM), which is a slowly progressive chronic myopathy developing in older individuals over a period of months to years with more severe symptoms. Many patients require treatment for many years. Polymyositis affects the distal musculature of the esophagus in the late stage of disease in up to 70% of the patients leading to the inability to swallow, as well as regurgitation problems that can cause aspiration pneumonia. The principal goals of therapy are to improve strength and improve physical functioning. Many patients require treatment for several years. The 5-year survival rate for treated patients is in the order of 95%. Up to one-third of PM patients may be left with some degree of residual muscle weakness.

Efficacy, safety, and biomarker analysis of Camrelizumab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN study)

BackgroundThis study aimed to evaluate the antitumor activity of camrelizumab, an antiprogrammed cell death-1 antibody, in pretreated recurrent or metastatic nasopharyngeal carcinoma (NPC) and to explore predictive biomarkers.MethodsPatients with recurrent (not amenable to locally curative treatment) or metastatic NPC who had failed at least two lines of chemotherapy were eligible to receive camrelizumab (200 mg intravenously every 2 weeks) for 2 years or until disease progression, intolerable adverse events, withdrawal of consents, or investigator decision. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC). Programmed cell death-ligand 1 (PD-L1) expression was assessed by immunohistochemistry. Other immune-related biomarkers including major histocompatibility complex class I and major histocompatibility complex class II (MHC-II) were assessed by multiplex immunofluorescence staining.ResultsBetween August 14, 2018, and December 30, 2019, a total of 156 patients were enrolled. The IRC-assessed ORR was 28.2% (95% CI 21.3% to 36.0%). The median progression-free survival was 3.7 months (95% CI 2.0 to 4.1) per IRC, and the median overall survival was 17.4 months (95% CI 15.2 to 21.9). The ORRs were 35.2% (95% CI 25.3% to 46.1%) vs 19.4% (95% CI 10.4% to 31.4%) in patients with tumor PD-L1 expression of ≥10% and<10%, respectively. Patients with durable clinical benefit (DCB), which was defined as complete response, partial response or stable disease of ≥18 weeks, had higher density of MHC-II+ cell in stroma than patients without DCB (median 868.1 (IQR 413.4–2854.0) cells/mm2 vs median 552.4 (IQR 258.4 to 1242.1) cells/mm2). MHC-II+ cell density did not correlate with PD-L1 expression, and a composite of high stromal MHC-II+ cell density and tumor PD-L1 expression further enriched patients who could benefit from camrelizumab.ConclusionsCamrelizumab had clinically meaningful antitumor activity in patients with recurrent or metastatic NPC. The composition of both MHC-II+ cell density and PD-L1 expression could result in better patient selection.

Downregulation of Cell Surface Major Histocompatibility Complex Class I Expression Is Mediated by the Left-End Transcription Unit of Fowl Adenovirus 9

Major histocompatibility complex class I (MHC-I) molecules play a critical role in the host’s antiviral response by presenting virus-derived antigenic peptides to cytotoxic T lymphocytes (CTLs), enabling the clearance of virus-infected cells. Human adenoviruses evade CTL-mediated cell lysis, in part, by interfering directly with the MHC-I antigen presentation pathway through the expression of E3-19K, which binds both MHC-I and the transporter associated with antigen processing protein and sequestering MHC-I within the endoplasmic reticulum. Fowl adenoviruses have no homologues of E3-19K. Here, we show that representative virus isolates of the species Fowl aviadenovirus C, Fowl aviadenovirus D, and Fowl aviadenovirus E downregulate the cell surface expression of MHC-I in chicken hepatoma cells, resulting in 71%, 11%, and 14% of the baseline expression level, respectively, at 12 h post-infection. Furthermore, this work reports that FAdV-9 downregulates cell surface MHC-I through a minimum of two separate mechanisms—a lysosomal-independent mechanism that requires the presence of the fowl adenovirus early 1 (FE1) transcription unit located within the left terminal genomic region between nts 1 and 6131 and a lysosomal-dependent mechanism that does not require the presence of FE1. These results establish a new functional role for the FE1 transcription unit in immune evasion. These studies provide important new information about the immune evasion of FAdVs and will enhance our understanding of the pathogenesis of inclusion body hepatitis and advance the progress made in next-generation FAdV-based vectors.

Major Histocompatibility Complex Class I in Hippocampus Promotes the Comorbid Depressive Symptoms in Cancer Induced Bone Pain via Regulating the Microglial TREM2/DAP12 Signaling

Pain and depression comorbidity affect the patients’ both physical and mental health and quality of life seriously. The comorbid depressive symptoms in cancer pain severely affect the recognition and treatment of pain. Similarly, cancer pain patients with depression are inclined toward more despair and greater impairment. The mechanisms responsible for the comorbid depressive symptoms in cancer induced bone pain have not been fully delineated and the currently available therapeutics for this pathological pain is relatively limited. In the present study, we observed that carcinoma cells implantation induced pain and depression comorbidity resulted in the upregulation of major histocompatibility complex class I (MHC-I) in hippocampus associated with the activation of TREM2/DAP12-mediated microglial signaling pathways. These observations were reversed by a lentiviral vector harboring RNA interference sequence targeting MHC-I injected into the hippocampus of tumor bearing mice. Together, these results suggest that MHC-I involves in the cancer induced bone pain and depression comorbidity through regulating the TREM2/DAP12-mediated signals in microglia of hippocampus. Suppression of MHC-I could be a therapeutic target for cancer induced bone pain.