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Chronic bone loss is an under-recognized complication of malaria, the underlying mechanism of which remains incompletely understood. We have previously shown that persistent accumulation of Plasmodium products in the bone marrow leads to chronic inflammation in osteoblast (OB) and osteoclast (OC) precursors causing bone loss through MyD88, an adaptor molecule for diverse inflammatory signals. However, the specific contribution of MyD88 signaling in OB or OC precursors in malaria-induced bone loss remains elusive. To assess the direct cell-intrinsic role of MyD88 signaling in adult bone metabolism under physiological and infection conditions, we used the Lox-Cre system to specifically deplete MyD88 in the OB or OC lineages. Mice lacking MyD88 primarily in the maturing OBs showed a comparable decrease in trabecular bone density by microcomputed tomography to that of controls after Plasmodium yoelii non-lethal infection. In contrast, mice lacking MyD88 in OC precursors showed significantly less trabecular bone loss than controls, suggesting that malaria-mediated inflammatory mediators are primarily controlled by MyD88 in the OC lineage. Surprisingly, however, depletion of MyD88 in OB, but not in OC, precursors resulted in reduced bone mass with decreased bone formation rates in the trabecular areas of femurs under physiological conditions. Notably, insulin-like growth factor-1, a key molecule for OB differentiation, was significantly lower locally and systemically when MyD88 was depleted in OBs. Thus, our data demonstrate an indispensable intrinsic role for MyD88 signaling in OB differentiation and bone formation, while MyD88 signaling in OC lineages plays a partial role in controlling malaria-induced inflammatory mediators and following bone pathology. These findings may lead to the identification of novel targets for specific intervention of bone pathologies, particularly in malaria-endemic regions. [ABSTRACT FROM AUTHOR]

Background: Although the surgical release of the sternocleidomastoid muscle (SCM) is required for residual congenital muscular torticollis (CMT), the surgical outcomes between bipolar and unipolar SCM release remained unclear. The purpose of the present study was to assess surgical outcomes after bipolar and unipolar release of SCM in adolescent/adult patients with neglected CMT. Methods: Twenty-one consecutive adolescent/adult patients with neglected CMT who underwent surgical treatment were enrolled. Clinical and radiographic outcomes were evaluated at preoperative and final follow-up. Results: The bipolar release of SCM was performed in 3 patients (B group; males, n = 1, females, n = 2) and the unipolar release of SCM in 18 patients (U group; males, n = 6, females, n = 12). The mean age at surgery was 40.0 ± 17.0 years in Group B, and that was 32.3 ± 13.1 years in Group U (p = 0.47). The mean follow-up period was 16.0 ± 5.7 months in Group B and 10.4 ± 7.6 months in Group U (p = 0.22). Cervicomandibular angle correction rates were comparable at 75.4 ± 2.4% for the B group and 73.1 ± 11.7% for the U group (p = 0.62). There was no significant difference in clinical outcome according to the modified Cheng and Tang score between the two groups (p = 0.89). No major complications arose, although one patient exhibited a transient neurological deficit of the greater auricular nerve, and one patient developed a hematoma in the B group. Conclusions: The unipolar SCM release appeared to be a non-inferiority and less invasive procedure, minimizing surgical scars and avoiding potential auricular nerve damage in adolescent/adult patients with neglected CMT. [ABSTRACT FROM AUTHOR]

The new coronavirus infection causes severe respiratory failure following respiratory tract infection with severe acute respiratory syndrome-related coronavirus (SARS-CoV-2). All currently approved vaccines are administered intramuscularly; however, intranasal administration enhances mucosal immunity, facilitating the production of a less invasive vaccine with fewer adverse events. Herein, a recombinant vaccine combining the SARS-CoV-2 spike protein receptor-binding domain (RBD), or S1 protein, with CpG-deoxyoligonucleotide (ODN) or aluminum hydroxide (alum) adjuvants was administered intranasally or subcutaneously to mice. Serum-specific IgG titers, IgA titers in the alveolar lavage fluid, and neutralizing antibody titers were analyzed. The nasal administration of RBD protein did not increase serum IgG or IgA titers in the alveolar lavage fluid. However, a significant increase in serum IgG was observed in the intranasal group administered with S1 protein with CpG-ODN and the subcutaneous group administered with S1 protein with alum. The IgA and IgG levels increased significantly in the alveolar lavage fluid only after the intranasal administration of the S1 protein with CpG-ODN. The neutralizing antibody titers in serum and bronchoalveolar lavage were significantly higher in the intranasal S1-CpG group than in every other group. Hence, the nasal administration of the S1 protein vaccine with CpG adjuvant might represent an effective vaccine candidate. [ABSTRACT FROM AUTHOR]

Incomplete Freund's adjuvant (IFA) has been used for many years to induce autoimmune diseases in animal models, including experimental autoimmune encephalitis and collagen-induced arthritis. However, it remains unclear why it is necessary to emulsify autoantigen and heat-killed Mycobacterium tuberculosis (HKMtb) with IFA to induce experimental autoimmune diseases. Here, we found that immunization with self-antigen and HKMtb was insufficient to induce autoimmune diseases in mice. Furthermore, IFA or one of its components, mineral oil, but not mannide monooleate, was required for the development of experimental autoimmune disease. Immunization with autoantigen and HKMtb emulsified in mineral oil facilitated innate immune activation and promoted the differentiation of pathogenic CD4 + T cells, followed by their accumulation in neuronal tissues. Several water-soluble hydrocarbon compounds were identified in mineral oil. Of these, immunization with HKMtb and autoantigen emulsified with the same amount of hexadecane or tridecylcyclohexane as mineral oil induced the development of experimental autoimmune encephalitis. In contrast, immunization with HKMtb and autoantigen emulsified with tridecylcyclohexane, but not hexadecane, at doses equivalent to those found in mineral oil, resulted in neuronal dysfunction. These data indicate that tridecylcyclohexane in mineral oil is a critical component in the induction of experimental autoimmune disease., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Bisphenol A (BPA) is widely used in manufacturing plastic products, and it has been reported that exposure through the airway or orally aggravates allergic airway inflammation. Because BPA is detected in the atmosphere and indoor environments, the eyes can also be exposed to BPA. After ocular exposure to BPA and antigen via eye drops, we observed enhanced antigen uptake of antigen-presenting cells (APCs) in tear duct-associated lymphoid tissue (TALT). Additionally, we observed the formation of germinal center (GC) B cells in TALT and induction of allergic airway inflammation in mice sensitized with BPA and antigen via eye drops, followed by airway antigen exposure. We also found that DNAX-activating protein of 12 kDa (DAP12)-deficient mice displayed impaired activation of APCs enhanced by ocular exposure to BPA. These results indicate that ocular sensitization to BPA and allergen triggers allergic inflammation via TALT activation, and that DAP12 might be a key molecule for modulating the ocular immune system., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pancreatic cancer is one of the most refractory malignancies. In situ vaccines (ISV), in which intratumorally injected immunostimulatory adjuvants activate innate immunity at the tumor site, utilize tumor-derived patient-specific antigens, thereby allowing for the development of vaccines in patients themselves. Near-infrared photoimmunotherapy (NIR-PIT) is a novel therapy that selectively kills cancer cells exclusively in the NIR-irradiated region. Extending our previous research showing that ISV using the unique nanoparticulate Toll-like receptor 9 (TLR9) ligand K3-SPG induced effective antitumor immunity, here we incorporated NIR-PIT into K3-SPG-ISV so that local tumor destruction by NIR-PIT augments the antitumor effect of ISV. In the mouse model of pancreatic cancer, the combination of K3-SPG-ISV and CD44-targeting NIR-PIT showed synergistic systemic antitumor effects and enhanced anti-programmed cell death-1 (PD-1) blockade. Mechanistically, strong intratumoral upregulation of interferon-related genes and dependency on CD8 + T cells were observed, suggesting the possible role of interferon and cytotoxic T cell responses in the induction of antitumor immunity. Importantly, this combination induced immunological memory in therapeutic and neoadjuvant settings. This study represents the first attempt to integrate NIR-PIT with ISV, offering a promising new direction for cancer immunotherapy, particularly for pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint blockade (ICB) immunotherapies have emerged as promising strategies for the treatment of cancer; however, there remains a need to improve their efficacy. Determinants of ICB efficacy are the frequency of tumor mutations, the associated neoantigens, and the T cell response against them. Therefore, it is expected that neoantigen vaccinations that boost the antitumor T cell response would improve ICB therapy efficacy. The aim of this study was to develop a highly immunogenic vaccine using pattern recognition receptor agonists in combination with synthetic long peptides to induce potent neoantigen-specific T cell responses. We determined that the combination of the TLR9 agonist K-type CpG oligodeoxynucleotides (K3 CpG) with the STING agonist c-di-AMP (K3/c-di-AMP combination) significantly increased dendritic cell activation. We found that immunizing mice with 20-mer of either an OVA peptide, low-affinity OVA peptides, or neopeptides identified from mouse melanoma or lung mesothelioma, together with K3/c-di-AMP, induced potent Ag-specific T cell responses. The combined K3/c-di-AMP adjuvant formulation induced 10 times higher T cell responses against neopeptides than the TLR3 agonist polyinosinic:polycytidylic acid, a derivative of which is the leading adjuvant in clinical trials of neoantigen peptide vaccines. Moreover, we demonstrated that our K3/c-di-AMP vaccine formulation with 20-mer OVA peptide was capable of controlling tumor growth and improving survival in B16-F10-OVA tumor-bearing C57BL/6 mice and synergized with anti-PD-1 treatment. Together, our findings demonstrate that the K3/c-di-AMP vaccine formulation induces potent T cell immunity against synthetic long peptides and is a promising candidate to improve neoantigen vaccine platform., (Copyright © 2024 by The American Association of Immunologists, Inc.)