Mucosal Sites Research Articles

STAR LIGHT Study: XBB.1.5 COVID-19 mRNA Vaccines Boost Systemic but Not Mucosal Immunity Against the SARS-CoV-2 JN.1 Variant in Patients with Chronic Liver Disease

Background: Patients with chronic liver disease (CLD) have impaired vaccine immunogenicity and an excess risk of severe COVID-19. While variant-adapted COVID-19 mRNA vaccines are recommended for vulnerable individuals, their efficacy in patients with CLD has not been studied. Methods: We present the first evaluation of XBB.1.5 COVID-19 vaccine immunogenicity against the SARS-CoV-2 JN.1 variant in patients with CLD. Serum anti-receptor binding domain (RBD) IgG, neutralization, and saliva anti-RBD IgG and IgA against wild-type SARS-CoV-2 (WT) and the XBB.1.5, EG.5.1, BA.2.86, and JN.1 variants were quantified before and 2–4 weeks following a fourth dose of XBB.1.5 mRNA vaccines. Results: Vaccination boosted anti-RBD IgG and neutralization against all tested variants including JN.1 (each p < 0.001). Following immunization, neutralization was lower against JN.1 compared to WT, XBB.1.5, and EG.5.1 (p < 0.001, p < 0.001, and p < 0.01, respectively). Vaccination reduced neutralization failure rates against BA.2.86 and JN.1 (each p < 0.05). The evasion of vaccine-induced antibodies by the tested variants was low, indicated by the positive correlation between anti-RBD IgG and neutralization. At mucosal sites, vaccination boosted anti-RBD IgG (each p < 0.01) but failed to induce infection-blocking IgA (each p > 0.05). Conclusion: XBB.1.5 vaccines protect CLD patients against recent SARS-CoV-2 variants, but developing vaccines with optimized mucosal immunogenicity is required to prevent SARS-CoV-2 transmission and recurrent seasonal COVID-19 outbreaks.

Clinico-pathological specificities of gingival carcinoma among 32 patients with oral cancer: a cross sectional retrospective and observational study

BackgroundThe study aimed to examine the prevalence of gingival cancers compared to other oral mucosal sites, analyze patient profiles, and identify risk factors.Materials and MethodsA retrospective monocentric study was conducted at the Department of Oral Medicine of Bretonneau Hospital in Paris, France. 32 patients diagnosed with oral mucosal cancer were included. Data extracted from electronic medical records encompassed patient demographics, cancer type, lesion location, and tobacco/alcohol use.Results46.9% were diagnosed with gingival cancer. Patients with gingival cancer had a mean age of 74.2 years old, higher than the mean age of 63.9 years old for those with non-gingival cancer. Men accounted for 60% of cases in the gingival cancer group. Squamous cell carcinoma was the predominant cancer type observed in both gingival and non-gingival cancers. Notably, 26.7% of gingival cancer patients used both alcohol and tobacco, all of them male. Among non-gingival cancer patients, 23.5% used both substances, with both sexes represented.ConclusionThis study provides insights into the higher prevalence of oral squamous cell carcinoma among men with risk factors and highlights characteristics of gingival squamous cell carcinoma. Effective management strategies should include comprehensive clinical assessments to ensure early detection and intervention for improved outcomes.

Anti-modified protein antibodies can be detected in saliva, but not in intestinal secretions of seropositive rheumatoid arthritis patients - evidence of site-specific mucosal autoantibody secretion in RA.

Anti-citrullinated protein antibodies (ACPA) have been detected in sputum and saliva, indicating that anti-modified protein antibodies (AMPA) can be produced at mucosal sites in rheumatoid arthritis (RA) patients. However, the body's largest mucosal compartment, the gut, has not yet been examined. We therefore investigated the presence of several AMPA (antibodies against citrullinated (ACPA), carbamylated (anti-CarP) and acetylated (AAPA) proteins) at different mucosal sites, including the intestinal tract. Paired fecal/ileal wash, saliva and serum samples of RA patients and healthy volunteers were collected in two independent cohorts. Data involving feces was replicated in a third cohort. In these secretions AMPA were analyzed using in-house ELISA with unmodified peptides as control. In fecal samples total IgA and anti-E. coli IgA were measured. ACPA, anti-CarP and AAPA IgA were measurable in saliva of seropositive RA patients (prevalence 9-40%). No AMPA could be detected in feces. IgA was present since total IgA and anti-E. coli IgA was detectable in feces of ACPA-positive RA patients and healthy donors. Results were confirmed in another cohort using colonoscopically collected ileal wash samples. Our study shows the presence of ACPA, anti-CarP and AAPA IgA in saliva of ACPA-seropositive RA patients. However, no AMPA could be detected in feces/ileal wash samples of these patients, although our assays were able to measure other antigen-specific antibodies. These data suggest that mucosal autoantibody secretion may occur in the oral mucosa of RA patients, while no evidence could be found for this process in the lower gastro-intestinal tract.

Mannose and Lactobionic Acid in Nasal Vaccination: Enhancing Antigen Delivery via C-Type Lectin Receptors.

Nasal vaccines are a promising strategy for enhancing mucosal immune responses and preventing diseases at mucosal sites by stimulating the secretion of secretory IgA, which is crucial for early pathogen neutralization. However, designing effective nasal vaccines is challenging due to the complex immunological mechanisms in the nasal mucosa, which must balance protection and tolerance against constant exposure to inhaled pathogens. The nasal route also presents unique formulation and delivery hurdles, such as the mucous layer hindering antigen penetration and immune cell access. This review focuses on cutting-edge approaches to enhance nasal vaccine delivery, particularly those targeting C-type lectin receptors (CLRs) like the mannose receptor and macrophage galactose-type lectin (MGL) receptor. It elucidates the roles of these receptors in antigen recognition and uptake by antigen-presenting cells (APCs), providing insights into optimizing vaccine delivery. While a comprehensive examination of targeted glycoconjugate vaccine development is outside the scope of this study, we provide key examples of glycan-based ligands, such as lactobionic acid and mannose, which can selectively target CLRs in the nasal mucosa. With the rise of new viral infections, this review aims to facilitate the design of innovative vaccines and equip researchers, clinicians, and vaccine developers with the knowledge to enhance immune defenses against respiratory pathogens, ultimately protecting public health.

Immunoglobulin M-based local production in skin-associated lymphoid tissue of flounder (Paralichthys olivaceus) initiated by immersion with inactivated Edwardsiella tarda

Fish skin, the mucosal site most exposed to external antigens, requires protection by an efficient local mucosal immune system. The mucosal reserve of IgM is recognized as an immune strategy that blocks pathogen invasion to maintain homeostasis, whereas the mechanism of skin-associated local IgM production induced by mucosal antigens is not well know. In this study, we found that the skin of flounder (Paralichthys olivaceus) was equipped with the immune cellular and molecular basis for processing mucosal antigens and triggering local specific responses, i.e., CD4+ Zap-70+ T cells, CD4- Zap-70+ T/NK cells, IgM+ MHCII+ B cells, PNA+ MHCII+ antigen-presenting cells, UEA-1+ WGA+ and UEA-1+ WGA- antigen-sampling cells, as well as secreted IgM and pIgR, as demonstrated by indirect immunofluorescence assay using different antibodies and lectins. After immersion immunization with inactivated Edwardsiella tarda, qPCR assay displayed up-regulation of immune-related genes in flounder skin. Flow cytometry analysis and EdU labeling demonstrated that the mucosal inactivated vaccine induced local proliferation and increased amounts of cutaneous IgM+ B cells. Skin explant culture proved the local production of specific IgM in the skin, which could bind to the surface of E. tarda. ELISA, laser scanning confocal microscopy, and western blot revealed that, in addition to the elevated IgM levels, pIgR protein level was significantly up-regulated in skin tissue and surface mucus containing the pIgR (secretory component, SC)-tetrameric IgM complex, indicating that mucosal vaccine stimulated up-regulation of IgM and pIgR, which were secreted as a complex into skin mucus to exert the protective effects as secretory IgM. These findings deepen the understanding of IgM-based local responses in the mucosal immunity of teleosts, which will be critical for subsequent investigation into the protective mechanism of mucosal vaccines for fish health.

Enhanced mucosal antibody- and T-cell responses against SARS-CoV-2 after heterologous intramuscular mRNA prime/intranasal protein boost vaccination with a combination adjuvant.

Current COVID-19 mRNA vaccines delivered intramuscularly (IM) induce effective systemic immunity, but with suboptimal immunity at mucosal sites, limiting their ability to impart sterilizing immunity. There is strong interest in rerouting immune responses induced in the periphery by parenteral vaccination to the portal entry site of respiratory viruses, such as SARS-CoV-2, by mucosal vaccination. We previously demonstrated the combination adjuvant, NE/IVT, consisting of a nanoemulsion (NE) and an RNA-based RIG-I agonist (IVT) induces potent systemic and mucosal immune responses in protein-based SARS-CoV-2 vaccines administered intranasally (IN). Herein, we demonstrate priming IM with mRNA followed by heterologous IN boosting with NE/IVT adjuvanted recombinant antigen induces strong mucosal and systemic antibody responses and enhances antigen-specific T cell responses in mucosa-draining lymph nodes compared to IM/IM and IN/IN prime/boost regimens. While all regimens induced cross-neutralizing antibodies against divergent variants and sterilizing immunity in the lungs of challenged mice, mucosal vaccination, either as homologous prime/boost or heterologous IN boost after IM mRNA prime was required to impart sterilizing immunity in the upper respiratory tract. Our data demonstrate the benefit of hybrid regimens whereby strong immune responses primed via IM vaccination are rerouted by IN vaccination to mucosal sites to provide optimal protection to SARS-CoV-2.

SARS-CoV-2 infection is associated with intestinal permeability, systemic inflammation, and microbial dysbiosis in hospitalized patients.

Coronavirus disease 2019 (COVID-19) and its associated severity have been linked to uncontrolled inflammation and may be associated with changes in the microbiome of mucosal sites including the gastrointestinal tract and oral cavity. These sites play an important role in host-microbe homeostasis, and disruption of epithelial barrier integrity during COVID-19 may potentially lead to exacerbated inflammation and immune dysfunction. Outcomes in COVID-19 are highly disparate, ranging from asymptomatic to fatal, and the impact of microbial dysbiosis on disease severity is unclear. Here, we obtained plasma, rectal swabs, oropharyngeal swabs, and nasal swabs from 86 patients hospitalized with COVID-19 and 12 healthy volunteers. We performed 16S rRNA sequencing to characterize the microbial communities in the mucosal swabs and measured concentrations of circulating cytokines, markers of gut barrier integrity, and fatty acids in the plasma samples. We compared these plasma concentrations and microbiomes between healthy volunteers and COVID-19 patients, some of whom had unfortunately died by the end of the study enrollment, and performed a correlation analysis between plasma variables and bacterial abundances. Rectal swabs of COVID-19 patients had reduced abundances of several commensal bacteria including Faecalibacterium prausnitzii and an increased abundance of the opportunistic pathogens Eggerthella lenta and Hungatella hathewayi. Furthermore, the oral pathogen Scardovia wiggsiae was more abundant in the oropharyngeal swabs of COVID-19 patients who died. The abundance of both H. hathewayi and S. wiggsiae correlated with circulating inflammatory markers including IL-6, highlighting the possible role of the microbiome in COVID-19 severity and providing potential therapeutic targets for managing COVID-19.IMPORTANCEOutcomes in coronavirus disease 2019 (COVID-19) are highly disparate and are associated with uncontrolled inflammation; however, the individual factors that lead to this uncontrolled inflammation are not fully understood. Here, we report that severe COVID-19 is associated with systemic inflammation, microbial translocation, and microbial dysbiosis. The rectal and oropharyngeal microbiomes of COVID-19 patients were characterized by a decreased abundance of commensal bacteria and an increased abundance of opportunistic pathogens, which positively correlated with markers of inflammation and microbial translocation. These microbial perturbations may, therefore, contribute to disease severity in COVID-19 and highlight the potential for microbiome-based interventions in improving COVID-19 outcomes.

Systemic administration of a potent mouse monoclonal antibody provides multisite protection against HPV16 infection

Although preventive vaccines for Human Papillomaviruses (HPV) are available, a definitive cure for the viral infection itself is currently lacking. There is a sizable population that remains inaccessible to HPV vaccination due to reasons such as high costs or lack of availability of the vaccines. Therefore, there remains a significant population susceptible to HPV infection. Persistent multisite infections with high-risk HPV types can cause cancer at several different anatomic sites.Especially HPV16 is a key etiologic factor for cervical, other ano-genital and oropharyngeal cancers. Therefore, it is imperative to develop pharmaceutical interventions for the treatment of viral infections. In this study, a panel of 9 neutralizing antibodies was screened using the hybridoma technique, with 20F6 being identified as the representative antibody. The purified 20F6 exhibited an IC50 of 0.0011 μg/ml against HPV16, demonstrating potent viral inhibitory activity. Moreover, it displayed cross-neutralizing efficacy towards other Alphapapillom 9 subtypes including HPV31, HPV33, HPV52, and HPV58 with respective IC50 values of 2.0 μg/ml, 7.3 μg/ml, 1.7 μg/ml, and 3.0 μg/ml. 20F6 recognizes the linear epitope MSLW, the first four amino-acids located at the very N-terminus of the HPV16 L1 protein. Administration of 20F6, 24 h prior to and following HPV16 pseudo-virion (PSV) challenge, conferred protection against infection in mice at doses as low as 1 mg/kg. Following intraperitoneal administration of 20F6, neutralizing antibodies were consistently detected at both oral and vaginal sites, indicating that prophylactic systemic administration of 20F6 may confer efficient protection against multiple susceptible mucosal sites.

A Polysaccharide-Based Oral-Vaccine Delivery System and Adjuvant for the Influenza Virus Vaccine.

Influenza virus enters the host body through the mucosal surface of the respiratory tract. An efficient immune response at the mucosal site can interfere with virus entry and prevent infection. However, formulating oral vaccines and eliciting an effective mucosal immune response including at respiratory mucosa presents numerous challenges including the potential degradation of antigens by acidic gastric fluids and the risk of antigen dilution and dispersion over a large surface area of the gut, resulting in minimal antigen uptake by the immune cells. Additionally, oral mucosal vaccines have to overcome immune tolerance in the gut. To address the above challenges, in the current study, we evaluated inulin acetate (InAc) nanoparticles (NPs) as a vaccine adjuvant and antigen delivery system for oral influenza vaccines. InAc was developed as the first polysaccharide polymer-based TLR4 agonist; when tailored as a nanoparticulate vaccine delivery system, it enhanced antigen delivery to dendritic cells and induced a strong cellular and humoral immune response. This study compared the efficacy of InAc-NPs as a delivery system for oral vaccines with Poly (lactic-co-glycolic acid) (PLGA) NPs, utilizing influenza A nucleoprotein (Inf-A) as an antigen. InAc-NPs effectively protected the encapsulated antigen in both simulated gastric (pH 1.1) and intestinal fluids (pH 6.8). Moreover, InAc-NPs facilitated enhanced antigen delivery to macrophages, compared to PLGA-NPs. Oral vaccination studies in Balb/c mice revealed that InAc-Inf-A NPs significantly boosted the levels of Influenza virus-specific IgG and IgA in serum, as well as total and virus-specific IgA in the intestines and lungs. Furthermore, mice vaccinated with InAc-Inf-A-NPs exhibited notably higher hemagglutination inhibition (HI) titers at mucosal sites compared to those receiving the antigen alone. Overall, our study underscores the efficacy of InAc-NPs in safeguarding vaccine antigens post-oral administration, enhancing antigen delivery to antigen-presenting cells, and eliciting higher virus-neutralizing antibodies at mucosal sites following vaccination.

Divergent synthesis of amino acid-linked O-GalNAc glycan core structures.

O-GalNAc glycans, also known as mucin-type O-glycans, are primary constituents of mucins on various mucosal sites of the body and also ubiquitously expressed on cell surface and secreted proteins. They have crucial roles in a wide range of physiological and pathological processes, including tumor growth and progression. In addition, altered expression of O-GalNAc glycans is frequently observed during different disease states. Research dedicated to unraveling the structure-function relationships of O-GalNAc glycans has led to the discovery of disease biomarkers and diagnostic tools and the development of O-glycopeptide-based cancer vaccines. Many of these efforts require amino acid-linked O-GalNAc core structures as building blocks to assemble complex O-glycans and glycopeptides. There are eight core structures (cores one to eight), from which all mucin-type O-glycans are derived. In this protocol, we describe the first divergent synthesis of all eight cores from a versatile precursor in practical scales. The protocol involves (i) chemical synthesis of the orthogonally protected precursor (3 days) from commercially available materials, (ii) chemical synthesis of five unique glycosyl donors (1-2 days for each donor) and (iii) selective deprotection of the precursor and assembly of the eight cores (2-4 days for each core). The procedure can be adopted to prepare O-GalNAc cores linked to serine, threonine and tyrosine, which can then be utilized directly for solid-phase glycopeptide synthesis or chemoenzymatic synthesis of complex O-glycans. The procedure empowers researchers with fundamental organic chemistry skills to prepare gram scales of any desired O-GalNAc core(s) or all eight cores concurrently.

Distinct mucosal endotypes as initiators and drivers of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a potentially devastating autoimmune disease. The great majority of patients with RA are seropositive for anti-citrullinated protein antibodies (ACPAs), rheumatoid factors, or other autoantibodies. The onset of clinically apparent inflammatory arthritis meeting classification criteria (clinical RA) is preceded by ACPA seropositivity for an average of 3-5 years, a period that is designated as 'at-risk' of RA for ACPA-positive individuals who do not display signs of arthritis, or 'pre-RA' for individuals who are known to have progressed to developing clinical RA. Prior studies of individuals at-risk of RA have associated pulmonary mucosal inflammation with local production of ACPAs and rheumatoid factors, leading to development of the 'mucosal origins hypothesis'. Recent work now suggests the presence of multiple distinct mucosal site-specific mechanisms that drive RA evolution. Indicatively, subsets of individuals at-risk of RA and patients with RA harbour a faecal bacterial strain that has exhibited arthritogenic activity in animal models and that favours T helper 17 (TH17) cell responses in patients. Periodontal inflammation and oral microbiota have also been suggested to promote the development of arthritis through breaches in the mucosal barrier. Herein, we argue that mucosal sites and their associated microbial strains can contribute to RA evolution via distinct pathogenic mechanisms, which can be considered causal mucosal endotypes. Future therapies instituted for prevention in the at-risk period, or, perhaps, during clinical RA as therapeutics for active arthritis, will possibly have to address these individual mechanisms as part of precision medicine approaches.

Harnessing the potential of the NALT and BALT as targets for immunomodulation using engineering strategies to enhance mucosal uptake.

Mucosal barrier tissues and their mucosal associated lymphoid tissues (MALT) are attractive targets for vaccines and immunotherapies due to their roles in both priming and regulating adaptive immune responses. The upper and lower respiratory mucosae, in particular, possess unique properties: a vast surface area responsible for frontline protection against inhaled pathogens but also simultaneous tight regulation of homeostasis against a continuous backdrop of non-pathogenic antigen exposure. Within the upper and lower respiratory tract, the nasal and bronchial associated lymphoid tissues (NALT and BALT, respectively) are key sites where antigen-specific immune responses are orchestrated against inhaled antigens, serving as critical training grounds for adaptive immunity. Many infectious diseases are transmitted via respiratory mucosal sites, highlighting the need for vaccines that can activate resident frontline immune protection in these tissues to block infection. While traditional parenteral vaccines that are injected tend to elicit weak immunity in mucosal tissues, mucosal vaccines (i.e., that are administered intranasally) are capable of eliciting both systemic and mucosal immunity in tandem by initiating immune responses in the MALT. In contrast, administering antigen to mucosal tissues in the absence of adjuvant or costimulatory signals can instead induce antigen-specific tolerance by exploiting regulatory mechanisms inherent to MALT, holding potential for mucosal immunotherapies to treat autoimmunity. Yet despite being well motivated by mucosal biology, development of both mucosal subunit vaccines and immunotherapies has historically been plagued by poor drug delivery across mucosal barriers, resulting in weak efficacy, short-lived responses, and to-date a lack of clinical translation. Development of engineering strategies that can overcome barriers to mucosal delivery are thus critical for translation of mucosal subunit vaccines and immunotherapies. This review covers engineering strategies to enhance mucosal uptake via active targeting and passive transport mechanisms, with a parallel focus on mechanisms of immune activation and regulation in the respiratory mucosa. By combining engineering strategies for enhanced mucosal delivery with a better understanding of immune mechanisms in the NALT and BALT, we hope to illustrate the potential of these mucosal sites as targets for immunomodulation.

Expansion and Maturation of Innate Lymphoid Cell Precursors Using Human iPSC-Derived Intestinal Organoids.

Innate lymphoid cells (ILC) are enriched at mucosal barrier sites where they play critical roles in development and disease. Mucosal organoids offer a robust platform for the simultaneous differentiation and expansion of all subsets of mature ILC from a shared peripheral blood precursor. Critically, organoid identity drives tissue-specific imprinting of the culture-derived mature innate lymphoid cells, allowing for the study of bidirectional interactions between, e.g., intestinal organoids and intestine-specific ratios and populations of ILC. This protocol reduces the need for feeder cell lines and complex cytokine cocktails used to mature and maintain ILC, instead relying on a native niche of protein signals provided by mucosal epithelial cells. This protocol details the generation of human intestinal organoids (HIO) from human-induced pluripotent stem cells (hiPSC), and the subsequent establishment of co-cultures between HIO and ILC precursors for expansion and maturation. This approach has extensive applications for mechanistic studies of fundamental biological processes and as a potential GMP-compatible source of ILC for future cell therapies.

CCL28 modulates neutrophil responses during infection with mucosal pathogens.

The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not well understood. Here, we show that CCL28 promotes neutrophil accumulation in the gut of mice infected with Salmonella and in the lung of mice infected with Acinetobacter. Neutrophils isolated from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, on their surface. The functional consequences of CCL28 deficiency varied between the two infections: Ccl28-/- mice were highly susceptible to Salmonella gut infection but highly resistant to otherwise lethal Acinetobacter lung infection. In vitro, unstimulated neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, all processes largely dependent on CCR3. Consistent with the different outcomes in the two infection models, neutrophil stimulation with CCL28 boosted the killing of Salmonella but not Acinetobacter. CCL28 thus plays a critical role in the immune response to mucosal pathogens by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but also exacerbate disease depending on the mucosal site and the infectious agent.

Exploring the pathogenesis of RA through the gut-articular axis-dysbiosis a potential factor.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with a complex etiology. It has been suggested that the pathogenesis of RA begins in the mucosa and then transitions to the joints when many factors interact, including microbial dysbiosis, inflammatory responses, and immune abnormalities at the mucosal site. Data from RA animals and patients suggest there are changes in the mucosal microflora before the onset of RA, and that dysbiosis of the mucosal ecology continues to play a role in the development of arthritis. Microbial dysbiosis of the mucosa reduces the normal barrier function of the intestinal tract, promotes inflammatory reactions in the mucosal areas of the intestines, and then activates the intestinal immune cells abnormally to produce a large number of auto-reactive antibodies that exacerbate arthritis. Current findings do not clarify whether dysbiosis is only a potential trigger for the development of RA. If it is possible to intervene in such microbial changes before the onset of RA, could the clinical symptoms of arthritis be prevented or reduced? Finding new ways to regulate gut flora composition to maintain gut barrier function is an ongoing challenge for the prevention and treatment of RA.

Rapid in situ forming PEG hydrogels for mucosal drug delivery.

In situ gelling polymeric biomaterials have proven useful as drug delivery vehicles to enable sustained release at sites of disease or injury. However, if delivered to mucosal tissues, such as the eyes, nose, gastrointestinal, and cervicovaginal tract, these gels must also possess the ability to adhere to an epithelium coated in mucus. Towards this end, we report a new rapid in situ gelling polyethylene glycol-based hydrogel. Unlike other chemistries that enable rapid gel formation which form via irreversible covalent bonds, we use a bio-reducible linker allowing the gels to be naturally degraded over several days once administered. We identified a set of 6 lead formulations, which rapidly form into disulfide-linked PEG hydrogels in 30 seconds or less. These rapidly forming PEG hydrogels were also able to conform and adhere to mucosal tissues via PEG-mucin entanglements and hydrogen bonding. Controlled release of protein-based cargoes from the PEG gels was achieved over several hours whereas 40 nm nanoparticle-based cargos were retained over 24 hours. We also found these rapid in situ forming PEG gels were well-tolerated by mammalian cells. These studies support further testing and development of rapid in situ forming PEG gels for drug delivery to improve therapeutic retention and efficacy at mucosal sites.

Proposal of a modified technique of Nikolsky's sign in oral autoimmune vesiculobullous diseases.

Nikolsky's sign, originally described for skin lesions, presents challenges when applied to the oral mucosa. To address this, a modified Nikolsky's sign has been proposed specifically for the oral mucosa. In this variant, a gentle breath of air from the air syringe embedded in the dental unit is used to inflate a pre-existing collapsed blister (non-induced technique). Alternatively, in the induced technique, a healthy peri-lesion mucosal site is gently scratched with a blunt dental tool, and after a few minutes, air is blown on the same area to inflate any newly formed blister. The sign is considered positive if a blister is raised from the blown surface. The described modified Nikolsky's sign improves the visualization of oral vesicles and blisters in a cost-effective, easy, and minimally invasive manner. Its elicitation can aid in referring patients to specialized tertiary care units.

Case Series of Acral and Mucosal Melanoma in a Diverse Patient Population.

Melanomas affecting acral and mucosal sites have distinct features and are associated with poorer prognosis. Patients of color may be disproportionately affected. Herein we discuss six ethnically diverse cases of acral and mucosal melanoma (AMM). More data on clinical, genetic, and environmental features of AMM are needed, but thorough physical examination can reduce the burden of disease now. J Drugs Dermatol. 2024;23(8):683-685. doi:10.36849/JDD.8311.

Long-term follow-up of a patient with Parkinson’s disease under nursing care after replacement of fixed implant-supported prostheses with an implant overdenture: a case report

BackgroundIn older patients with progressive neurodegeneration, replacing fixed implant-supported prostheses (FIP) with implant overdentures (IOD) has been proposed to prevent future mucosal injury and create an oral environment that is easier for caregivers to clean. However, there have been no reports on the progress after replacing FIP with IOD. In this report, we present the progress of an older patient with Parkinson’s disease in whom FIP was replaced with IOD.Case presentationAn 81-year-old male patient with Parkinson’s disease presented to our outpatient clinic with bruxism and crossbites. FIPs, with five Brånemark system implants, were placed in the bilateral lower molars. The FIP was replaced with an IOD with two locator attachments to create an oral environment that was easier for caregivers to clean and allow easy recovery of masticatory function if residual teeth were fractured in the care environment. As his systemic condition deteriorated, treatment was changed from outpatient to in-home visits. During dental care visits, professional oral cleaning and denture repair were continued, and good nutritional status was maintained. However, the patient developed cholecystitis and was hospitalized. During hospitalization, gastrostomy was performed because he developed aspiration pneumonia. After discharge from the hospital, the patient remained in bed all day and could not wear an IOD, resulting in buccal mucosa ulceration due to abrasion of the locator abutment. We decided to replace the abutment with cover screws; however, not all the implants could sleep submucosally. Although regular oral cleaning was resumed, new ulcers developed even when cover screws were installed. Additionally, swelling and drainage were observed at the peri-implant mucosal site where peri-implantitis had once occurred during an outpatient visit. The patient was readmitted to the hospital for a urinary tract infection, and subsequent visits were abandoned.ConclusionsBy replacing FIP with IOD in an older patient with Parkinson’s disease, we addressed a barrier to caregiver-provided oral management. The removable prosthesis facilitated smooth oral care by caregivers and functional recovery in the event of trouble with residual teeth. However, it could not completely avoid the recurrence of buccal mucosal ulcers or peri-implantitis.

PP2A catalytic subunit alpha is critically required for CD8+ T-cell homeostasis and antibacterial responses.

Although the functions of tyrosine phosphatases in T-cell biology have been extensively studied, our knowledge on the contribution of serine/threonine phosphatases in T cells remains poor. Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine phosphatases. It is important in thymocyte development and CD4+ T-cell differentiation. Utilizing a genetic model in which its catalytic subunit alpha isoform (PP2A Cα) is deleted in T cells, we investigated its contribution to CD8+ T-cell homeostasis and effector functions. Our results demonstrate that T-cell intrinsic PP2A Cαis critically required for CD8+ T-cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A Cα-deficient CD8+ T cells exhibit reduced proliferation and survival. CD8+ T-cell antibacterial response is strictly dependent on PP2A Cα.Expression of Bcl2 transgene rescues CD8+ T-cell homeostasis in spleens, but not in intestinal mucosal site, nor does it restore defective antibacterial responses. Finally, proteomics and phosphoproteomics analyses reveal potential targets dependent on PP2A Cα,including mTORC1 and AKT.Thus, PP2A Cα is a key modulator of CD8+ T-cell homeostasis and effector functions.