Maackia amurensis seed lectin (MASL) and soluble human podoplanin (shPDPN) sequence analysis and effects on human oral squamous cell carcinoma (OSCC) cell migration and viability.

Maackia amurensis lectins serve as research and botanical agents that bind to sialic residues on proteins. For example, M. amurensis seed lectin (MASL) targets the sialic acid modified podoplanin (PDPN) receptor to suppress arthritic chondrocyte inflammation, and inhibit tumor cell growth and motility. However, M. amurensis lectin nomenclature and composition are not clearly defined. Here, we sought to definitively characterize MASL and its effects on tumor cell behavior. We utilized SDS-PAGE and LC-MS/MS to find that M. amurensis lectins can be divided into two groups. MASL is a member of one group which is composed of subunits that form dimers, evidently mediated by a cysteine residue in the carboxy region of the protein. In contrast to MASL, members of the other group do not dimerize under nonreducing conditions. These data also indicate that MASL is composed of 4 isoforms with an identical amino acid sequence, but unique glycosylation sites. We also produced a novel recombinant soluble human PDPN receptor (shPDPN) with 17 threonine residues glycosylated with sialic acid moieties with potential to act as a ligand trap that inhibits OSCC cell growth and motility. In addition, we report here that MASL targets PDPN with very strong binding kinetics in the nanomolar range. Moreover, we confirm that MASL can inhibit the growth and motility of human oral squamous cell carcinoma (OSCC) cells that express the PDPN receptor. Taken together, these data characterize M. amurensis lectins into two major groups based on their intrinsic properties, clarify the composition of MASL and its subunit isoform sequence and glycosylation sites, define sialic acid modifications on the PDPN receptor and its ability to act as a ligand trap, quantitate MASL binding to PDPN with KD in the nanomolar range, and verify the ability of MASL to serve as a potential anticancer agent.

Generalized lymphadenopathy and 18-fluorine fluorodeoxyglucose positron emission tomography/computed tomography: targeting diagnostic intervention, characterizing disease extent, and assessing treatment efficacy in syphilis.

18-Fluorine fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) has been shown to have use in the diagnosis of inflammatory and infectious diseases in addition to its primary use in cancer. We describe a case of early neurosyphilis that initially presented as symmetric, generalized lymphadenopathy on PET/CT. We conclude that PET/CT may play a role in evaluating targeted diagnostic interventions, disease extent, and treatment efficacy for disseminated syphilis.

Tolerance-like mediated suppression by mesenchymal stem cells in patients with dust mite allergy-induced asthma.

BACKGROUND: Mesenchymal stem cells (MSCs) can suppress and enhance immune functions. MSCs show promise as off-the-shelf cellular therapy for several disorders, including inflammation. OBJECTIVE: We investigated the effects of MSCs on the proliferation of PBMCs to allergic subjects (dust mite [DM]), allergic asthmatic subjects, or both. METHODS: Proliferation was studied by using tritiated thymidine uptake with or without MSCs. The refractoriness of PBMCs to DM was examined after preconditioning with MSCs and after repeated challenge with low-dose DM. Flow cytometry was used to study regulatory T cells and dendritic cells (DCs), and ELISA was used to study cytokine production. RESULTS: Seven subjects with allergic asthma met the inclusion/exclusion criteria. MSCs significantly (P < .05) reduced the proliferation of 6 subjects with allergic asthma but not those with allergy alone. The effect was specific to the allergen because MSCs did not affect challenges to tetanus toxoid. There was no change in CD4/CD25/forkhead box protein 3-positive cells, although there were decreased IFN-γ and increased IL-10 levels. Numbers of mature DCs were increased 6-fold. Refractoriness to DM was achieved by means of repeated exposure to low-dose DM and MSCs and also MSC- preconditioned MSC. CONCLUSION: MSCs suppressed the proliferation of DM-challenged PBMCs from allergic asthmatic subjects but not from allergic subjects without asthma. MSCs blunted the maturation of DCs but not regulatory T cells. Repeated exposure to low-dose DM and MSCs, as well as preconditioning of PBMCs with MSCs, caused refractoriness to DM. These findings have implications for the use of MSCs in attenuation of the inflammatory responses to allergic triggers in asthmatic patients with off-the-shelf MSCs.

Common Neurologic Features of Lyme Disease That May Present to a Rheumatologist.

Lyme disease, caused by Borrelia burgdorferi (Bb) infection, has a broad spectrum of clinical manifestations and severity. Patients with possible Lyme disease may seek out or be referred to rheumatologists. Today, the most common reason to engage a rheumatologist is due to complaints of arthralgia. After skin, neurologic manifestations of Lyme disease are now among the most common. Therefore, it is important for rheumatologists to be aware of clues that suggest neurologic Lyme disease and prompt help from a neurologist experienced with Lyme disease.

COVID-19 Vaccination as a Potential Trigger for New-Onset Systemic Lupus Erythematosus.

Immune hyperactivation has been linked to various vaccines. We present a potential association of new-onset systemic lupus erythematosus (SLE) post-COVID-19 immunization. The patient is a 54-year-old male admitted for evaluation of flu-like symptoms two weeks after receiving the second dose of the COVID-19 vaccine. Physical examination revealed high-grade fever, diffuse bilateral non-tender cervical lymphadenopathy, and erythematous maculopapular palpable purpuric lesions on bilateral feet. Laboratory evaluation showed a significant hypocomplementemia (C3 < 11 mg/dL, C4 < 3 mg/dL, and CH50 < 10 U/mL), high titer antinuclear antibody, anti-dsDNA antibodies, anti-Sjogren's syndrome-related antigen A antibodies, anti-Sjogren's syndrome-related antigen B antibodies, anti-Smith antibodies, anti-ribonucleoprotein antibodies, anti-histone antibodies with a negative malignancy, and infection workup. The patient was treated with a high dose of steroids with a positive response. This case highlights the possibility of SLE, a rare adverse event following COVID-19 vaccination.

A Case of Severe Refractory Pemphigus Vulgaris in a Patient With Stable Esophageal Malignancy.

Pemphigus is a broad term that is used to describe a group of bullous autoimmune diseases affecting the skin and mucous membranes; the pathogenesis involves autoantibodies directed against various cell junction desmosomal proteins. In patients with a history of malignancy who present with bullous lesions, the differential diagnosis may include, but is not limited to, paraneoplastic pemphigus (PNP) and pemphigus vulgaris (PV) secondary to a primary autoimmune process, or induced by chemotherapy or radiation therapy. In this report, we present a case of refractory PV in a patient with stable esophageal cancer, five years after undergoing radiation therapy. He was poorly responsive to corticosteroids and intravenous immunoglobulin (IVIG). PNP or PV in a patient with stable esophageal malignancy has not been previously reported. PNP and PV can have overlapping autoantigens [desmoglein types 1 and 3 (DSG1 and DSG3)] as well as similar presentations. Thus, distinguishing between the two may be challenging in a patient with a history of cancer. More research must be done to determine if PNP can be seen in a patient with stable esophageal malignancy and, similarly, if PV can be precipitated by stable esophageal malignancy. Such research would aid in determining whether or not similar presentations are more severe or refractory to standard treatment regimens, thereby contributing to improve treatment strategies.

Not all Sicca is Sjögren's and not all Sjögren's is Sicca.

Symptoms of dry eyes or dry mouth, otherwise known as sicca symptoms, are not always present in patients with Sjögren's syndrome (SS). Approximately 20% of patients with SS do not have sicca symptoms. An unusual case of a patient presenting with complete left-sided facial hemiparesis, a history of partial bilateral sensorineural hearing loss who was found to have elevated antinuclear antibody (ANA) with high titer positive SSA/Ro antibody, evidence of bilateral parotitis on imaging and absence of sicca symptoms, prompted us to perform a literature review. Twelve case reports relating facial nerve palsy and Sjögren's were found and only one described a similar constellation of features of unilateral facial weakness and otalgia. Management of facial nerve palsy related to Sjögren's is unclear but pharmacological agents have included corticosteroids, intravenous immune globulin (IVIG), cyclophosphamide, and plasmapheresis. This case report describes a patient whose facial nerve palsy is attributed to SS, explores peripheral and central nervous system involvement in SS, and provides some recommended treatments.

Arthritis and Diagnostics in Lyme Disease.

The diagnosis of Lyme disease, caused by Borrelia burgdorferi, is clinical but frequently supported by laboratory tests. Lyme arthritis is now less frequently seen than at the time of its discovery. However, it still occurs, and it is important to recognize this, the differential diagnoses, and how laboratory tests can be useful and their limitations. The most frequently used diagnostic tests are antibody based. However, antibody testing still suffers from many drawbacks and is only an indirect measure of exposure. In contrast, evolving direct diagnostic methods can indicate active infection.

Adult Inflammatory Multi-System Syndrome Mimicking Kawasaki Disease in a Patient With COVID-19.

We describe a 46-year-old male with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who presented as a Kawasaki-like syndrome with features including prolonged fever, bilateral conjunctivitis, oral mucosal swelling, diffuse erythematous rash, cervical and hilar lymphadenopathy, as well as cardiovascular complications and multi-organ failure. There are several reports of a similar clinical entity mimicking Kawasaki disease (KD) in the pediatric population, which has been termed Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) by the Royal College of Pediatric and Child Health. To our knowledge, to date, there has been only one case report of COVID-19 presenting as KD in an adult patient.

Inhibition of IRF5 hyperactivation protects from lupus onset and severity.

The transcription factor IFN regulatory factor 5 (IRF5) is a central mediator of innate and adaptive immunity. Genetic variations within IRF5 are associated with a risk of systemic lupus erythematosus (SLE), and mice lacking Irf5 are protected from lupus onset and severity, but how IRF5 functions in the context of SLE disease progression remains unclear. Using the NZB/W F1 model of murine lupus, we show that murine IRF5 becomes hyperactivated before clinical onset. In patients with SLE, IRF5 hyperactivation correlated with dsDNA titers. To test whether IRF5 hyperactivation is a targetable function, we developed inhibitors that are cell permeable, nontoxic, and selectively bind to the inactive IRF5 monomer. Preclinical treatment of NZB/W F1 mice with an inhibitor attenuated lupus pathology by reducing serum antinuclear autoantibodies, dsDNA titers, and the number of circulating plasma cells, which alleviated kidney pathology and improved survival. Clinical treatment of MRL/lpr and pristane-induced lupus mice with an inhibitor led to significant reductions in dsDNA levels and improved survival. In ex vivo human studies, the inhibitor blocked SLE serum-induced IRF5 activation and reversed basal IRF5 hyperactivation in SLE immune cells. We believe this study provides the first in vivo clinical support for treating patients with SLE with an IRF5 inhibitor.

Oral Tuberculosis: A Rare Manifestation of Disseminated Disease in a Patient with Dermatomyositis on Chronic Corticosteroids.

Tuberculosis remains one of the leading causes of death around the world despite advancements in diagnostic testing and medical therapies. It commonly affects the lungs, but isolated extra pulmonary clinical manifestations have been reported. Tuberculosis of the oral cavity is exceedingly rare. We present a case of a patient with dermatomyositis on chronic steroid therapy, who presented with tuberculosis involving the tongue as the only clinical manifestation of disseminated disease. Physicians must be aware of extra pulmonary manifestations of tuberculosis in patients at risk, in order to avoid delays in diagnosis and treatment and to prevent further contagion.

Vertigo as a predominant manifestation of neurosarcoidosis.

Sarcoidosis is a granulomatous disease of unknown etiology that affects multiple organ systems. Neurological manifestations of sarcoidosis are less common and can include cranial neuropathies and intracranial lesions. We report the case of a 21-year-old man who presented with vertigo and uveitis. Extensive workup including brain imaging revealed enhancing focal lesions. A lacrimal gland biopsy confirmed the diagnosis of sarcoidosis. The patient was initially treated with prednisone, which did not adequately control his symptoms, and then was switched to methotrexate with moderate symptomatic improvement. Our patient had an atypical presentation with vertigo as the predominant manifestation of sarcoidosis. Patients with neurosarcoidosis typically present with systemic involvement of sarcoidosis followed by neurologic involvement. Vertigo is rarely reported as an initial manifestation. This case highlights the importance of consideration of neurosarcoidosis as an entity even in patients that may not have a typical presentation or systemic involvement of disease.

Expression and targeting of lymphocyte function-associated antigen 1 (LFA-1) on white blood cells for treatment of allergic asthma.

Allergic asthma is a chronic respiratory disease that results from an exaggerated inflammatory response in the airways. Environment stimuli, such as pollen and HDM, cause activation and migration of inflammatory WBCs into the respiratory tract, where they cause lung damage. Migration of these WBCs is dependent on the active configuration of the ß2 integrin LFA-1. The experimental therapeutic agent LtxA specifically targets active LFA-1 and causes cell death. We investigated the association between LFA-1 and allergic asthma and hypothesized that targeting LFA-1 with LtxA could be an attractive strategy for treatment of the condition. We examined LFA-1 (CD11a) levels on PBMCs from patients with allergic asthma compared with healthy controls. Patients exhibited a significantly higher percentage of PBMCs expressing LFA-1 than healthy controls. Furthermore, the level of LFA-1 expression on patient PBMCs was greater than on healthy PBMCs. We identified a unique cellular population in patients that consisted of CD4(-) CD11a(hi) cells. We also evaluated LtxA in a HDM extract-induced mouse model for allergic asthma. LtxA caused resolution of disease in mice, as demonstrated by a decrease in BALF WBCs, a reduction in pulmonary inflammation and tissue remodeling, and a decrease in proinflammatory cytokines IL-4, IL-5, IL-9, IL-17F, and IL-23α in lung tissue. LFA-1 may serve as an important marker in allergic asthma, and the elimination of activated WBCs by use of LtxA could be a viable therapeutic strategy for treating patients with this condition.

Retrospective analysis of treatment modalities in diabetic muscle infarction.

BACKGROUND: Diabetic muscle infarction (DMI) is a spontaneous necrosis of skeletal muscle of unknown etiology. The major risk factor is longstanding uncontrolled diabetes mellitus (DM). Optimal treatment for DMI is not known. The purpose of this study was to analyze the outcome of surgical treatment, physiotherapy, and bed rest in DMI. METHODS: We searched Medline from its inception to April 2013. We selected cases that provided sufficient data on recovery duration, recurrences, and non-recurrences. Baseline characteristics, including age, sex, microvascular complications, lesion size estimated on magnetic resonance imaging, type of diabetes, and duration of diabetes were assessed. The primary outcome was mean time to recovery from initial treatment and secondary outcomes were mean time to recurrence and recurrence rate. RESULTS: Mean time to recovery was 149 (95% confidence interval [CI] 113-186), 71 (95% CI 47-96), and 43 (95% CI 30-57) days for surgery, physiotherapy and bed rest, respectively. These figures were statistically significant only for surgery versus physiotherapy and surgery versus bed rest (P<0.01). Mean time to recurrence was 30, 107, and 297 days for surgery, physiotherapy, and bed rest, respectively. The recurrence rate was 57%, 44%, and 24% for surgery, physiotherapy, and bed rest, respectively. CONCLUSION: Our results show a similar outcome for physiotherapy as compared with bed rest. It also confirms nonsurgical treatment as a better therapeutic option compared with surgical treatment.

Pollen-induced antigen presentation by mesenchymal stem cells and T cells from allergic rhinitis.

Mesenchymal stem cells (MSCs) are promising cellular suppressor of inflammation. This function of MSCs is partly due to their licensing by inflammatory mediators. In cases with reduced inflammation, MSCs could become immune-enhancer cells. MSCs can suppress the inflammatory response of antigen-challenged lymphocytes from allergic asthma. Although allergic rhinitis (AR) is also an inflammatory response, it is unclear if MSCs can exert similar suppression. This study investigated the immune effects (suppressor vs enhancer) of MSCs on allergen-stimulated lymphocytes from AR subjects (grass or weed allergy). In contrast to subjects with allergic asthma, MSCs caused a significant (P<0.05) increase in the proliferation of antigen-challenged lymphocytes from AR subjects. The increase in lymphocyte proliferation was caused by the MSCs presenting the allergens to CD4(+) T cells (antigen-presenting cells (APCs)). This correlated with increased production of inflammatory cytokines from T cells, and increased expressions of major histocompatibility complex (MHC)-II and CD86 on MSCs. The specificity of APC function was demonstrated in APC assay using MSCs that were knocked down for the master regulator of MHC-II transcription, CIITA. The difference in the effects of MSCs on allergic asthma and AR could not be explained by the sensitivity to the allergen, based on skin tests. Thus, we deduced that the contrasting immune effects of MSCs for antigen-challenged lymphocytes on AR and allergic asthma could be disease specific. It is possible that the enhanced inflammation from asthma might be required to license the MSCs to become suppressor cells. This study underscores the need for robust preclinical studies to effectively translate MSCs for any inflammatory disorder.