Immune-based Disease Research Articles

Insights into membrane interactions and their therapeutic potential

Recent research into membrane interactions has uncovered a diverse range of therapeutic opportunities through the bioengineering of human and non-human macromolecules.Although the majority of this research is focussed on fundamental developments, emerging studies are showcasing promising new technologies to combat conditions such as cancer, Alzheimer's and inflammatory and immune-based disease, utilising the alteration of bacteriophage, adenovirus, bacterial toxins, type 6 secretion systems, annexins, mitochondrial antiviral signalling proteins and bacterial nano-syringes. To advance the field further, each of these opportunities need to be better understood, and the therapeutic models need to be further optimised.Here, we summarise the knowledge and insights into several membrane interactions and detail their current and potential uses therapeutically.

Thymosin beta 4: A potential novel adjunct treatment for bacterial keratitis.

Microbial keratitis is a rapidly progressing, visually debilitating infection of the cornea that can lead to corneal scarring, endophthalmitis, and perforation. Corneal opacification or scarring, a complication of keratitis, is among the leading causes of legal blindness worldwide, second to cataracts.Pseudomonas aeruginosaandStaphylococcus aureusare the two bacteria most commonly associated with this type of infection. Risk factors include patients who are immunocompromised, those who have undergone refractive corneal surgery, and those with prior penetrating keratoplasty, as well as extended wear contact lens users. Current treatment of microbial keratitis primarily addresses the pathogen using antibiotics. Bacterial clearance is of utmost importance yet does not guarantee good visual outcome. Clinicians are often left to rely upon the eye's innate ability to heal itself, as there are limited options beyond antibiotics and corticosteroids for treating patients with corneal infection. Beyond antibiotics, agents in use, such as lubricating ointments, artificial tears, and anti-inflammatory drops, do not fully accommodate clinical needs and have many potential harmful complications. To this end, treatments are needed that both regulate the inflammatory response and promote corneal wound healing to resolve visual disturbances and improve quality of life. Thymosin beta 4 is a small, naturally occurring 43-amino-acid protein that promotes wound healing and reduces corneal inflammation and is currently in Phase 3 human clinical trials for dry eye disease. Our previous work has shown that topical Tβ4 as an adjunct to ciprofloxacin treatment reduces inflammatory mediators and inflammatory cell infiltrates (neutrophils/PMN and macrophages) while enhancing bacterial killing and wound healing pathway activation in an experimental model ofP. aeruginosa-induced keratitis. Adjunctive thymosin beta 4 treatment holds novel therapeutic potential to regulate and, optimally, resolve disease pathogenesis in the cornea and perhaps other infectious and immune-based inflammatory disease. We plan to establish the importance of thymosin beta 4 as a therapeutic agent in conjunction with antibiotics with high impact for immediate clinical development.

The Presence of Immune-Mediated Synovial Membrane Disease in Low and High Inflammatory Arthropathies of the Temporomandibular Joint: A Serologic, Arthroscopic, and Histopathologic Study

The purpose of this study was to describe serologic, arthroscopic, and histopathologic findings suggestive of immune-mediated synovial membrane disease and assess for distinctions between pathologic findings in low and high inflammatory conditions of the temporomandibular joint (TMJ). Arthroscopic findings have been investigated previously, with arthroscopic-visualization of petechiae synovitis and the histologic-presence of plasma cells indicating high inflammatory immune-based synovial membrane disease (Hakim et al 2020).

COVID-19 vaccination: Recommendations for management of patients with allergy or immune-based diseases.

As South Africa continues to battle the second wave of SARS-CoV-2 infections, the imminent arrival of vaccines against COVID-19 offers hope. Vaccine roll-out has been accompanied by heightened media coverage that has created both excitement and anxiety, reporting on the shortened timeline of vaccine trials and approvals, as well as the recent series of anaphylaxis cases associated with the two approved mRNA COVID-19 vaccines. Patients with allergic and other immune-based diseases are subgroups especially concerned about vaccine safety and efficacy. This practice guideline offers broad recommendations for COVID-19 vaccination in various subgroups of allergic and immunebased disease, highlighting risk/benefit evaluation, and where and how routine vaccination should be altered.

A brief insight on the etiopathogenesis of oral lichen planus

Oral Lichen Planus (OLP) is a relatively common, systemic, immune based disease. It usually, involves the oral mucosa, but other sites like the skin, genital mucosa, and scalp are also affected. In this auto-cytotoxic muco-cutaneous disease, the T lymphocytes trigger apoptosis of epithelial cells leading to chronic inflammation. OLP is mediated by both antigen specific and nonspecific pathways. Antigen presentation through basal keratinocytes and antigen-specific keratinocyte destruction by CD8+ cytotoxic T-cells are within the specific pathway spectrum. Whilst the nonspecific methods involve mast cell degeneration; leading to granular release and matrix metalloproteinase (MMP) activation. The process ultimately results in clustering of T cells in the upper layer of lamina propria, basal lamina disruption, T-cell inflow within the epithelium, along with apoptotic death of keratinocytes. The normal oral mucosa may be an immune privileged site and breach of the immune barrier could result in OLP and possibly other autoimmune oral mucosal diseases owing to deficient antigen-specific TGF-β1-mediated immunosuppression. However, many among these immuo pathologic mechanisms are still shroud in mystery.

Review of Structural Features and Binding Capacity of Polyphenols to Gluten Proteins and Peptides In Vitro: Relevance to Celiac Disease.

Polyphenols have been extensively studied due to their beneficial effects on human health, particularly for the prevention and treatment of diseases related to oxidative stress. Nevertheless, they are also known to have an anti-nutritional effect in relation to protein metabolism. This effect is a consequence of its binding to digestive enzymes and/or protein substrates. Dietary gluten is the main trigger of celiac disease, a common immune-based disease of the small intestine and for which the only treatment available is the adherence to a gluten-free diet. Recent studies have addressed the use of dietary polyphenols to interact with gluten proteins and avoid its downstream deleterious effects, taking the advantage of the anti-nutritive nature of polyphenols by protein sequestering. Flavonoids, coumarins and tannins have shown the ability to form insoluble complexes with gluten proteins. One of the most promising molecules has been epigallocatechin-3-gallate, which through its binding to gliadins, was able to reduce gliadins digestibility and its ability to stimulate monolayer permeability and transepithelial transport of immunodominant peptides in cell models. This review focuses on the structural features and binding capacity of polyphenols to gluten proteins and peptides, and the prospects of developing an adjuvant therapy in celiac disease.

Symptoms Prompting Interest in Celiac Disease and the Gluten-Free Diet: Analysis of Internet Search Term Data.

BackgroundCeliac disease, a common immune-based disease triggered by gluten, has diverse clinical manifestations, and the relative distribution of symptoms leading to diagnosis has not been well characterized in the population.ObjectiveThis study aimed to use search engine data to identify a set of symptoms and conditions that would identify individuals at elevated likelihood of a subsequent celiac disease diagnosis. We also measured the relative prominence of these search terms before versus after a search related to celiac disease.MethodsWe extracted English-language queries submitted to the Bing search engine in the United States and identified those who submitted a new celiac-related query during a 1-month period, without any celiac-related queries in the preceding 9 months. We compared the ratio between the number of times that each symptom or condition was asked in the 14 days preceding the first celiac-related query of each person and the number of searches for that same symptom or condition in the 14 days after the celiac-related query.ResultsWe identified 90,142 users who made a celiac-related query, of whom 6528 (7%) exhibited sustained interest, defined as making a query on more than 1 day. Though a variety of symptoms and associated conditions were also queried before a celiac-related query, the maximum area under the receiver operating characteristic curve was 0.53. The symptom most likely to be queried more before than after a celiac-related query was diarrhea (query ratio [QR] 1.28). Extraintestinal symptoms queried before a celiac disease query included headache (QR 1.26), anxiety (QR 1.10), depression (QR 1.03), and attention-deficit hyperactivity disorder (QR 1.64).ConclusionsWe found an increase in antecedent searches for symptoms known to be associated with celiac disease, a rise in searches for depression and anxiety, and an increase in symptoms that are associated with celiac disease but may not be reported to health care providers. The protean clinical manifestations of celiac disease are reflected in the diffuse nature of antecedent internet queries of those interested in celiac disease, underscoring the challenge of effective case-finding strategies.

Neumonía por Pneumocystis jiroveci: características clínicas y factores de riesgo asociados a mortalidad en una Unidad de Cuidados Intensivos

ObjectiveTo describe the epidemiological characteristics of the population with Pneumocystis jiroveci (P. jiroveci) pneumonia, analyzing risk factors associated with the disease, predisposing factors for admission to an intensive care unit (ICU), and prognostic factors of mortality. Design and patientsA retrospective observational study was carried out, involving a cohort of patients consecutively admitted to a hospital in Spain from 1 January 2007 to 31 December 2011, with a final diagnosis of P. jiroveci pneumonia. SettingThe ICU and hospitalization service of Hospital del Mar, Barcelona (Spain). ResultsWe included 36 patients with pneumonia due to P. jiroveci. Of these subjects, 16 required ICU admission (44.4%). The average age of the patients was 41.3±12 years, and 23 were men (63.9%). A total of 86.1% had a history of human immunodeficiency virus (HIV) infection, and the remaining 13.9% presented immune-based disease subjected to immunosuppressive therapy. Risk factors associated to hospital mortality were age (51.8 vs. 37.3 years, P=.002), a higher APACHE score upon admission (17 vs. 13 points, P=.009), the need for invasive mechanical ventilation (27.8% vs. 11.1%, P=.000), requirement of vasoactive drugs (25.0% vs. 11.1%, P=.000), fungal coinfection (22.2% vs. 11.1%, P=.001), pneumothorax (16.7% vs. 83.3%, P=.000) and admission to the ICU (27.8% vs. 72.2% P=.000). ConclusionsThe high requirement of mechanical ventilation and vasoactive drugs associated with fungal coinfection and pneumothorax in patients admitted to the ICU remain as risk factors associated with mortality in patients with P. jiroveci pneumonia.

Construction and Clinical Validation of a Questionnaire-based Risk Score to Identify Patients Suffering from Immunodeficiency or Systemic Autoimmunity

Aims: A self-reporting tool for identifying adults at risk for immune-based diseases was designed and termed immune system assessment questionnaire (ISAQ). It was the aim of this study to validate this novel questionnaire in groups of patients with defined immunodeficiency or autoimmune diseases in comparison to normal adults. Study Design: Non-randomised, cross-sectional observational study in groups of Original Research Article British Journal of Medicine & Medical Research, 4(29): 4751-4769, 2014 4752 patients and normal adults. Place and Duration of Study: Department of Rheumatology and Clinical Immunology and Clinical Epidemiology Group, Institute of Medical Biometry and Medical Informatics University Medical Center Freiburg, Germany. Questionnaires from patients and controls were collected between March 2005 and November 2010. Methodology: Two experienced clinical immunologists selected 17 informative topics including frequency and duration of infections, previous surgery on immunological organs, recent polytrauma, vaccination history, allergies, co-morbidities, use of antibiotics and immunomodulating agents. The ensuing questions were differently weighted based on published evidence and assumed relevance for immunological dysfunction. The questionnaire was distributed to 539 cases suffering from chronic immunodeficiency (n=322) or autoimmunity (n=217) and to 1020 healthy controls. An ISAQ score was calculated for each participant based on the sum of the weighted items. Results: The median ISAQ-score was 39.5 for cases and 30.4 for controls. 93.7% of all controls scored lower than the median of the cases, which resulted in an AUC of the ROC curve of 0.838 (95%CI: 0.817-0.859). Items with highest predictive value were frequency and duration of infections, use of antibiotics, corticosteroids, immunosuppressants, sinus-mucosa resection, chronic disease of kidney, lungs, gut and hematopoietic system. Although the results indicate that neither the item selection nor the weighting of single items were optimal, several sub-scores with reduced item number could not substitute for the whole ISAQ. Conclusion: The ISAQ can discriminate between healthy individuals and persons suffering from immune-based disease. The ISAQ performs better for chronic immunodeficiency than for chronic rheumatic diseases; the highest values were obtained for common variable immunodeficiency (CVID) and systemic vasculitides. Future studies are needed to refine item selection and validate the score for predicting immune dysfunction.

Antioxidant and antiasthmatic effects of saucerneol D in a mouse model of airway inflammation

Chronic airway inflammation is a hallmark of asthma, which is an immune-based disease. We evaluated the ability of saucerneol D, a tetrahydrofuran-type sesquilignan isolated from Saururus chinensis, to regulate airway inflammation in an ovalbumin (OVA)-induced airway inflammation model. Furthermore, we determined whether heme oxygenase (HO)-1 was required for the protective activity of saucerneol D. The airways of OVA-sensitized mice exposed to an OVA challenge developed eosinophilia and mucus hypersecretion and exhibited increased cytokine levels. Mice were administered saucerneol D orally at doses of 20 and 40 mg/kg once daily on days 26–30. Saucerneol D administered orally significantly inhibited the number of OVA-induced inflammatory cells and the production of immunoglobulin E as well as Th2-type cytokines. Histopathology studies revealed a marked decrease in lung inflammation and goblet cell hyperplasia after saucerneol D treatment. In addition, saucerneol D induced HO-1 and led to a marked decrease in OVA-induced reactive oxygen species and malondialdehyde and an increase in superoxide dismutase and glutathione in lung tissues. These antioxidant effects were correlated with HO-1 induction. In our experiments, saucerneol D treatment reduced airway inflammation and suppressed oxidative stress in an OVA-induced asthma model.

Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report

Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report

Anti-Inflammatory Effects of the Neurotransmitter Agonist Honokiol in a Mouse Model of Allergic Asthma

Chronic airway inflammation is a hallmark of asthma, an immune-based disease with great societal impact. Honokiol (HNK), a phenolic neurotransmitter receptor (γ-aminobutyric acid type A) agonist purified from magnolia, has anti-inflammatory properties, including stabilization of inflammation in experimentally induced arthritis. The present study tested the prediction that HNK could inhibit the chronic inflammatory component of allergic asthma. C57BL/6 mice sensitized to and challenged with OVA had increased airway hyperresponsiveness to methacholine challenge and eosinophilia compared with naive controls. HNK-treated mice showed a reduction in airway hyperresponsiveness as well as a significant decrease in lung eosinophilia. Histopathology studies revealed a marked drop in lung inflammation, goblet cell hyperplasia, and collagen deposition with HNK treatment. Ag recall responses from HNK-treated mice showed decreased proinflammatory cytokines in response to OVA, including TNF-α-, IL-6-, Th1-, and Th17-type cytokines, despite an increase in Th2-type cytokines. Regulatory cytokines IL-10 and TGF-β were also increased. Assessment of lung homogenates revealed a similar pattern of cytokines, with a noted increase in the number of FoxP3(+) cells in the lung. HNK was able to alter B and T lymphocyte cytokine secretion in a γ-aminobutyric acid type A-dependent manner. These results indicate that symptoms and pathology of asthma can be alleviated even in the presence of increased Th2 cytokines and that neurotransmitter agonists such as HNK have promise as a novel class of anti-inflammatory agents in the treatment of chronic asthma.

Breaking Patterns of Environmentally Influenced Disease for Health Risk Reduction: Immune Perspectives

BackgroundDiseases rarely, if ever, occur in isolation. Instead, most represent part of a more complex web or “pattern” of conditions that are connected via underlying biological mechanisms and processes, emerge across a lifetime, and have been identified with the aid of large medical databases.ObjectiveWe have described how an understanding of patterns of disease may be used to develop new strategies for reducing the prevalence and risk of major immune-based illnesses and diseases influenced by environmental stimuli.FindingsExamples of recently defined patterns of diseases that begin in childhood include not only metabolic syndrome, with its characteristics of inflammatory dysregulation, but also allergic, autoimmune, recurrent infection, and other inflammatory patterns of disease. The recent identification of major immune-based disease patterns beginning in childhood suggests that the immune system may play an even more important role in determining health status and health care needs across a lifetime than was previously understood.ConclusionsFocusing on patterns of disease, as opposed to individual conditions, offers two important venues for environmental health risk reduction. First, prevention of developmental immunotoxicity and pediatric immune dysfunction can be used to act against multiple diseases. Second, pattern-based treatment of entryway diseases can be tailored with the aim of disrupting the entire disease pattern and reducing the risk of later-life illnesses connected to underlying immune dysfunction. Disease-pattern–based evaluation, prevention, and treatment will require a change from the current approach for both immune safety testing and pediatric disease management.

Identifying patterns of immune-related disease: use in disease prevention and management

Childhood susceptibility to diseases linked with immune dysfunction affects over a quarter of the pediatric population in some countries. While this alone is a significant health issue, the actual impact of immune-related diseases extends over a lifetime and involves additional secondary conditions. Some comorbidities are well known (e.g., allergic rhinitis and asthma). However, no systematic approach has been used to identify life-long patterns of immune-based disease where the primary condition arises in childhood. Such information is useful for both disease prevention and treatment approaches. Recent primary research papers as well as review articles were obtained from PubMed, Chem Abstracts, Biosis and from the personal files of the authors. Search words used were: the diseases and conditions shown Figs. 1 and 2 in conjunction with comorbid, comorbidities, pediatric, childhood, adult, immune, immune dysfunction, allergy, autoimmune, inflammatory, infectious, health risks, environment, risk factors. Childhood diseases such as asthma, type-1 diabetes, inflammatory bowel disease, respiratory infections /rhinitis, recurrent otitis media, pediatric celiac, juvenile arthritis and Kawasaki disease are examples of significant childhood health problems where immune dysfunction plays a significant role. Each of these pediatric diseases is associated with increased risk of several secondary conditions, many of which appear only later in life. To illustrate, four prototypes of immune-related disease patterns (i.e., allergy, autoimmunity, inflammation and infectious disease) are shown as tools for: 1) enhanced disease prevention; 2) improved management of immune-based pediatric diseases; and 3) better recognition of underlying pediatric immune dysfunction. Identification of immune-related disease patterns beginning in childhood provides the framework for examining the underlying immune dysfunctions that can contribute to additional diseases in later life. Many pediatric diseases associated with dysfunctional immune responses have been linked with an elevated risk of other diseases or conditions as the child ages. Diseases within a pattern may be interlinked based on underlying immune dysfunctions and/or current therapeutic approaches for managing the entryway diseases. It may be beneficial to consider treatment options for the earliest presenting diseases that will concomitantly reduce the risk of immune-linked secondary conditions. Additionally, improved disease prevention is possible with more relevant and age-specific immune safety testing.

Ten Years of the Immune Tolerance Network: An Integrated Clinical Research Organization

The U.S. National Institutes of Health Roadmap and the U.S. Food and Drug Administration's Critical Path Initiative have endorsed the establishment of large academic clinical research networks as part of the solution to the growing divide between increased R&D spending and the lagging number of new drugs making it to market. Clearly, the role of these networks as translational science incubators that complement industry-sponsored programs is laudable and much-needed. However, the path to success for such organizations is less clear. Here, drawing on the experiences of the Immune Tolerance Network, a multidisciplinary clinical research network founded in 1999, we discuss some of the barriers inherent in developing such consortia and offer firsthand insight into the planning, resources, and organizational infrastructure required for a successful research program.

Real-time Characterization of Antibodies and Biomarker Detection in the Study of Immune-based Disease

Real-time Characterization of Antibodies and Biomarker Detection in the Study of Immune-based Disease

Defective T cells from gld mice play a pivotal role in development of Thy-1.2+B220+ cells and autoimmunity.

The gld mouse represents a fascinating animal model of autoimmune disease, which is characterized by massive development of Thy-1.2+B220+ CD4-CD8- cells. These cells thus have double positive markers for T and B cells, but are double negative for CD4 and CD8 markers and are thus designated DN cells in the present context. An additional important feature in gld mice is a defect in expression of Fas ligand. To investigate the regulatory role of bone marrow-derived cells for the development of these DN cells and of gld autoimmunity, we constructed chimeric mice transplanted with fetal liver cells or fetal thymus from gld mice into nonirradiated severe combined immunodeficient (SCID) mice. These chimeric mice regenerated, developed both these DN cells and the gld autoimmune syndrome and also generalized lymphoproliferative disorders. However, when fetal liver cells from both gld and non-gld mice (C57BL/10 Thy-1.1 mice) were co-transplanted into SCID mice, the development of DN cells was apparently inhibited. Further, this inhibition was also seen in SCID mice that had been grafted with both gld and non-gld fetal thymus revealing the pivotal role played by T cells in development of DN cells. When B cells purified from non-gld (C3H+/+) mice were transplanted into SCID mice grafted with gld fetal thymus, the development of DN cells was not inhibited. Taken together, these findings indicate that T cells from non-gld mice inhibit the expression of gld features, e.g., lymphoproliferation, immune-based nephritic disease, and autoantibody production. These findings also suggest that the Fas ligand is selectively expressed on T cells.