Bone Status in a Mouse Model of Experimental Autoimmune-Orchitis.

Investigations in male patients with fertility disorders revealed a greater risk of osteoporosis. The rodent model of experimental autoimmune-orchitis (EAO) was established to analyze the underlying mechanisms of male infertility and causes of reduced testosterone concentration. Hence, we investigated the impact of testicular dysfunction in EAO on bone status. Male mice were immunized with testicular homogenate in adjuvant to induce EAO (n = 5). Age-matched mice were treated with adjuvant alone (adjuvant, n = 6) or remained untreated (control, n = 7). Fifty days after the first immunization specimens were harvested. Real-time reverse transcription-PCR indicated decreased bone metabolism by alkaline phosphatase and Cathepsin K as well as remodeling of cell-contacts by Connexin-43. Micro computed tomography demonstrated a loss of bone mass and mineralization. These findings were supported by histomorphometric results. Additionally, biomechanical properties of femora in a three-point bending test were significantly altered. In summary, the present study illustrates the induction of osteoporosis in the investigated mouse model. However, results suggest that the major effects on bone status were mainly caused by the complete Freund's adjuvant rather than the autoimmune-orchitis itself. Therefore, the benefit of the EAO model to transfer laboratory findings regarding bone metabolism in context with orchitis into a clinical application is limited.

The effects of immunostimulatory herbal supplements on autoimmune skin diseases.

The use of herbal supplements that promise to improve immune health has gained popularity among dermatology patients. However, there is little to no evidence that herbal supplements improve dermatologic conditions. Several in vitro and in vivo studies have shown that Spirulina platensis, Aphanizomenon flos-aqua, Chlorella, Echinacea, and alfalfa activate immune cells via certain cytokines and chemokines. Case reports suggest the association of ingesting immunostimulatory herbs and the clinical onset or flares of diseases characterized by an exaggerated immune response such as lupus erythematosus, dermatomyositis, and autoimmune blistering disorders. Therefore, it is imperative to investigate the prevalence of herbal supplement use in this patient population. In addition, in vitro studies should examine the underlying mechanisms by which herbs stimulate immune pathways that are already overactive in autoimmune patients.

Eye movements in demyelinating, autoimmune and metabolic disorders.

PURPOSE OF REVIEW: In the last three decades, the use of eye movements and vestibular testing in many neurological disorders has accelerated, primarily because of practical technologic developments. Although the acute vestibular syndrome is a prime example of this progress, more chronic neurologic and systemic disorders have received less attention. We focus here on recent contributions relating vestibular and ocular motor abnormalities in inflammatory, demyelinating, metabolic, and peripheral nervous system disorders RECENT FINDINGS: Vestibular abnormalities have been identified in acute demyelinating neuropathies (AIDP), in novel genetic mutations responsible for CANVAS (cerebellar ataxia, neuropathy vestibular areflexia syndrome), and in other inherited neuropathies (variants of Charcot-Marie-Tooth disease). In addition, there are differentiating characteristics between the most common CNS demyelinating disorders: multiple sclerosis and neuromyelitis optica (NMO). We summarize new information on Vitamin D metabolism in benign paroxysmal positional vertigo (BPPV), followed by a brief review of the vestibular and ocular motor findings in Wernicke's encephalopathy. We conclude with findings in several paraneoplastic/autoimmune disorders. SUMMARY: This literature review highlights the impact of a careful vestibular and ocular motor evaluation in common neurologic disorder, not only for the initial diagnosis but also for monitoring disease and rehabilitation. A careful examination of eye movements and vestibular function, supplemented with new video techniques to quantify the findings, should be part of the standard neurologic examination.

Network-wide abnormalities explain memory variability in hippocampal amnesia.

Patients with hippocampal amnesia play a central role in memory neuroscience but the neural underpinnings of amnesia are hotly debated. We hypothesized that focal hippocampal damage is associated with changes across the extended hippocampal system and that these, rather than hippocampal atrophy per se, would explain variability in memory between patients. We assessed this hypothesis in a uniquely large cohort of patients (n = 38) after autoimmune limbic encephalitis, a syndrome associated with focal structural hippocampal pathology. These patients showed impaired recall, recognition and maintenance of new information, and remote autobiographical amnesia. Besides hippocampal atrophy, we observed correlatively reduced thalamic and entorhinal cortical volume, resting-state inter-hippocampal connectivity and activity in posteromedial cortex. Associations of hippocampal volume with recall, recognition, and remote memory were fully mediated by wider network abnormalities, and were only direct in forgetting. Network abnormalities may explain the variability across studies of amnesia and speak to debates in memory neuroscience.

[Research progress on roles of vitamin D in endometriosis].

In addition to regulating calcium and phosphorus metabolism to maintain strong bones, vitamin D also has immune regulating and anti-inflammatory effects. Moreover, it is related to chronic inflammatory diseases, autoimmune diseases and cancer. Many studies indicate the roles of vitamin D in the development and progression of endometriosis including the effects on modulation of immune responses, inflammation reactions, cell proliferation and apoptosis, angiogenesis, adhesion and invasion. Vitamin D supplementation can relieve pain and improve endometrial receptivity associated with endometriosis and play a preventive and therapeutic role. This paper summarizes the roles of vitamin D in endometriosis.

Hypoxic stress: A risk factor for post-concussive hypopituitarism?

Hypopituitarism diagnosed months or years following concussive injury can cause a variety of endocrine disturbances including insufficient secretion of human growth, luteinizing, follicle stimulating, thyroid stimulating, adrenocorticotrophic, and antidiuretic hormones. Recent evidence suggests that autoimmune reactions against pituitary and/or hypothalamic tissue constitute an etiologic factor for this hypopituitarism. One important trigger for autoimmunity is hypoxic stress. This trigger may be especially important in the post-concussive brain, which is particularly vulnerable to hypoxic stress. The vulnerable vasculature of the hypothalamic infundibulum can be a source of local exacerbation of any systemic hypoxia. Taking the above into account, it seems reasonable to hypothesize that hypoxic stress is a risk factor for post-concussive hypopituitarism. Following a discussion of literature relevant to this hypothesis, we suggest retrospective and prospective research methods for testing the hypothesis. Retrospective methods for hypothesis testing include comparing post-concussion victims with and without evidence of hypopituitarism in terms of their history of respiratory problems such as smoking, exposure to indoor and outdoor air pollution, chronic obstructive pulmonary disease, asthma, obstructive sleep apnea, and opioid use or abuse. Significantly greater incidence of respiratory history among the hypopituitarism patients would support the hypothesis. Prospective methods include performing detailed respiratory history and examination immediately post-injury, then performing periodic endocrine panels to detect hypopituitarism during long-term follow up. The hypothesis will be supported if development of hypopituitarism among patients with positive respiratory history or examination findings post-injury is more frequent than hypopituitarism among concussion victims with negative respiratory history and exam findings. If the hypothesis is supported, effective prevention of post-concussive hypopituitarism should include efforts to support optimal respiratory function. Such efforts may be relevant to treatment as well. These efforts would include respiratory therapy, smoking cessation, treatment of obstructive sleep apnea, prudent stepping down of opioid use, incentive spirometry, aerobic exercise, and other conventional measures as indicated. Non-Western measures such as yoga should be considered as well. In addition, chiropractic care as an intervention that may ameliorate hypoxia at the systemic and local levels is discussed.

Novel therapeutic strategy for cancer and autoimmune conditions: Modulating cell metabolism and redox capacity.

Dysregulation of cell metabolism and redox balance is implicated in the pathogenesis and progression of cancer and autoimmune diseases. Because the cell proliferation and apoptotic regulatory pathways are interconnected with metabolic and redox signalling pathways, the current mono-target treatment is ineffective, and multi-drug resistance remains common. Complex diseases are often implicated in a network-based context of pathology; therefore, a new holistic intervention approach is required to block multi-crosstalk in such complicated circumstances. The use of therapeutic agents isolated from herbs to holistically modulate metabolism and redox state has been shown to relieve carcinoma growth and the inflammatory response in autoimmune disorders. Multiple clinically applied or novel herbal chemicals with metabolic and redox modulatory capacity as well as low toxicity have recently been identified. Moreover, new metabolic targets and mechanisms of drug action have been discovered, leading to the exploration of new pathways for drug repositioning, clinical biomarker spectra, clinical treatment strategies and drug development. Taken together with multiple supporting examples, the modulation of cell metabolism and the redox capacity using herbal chemicals is emerging as a new, alternative strategy for the holistic treatment of cancer and autoimmune disorders. In the future, the development of new diagnostic tools based on the detection of metabolic and redox biomarkers, reformulation of optimized herbal compositions using artificial intelligence, and the combination of herbs with mono-targeting drugs will reveal new potential for clinical application.

Premature ovarian failure of autoimmune etiology in 46XX patients: is there a hope?

OBJECTIVES: To evaluate the efficacy of live bee stings at fertility points and acupuncture in treating symptoms and managing infertility in premature ovarian failure (POF) of autoimmune etiology. PATIENTS AND METHODS: Patients with primary POF were allocated randomly into two groups: group I: subjected to acupuncture at specific fertility points and group II: subjected to live bee stings at sites of fertility points. RESULTS: A total of 24 cases show significant reduction of Follicle stimulating hormone (FSH) level to normal range with gradual decline over the study duration: 13 cases in group I and 11 cases in group II. Eight cases got pregnant while the other 13 cases regained normal menses but still infertile. CONCLUSIONS: Both bee sting therapy and acupuncture were effective in reduction of FSH levels with restoration of regular menstrual patterns and restoration of fertility. The bee sting therapy was superior in the pregnancy rate, while acupuncture was superior in alleviation of symptoms.

Use of Autologous Serum Tears for the Treatment of Ocular Surface Disease From Patients With Systemic Autoimmune Diseases.

PURPOSE: To describe the safety and efficacy of autologous serum tears (AST) in managing ocular surface disease resistant to conventional therapy in patients with systemic autoimmune disease(s). DESIGN: Retrospective, interventional case series. METHODS: Records of patients from 2009 to 2015 with systemic autoimmune disease treated with AST (20%-50%) for chronic surface disease were analyzed. Standardized measures of subjective dry eye symptoms, objective dry eye staining of the cornea, and slit-lamp findings including punctate epithelial erosion (PEE), filamentary keratopathy (FK), and corneal epithelial defects (KED) were compared during first and last visit. We attempted to standardize outcomes by creating a scale from 1 to 4 for subjective and objective components: worsening (1), no improvement (2), partial improvement (3), and complete resolution (4). RESULTS: Fifty-one patients (101 eyes) were included. The mean age was 59.8 ± 13.2 years (72.5% female). Average use of AST was 14.3 ± 11.7 months. Complete objective improvement of initial slit-lamp findings was achieved in 30% and partial improvement in 55% of eyes. Presence of PEE, FK, and KED decreased from 92.1% to 52.5% (P < .001), from 22.8% to 9.9% (P = .02), and from 5% to 2% (P = .44) of the eyes, respectively. Full subjective improvement of symptoms was achieved in 34.6%, partial in 50.5%, and none in 14.9% of patients. No adverse side effects were noted during follow-up. CONCLUSIONS: AST are a safe and effective adjunct therapy in improving both objective signs and subjective symptoms of ocular surface disorders associated with systemic autoimmune disease(s).

Embarazo y enfermedades autoinmunitarias / Pregnancy and autoimmune diseases

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A Review of the Course and Treatment of Non-Infectious Uveitis during Pregnancy.

Inflammatory conditions such as autoimmune uveitis often occur in women of childbearing age. During pregnancy, women may experience exacerbations of their disease in the first trimester. In the later stages of pregnancy, however, the uveitis tends to remain less active. The management of uveitis during pregnancy is a challenging task, forcing the physician to re-evaluate the patient's current therapy and offer alternative options that pose the least risk to the patient and fetus. This article will review treatments widely used for uveitis, including corticosteroid therapy, anti-metabolites, calcineurin inhibitors, and biologic therapy. It will evaluate the use of these medications in pregnancy and the postpartum state.

Autoimmune uveitis: clinical, pathogenetic, and therapeutic features.

Autoimmune uveitis (AU), an inflammatory non-infectious process of the vascular layer of the eye, can lead to visual impairment and, in the absence of a timely diagnosis and suitable therapy, can even result in total blindness. The majority of AU cases are idiopathic, whereas fewer than 20 % are associated with systemic diseases. The clinical severity of AU depends on whether the anterior, intermediate, or posterior part of the uvea is involved and may range from almost asymptomatic to rapidly sight-threatening forms. Race, genetic background, and environmental factors can also influence the clinical picture. The pathogenetic mechanism of AU is still poorly defined, given its remarkable heterogeneity and the many discrepancies between experimental and human uveitis. Even so, the onset of AU is thought to be related to an aberrant T cell-mediated immune response, triggered by inflammation and directed against retinal or cross-reactive antigens. B cells may also play a role in uveal antigen presentation and in the subsequent activation of T cells. The management of AU remains a challenge for clinicians, especially because of the paucity of randomized clinical trials that have systematically evaluated the effectiveness of different drugs. In addition to topical treatment, several different therapeutic options are available, although a standardized regimen is thus far lacking. Current guidelines recommend corticosteroids as the first-line therapy for patients with active AU. Immunosuppressive drugs may be subsequently required to treat steroid-resistant AU and for steroid-sparing purposes. The recent introduction of biological agents, such as those targeting tumor necrosis factor-α, is expected to remarkably increase the percentages of responders and to prevent irreversible sight impairment. This paper reviews the clinical features of AU and its crucial pathogenetic targets in relation to the current therapeutic perspectives. Also, the largest clinical trials conducted in the last 12 years for the treatment of AU are summarized and critically discussed.

Chronic and non-healing wounds: The story of vascular endothelial growth factor.

The pathophysiology of the chronicity and non-healing status of wounds remains unknown. This paper presents the following hypothesis: abnormal patterns of vascular endothelial growth factor receptors (VEGFRs) are the culprits of wound chronicity and non-healing. More specifically, for patients with poor circulation, the decreased VEGFR-2 level is the cause of poor wound healing; for patients with non-compromised circulation, for example, patients with concurrent chronic wounds and active autoimmune diseases, the increased VEGFR-1 level is related to the non-healing status of wounds. The hypothesis is supported by the following facts. VEGFR-1 is the main contributor for inflammation and VEGFR-2 facilitates angiogenesis; soluble VEGFR-1 (sVEGFR-1) inactivates both VEGFR-1 and VEGFR-2. Patients with auto-immune disease have abnormally increased VEGFR-1 and decreased sVEGFR. Wounds in patients with active autoimmune diseases have poor response to electric stimulation which facilitates chronic wound healing in patients without active autoimmune diseases via increasing vascular endothelial growth factor (VEGF) secretion. Patients with chronic wounds (including diabetic foot ulcers and venous leg ulcers) but no active autoimmune diseases have decreased VEGFR-2 levels. We thus believe that abnormal patterns of VEGFRs are the culprits of wound chronicity and non-healing. For wounds with compromised circulation, VEGFR-2 decrease contributes to its chronicity; whereas for wounds with non-compromised circulation, VEGFR-1 increase is the leading cause of the non-healing status of chronic wounds. Treatments and research in wound care should be tailored to target these changes based on circulation status of wounds. Complete elucidation of changes of VEGFRs in chronic and non-healing wounds will enhance our understandings in tissue healing and thus better our selection of appropriate treatments for chronic and non-healing wounds.

Heat shock protein 90: a pathophysiological factor and novel treatment target in autoimmune bullous skin diseases.

The chaperone heat shock protein 90 (Hsp90), a cell stress-inducible molecule that regulates activity of many client proteins responsible for cellular growth, differentiation and apoptosis, has been proposed as an important therapeutic target in patients with malignancies. More recently, its active participation in (auto)immune processes has been recognized as evidenced by amelioration of inflammatory disease pathways through pharmacological inhibition of Hsp90 in rodent models of autoimmune encephalomyelitis, rheumatoid arthritis and systemic lupus erythematosus. Based on own current research results, this viewpoint essay provides important insights that Hsp90 is also involved as a notable pathophysiological factor in autoimmune blistering dermatoses including epidermolysis bullosa acquisita, bullous pemphigoid and possibly dermatitis herpetiformis. The observed in vitro, ex vivo and in vivo efficacy of anti-Hsp90 treatment in experimental models of autoimmune bullous diseases and its underlying multimodal anti-inflammatory mechanisms of interference with key contributors to autoimmune-mediated blister formation supports the introduction of selective non-toxic Hsp90 inhibitors into the clinical setting for the treatment of patients with these disorders.

Targeted delivery systems for biological therapies of inflammatory diseases.

INTRODUCTION: Inflammatory diseases, including autoimmune diseases and autoinflammatory diseases, are characterized by the imbalance of pro-inflammatory cytokines and anti-inflammatory cytokines. Targeted systems allow for specific delivery and sustained release of biological agents to inflamed tissues and macrophages, hence reducing their side effects. AREAS COVERED: This review discusses various targeting strategies for biological therapies of inflammatory diseases, with a focus on modulating macrophage functional polarization from an M1 to M2 phenotype. Furthermore, recent advances in the development of targeted delivery systems for gene therapy against inflammatory diseases including liposomal therapeutics, polymeric nanoparticles and microspheres, and multi-compartmental delivery systems are summarized. EXPERT OPINION: Molecular advances have uncovered various targets for biological therapies against inflammatory diseases. Despite substantial promise, the potential translation from the bench to the clinic is limited due to poor systemic stability of the delivery systems, low tissue distribution, and safety concerns. In order to develop clinically translatable targeted delivery systems, thorough evaluation of the efficacy and toxicity in relevant animal models and in different inflammatory diseases is needed. In addition, issues related to long-term storage stability, scale-up and manufacturing of the systems need to be addressed.

Is vitamin D a player or not in the pathophysiology of autoimmune thyroid diseases?

1,25-Dihydroxyvitamin D is a steroid hormone derived from vitamin D, playing an important role in maintaining an adequate serum level of calcium and phosphorus. It is now clear that vitamin D exerts an endocrine action on the cells of the immune system, generating anti-inflammatory and immunoregulatory effects. The mechanisms underlying the role of vitamin D in autoimmunity are not completely understood. Lower vitamin D levels have been found in several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases, autoimmune thyroid diseases (i.e. Hashimoto's thyroiditis and Graves' disease) and autoimmune gastritis. Several genetic studies have demonstrated an association between thyroid autoimmunity susceptibility and gene polymorphisms of vitamin D receptor, vitamin D binding protein, 1-alpha-hydroxylase and 25-hydroxylase. Of note, some papers do not confirm this connection. With regard to the role of vitamin D in autoimmune thyroid diseases, available data remain controversial. Only few reports have analyzed the supposed association between autoimmune thyroid diseases and vitamin D concentration with inconclusive results. In our experience, low serum levels of vitamin D do not correlate either with Hashimoto's thyroiditis or with Graves' disease. The inability to achieve an unambiguous conclusion is in part due to the limitations in study design. In fact, most of the studies are cross-sectional surveys with a small number of subjects. In addition, the heterogeneity of the study population, seasonal variation of blood sampling, inter-method analytical variability of vitamin D assays and different definitions of vitamin D deficiency/insufficiency contribute to contradicting results. Therefore, further randomized, controlled, prospective trials are needed in order to demonstrate the causality of vitD in AITD and consequently the role of vitamin D supplementation in prevention or improvement of AITD, providing also information on the best formulation, dose and timing of supplementation.

Role of vitamin D in acquired immune and autoimmune diseases.

Vitamin D has been attributed roles in the pathogenesis and prevention of several diseases such as cancer, cardiovascular disease, multiple sclerosis, diabetes, autism and autoimmune diseases. The concomitant expression of the 25-hydroxyvitamin D3-1α-hydroxylase and of the vitamin D3 receptor in animal and human tissues and organs other than bone supports this paradigm. Translated into the clinical field, meta-analyses and systematic reviews have also revealed an association between vitamin D insufficiency or deficiency and non-osseous diseases. Although relying on the large databases, they are diverse in nature and involve participants of varying age and evolving in different environments. Furthermore, they do not allow any analysis of a possible causal relationship between vitamin D supplementation and clinical outcomes. Following a brief historical account, this review addresses these caveats, and gives examples of randomized controlled trials conducted in the fields of acquired immune and autoimmune diseases.

The role of lipid-activated nuclear receptors in shaping macrophage and dendritic cell function: From physiology to pathology.

Nuclear receptors are ligand-activated transcription factors linking lipid signaling to the expression of the genome. There is increasing appreciation of the involvement of this receptor network in the metabolic programming of macrophages and dendritic cells (DCs), essential members of the innate immune system. In this review we focus on the role of retinoid X receptor, retinoic acid receptor, peroxisome proliferator-associated receptor γ, liver X receptor, and vitamin D receptor in shaping the immune and metabolic functions of macrophages and DCs. We also provide an overview of the contribution of macrophage- and DC-expressed nuclear receptors to various immunopathologic conditions, such as rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, asthma, and some others. We suggest that systematic analyses of the roles of these receptors and their activating lipid ligands in immunopathologies combined with complementary and focused translational and clinical research will be crucial for the development of new therapies using the many molecules available to target nuclear receptors.

Novel pebbles in the mosaic of autoimmunity.

Almost 25 years ago, the concept of the 'mosaic of autoimmunity' was introduced to the scientific community, and since then this concept has continuously evolved, with new pebbles being added regularly. We are now looking at an era in which the players of autoimmunity have changed names and roles. In this issue of BMC Medicine, several aspects of autoimmunity have been addressed, suggesting that we are now at the forefront of autoimmunity science. Within the environmental factors generating autoimmunity are now included unsuspected molecules such as vitamin D and aluminum. Some adjuvants such as aluminum are recognized as causal factors in the development of the autoimmune response. An entirely new syndrome, the autoimmune/inflammatory syndrome induced by adjuvants (ASIA), has been recently described. This is the new wind blowing within the branches of autoimmunity, adding knowledge to physicians for helping patients with autoimmune disease.