Sertoli cells have a functional NALP3 inflammasome that can modulate autophagy and cytokine production

Sertoli cells, can function as non-professional tolerogenic antigen-presenting cells, and sustain the blood-testis barrier formed by their tight junctions. The NOD-like receptor family members and the NALP3 inflammasome play a key role in pro-inflammatory innate immunity signalling pathways. Limited data exist on NOD1 and NOD2 expression in human and mouse Sertoli cells. Currently, there is no data on inflammasome expression or function in Sertoli cells. We found that in primary pre-pubertal Sertoli cells and in adult Sertoli line, TLR4\NOD1 and NOD2 crosstalk converged in NF?B activation and elicited a NALP3 activation, leading to de novo synthesis and inflammasome priming. This led to caspase-1 activation and IL-1? secretion. We demonstrated this process was controlled by mechanisms linked to autophagy. NOD1 promoted pro-IL-1? restriction and autophagosome maturation arrest, while NOD2 promoted caspase-1 activation, IL-1? secretion and autophagy maturation. NALP3 modulated NOD1 and pro-IL-1? expression, while NOD2 inversely promoted IL-1?. This study is proof of concept that Sertoli cells, upon specific stimulation, could participate in male infertility pathogenesis via inflammatory cytokine induction

An update on vitamin B12-related gene polymorphisms and B12 status.

Vitamin B12 is an essential micronutrient in humans needed for health maintenance. Deficiency of vitamin B12 has been linked to dietary, environmental and genetic factors. Evidence for the genetic basis of vitamin B12 status is poorly understood. However, advancements in genomic techniques have increased the knowledge-base of the genetics of vitamin B12 status. Based on the candidate gene and genome-wide association (GWA) studies, associations between genetic loci in several genes involved in vitamin B12 metabolism have been identified. The objective of this literature review was to identify and discuss reports of associations between single-nucleotide polymorphisms (SNPs) in vitamin B12 pathway genes and their influence on the circulating levels of vitamin B12. Relevant articles were obtained through a literature search on PubMed through to May 2017. An article was included if it examined an association of a SNP with serum or plasma vitamin B12 concentration. Beta coefficients and odds ratios were used to describe the strength of an association, and a  < 0.05 was considered as statistically significant. Two reviewers independently evaluated the eligibility for the inclusion criteria and extracted the data. From 23 studies which fulfilled the selection criteria, 16 studies identified SNPs that showed statistically significant associations with vitamin B12 concentrations. Fifty-nine vitamin B12-related gene polymorphisms associated with vitamin B12 status were identified in total, from the following populations: African American, Brazilian, Canadian, Chinese, Danish, English, European ancestry, Icelandic, Indian, Italian, Latino, Northern Irish, Portuguese and residents of the USA. Overall, the data analyzed suggests that ethnic-specific associations are involved in the genetic determination of vitamin B12 concentrations. However, despite recent success in genetic studies, the majority of identified genes that could explain variation in vitamin B12 concentrations were from Caucasian populations. Further research utilizing larger sample sizes of non-Caucasian populations is necessary in order to better understand these ethnic-specific associations

Periodontitis induced by bacterial infection exacerbates features of Alzheimer\u27s disease in transgenic mice.

Periodontitis is a localized infectious disease caused by periodontopathic bacteria,such as Porphyromonas gingivalis. Recently, it has been suggested that bacterial infections may contribute to the onset and the progression of Alzheimer’s disease (AD). However, we do not have any evidence about a causative relationship between periodontitis and AD. In this study, we investigated by using a transgenic mouse model of AD whether periodontitis evoked by P. gingivalis modulates the pathological features of AD. Cognitive function was significantly impaired in periodontitis-induced APP-Tg mice, compared to that in control APP-Tg mice. Levels of Amiloid β (Aβ) deposition, Aβ40, and Aβ42 in both the hippocampus and cortex were higher in inoculated APP-Tg mice than in control APP-Tg mice. Furthermore, levels of IL-1β and TNF-α in the brain were higher in inoculated mice than in control mice. The levels of LPS were increased in the serum and brain of P. gingivalis-inoculated mice. P. gingivalis LPS-induced production of Aβ40 and Aβ42 in neural cell cultures and strongly enhanced TNF-α and IL-1β production in a culture of microglial cells primed with Aβ. Periodontitis evoked by P. gingivalismay exacerbate brain Aβ deposition, leading to enhanced cognitive impairments, by a mechanism that involves triggering brain inflammation

Interleukin 31 and targeted vaccination in a case series of six horses with chronic pruritus

Chronic pruritus is defined as prolonged itching symptoms associated with a variety of skin conditions. These pruritic conditions clinically manifest in a dermatitis phenotype and commonly are of allergic origin with hypersensitivities towards environmental allergens. Interleukin-31 (IL-31) is a common player in allergic pruritus across species. The objective of the study was evaluation of the clinical efficacy of a therapeutic vaccine targeting IL-31 in horses with chronic pruritus of unknown origin (CPUO) and that could not be explained by insect bite hypersensitivity (IBH). This consecutive case series pilot study included client-owned horses with a long history of CPUO. Four horses affected by year-round CPUO were vaccinated with a vaccine consisting of equine IL-31 (eIL-31) covalently coupled to a virus-like particle (VLP) derived from cucumber mosaic virus containing a tetanus toxoid universal T cell epitope (CuMVTT). Clinical signs and pruritic behaviour were documented by photography and owner questionnaire pre and post vaccination. In addition, in three CPUO horses, levels of IL-31, thymic stromal lymphopoietin (TSLP) and monocyte chemoattractant protein 1 (MCP-1) were quantified from skin punch biopsies. IL-31, TSLP and MCP-1 levels were upregulated in pruritic, alopecic skin lesions compared to healthy skin of the same horse. Clinical signs and pruritic behaviour improved in all four horses upon vaccination with eIL-31-CuMVTT vaccine. The vaccine was well tolerated without safety concerns throughout the study. The main limitations of this study are the absence control treated horses and allergy diagnostics. It was concluded that Anti-IL-31 therapy might be applied as an allergen-independent treatment option for horses with CPUO overcoming the challenges of identifying the allergic trigger

Vaccination against Alzheimer disease: an update on future strategies.

Alzheimer disease is a devastating chronic disease without adequate therapy. More than 10 years ago, it was demonstrated in transgenic mouse models that vaccination may be a novel, disease-modifying therapy for Alzheimer. Subsequent clinical development has been a roller-coaster with some positive and many negative news. Here, we would like to summarize evidence that next generation vaccines optimized for old people and focusing on patients with mild disease stand a good chance to proof efficacious for the treatment of Alzheimer

Active vaccination against interleukin‐5 as long‐term treatment for insect‐bite hypersensitivity in horses

Background Insect‐bite hypersensitivity (IBH) in horses is a chronic allergic dermatitis caused by insect bites. Horses suffer from pruritic skin lesions, caused by type‐I/type‐IV allergic reactions accompanied by prominent eosinophil infiltration into the skin. Interleukin‐5 (IL‐5) is the key cytokine for eosinophils and we have previously shown that targeting IL‐5 by vaccination reduces disease symptoms in horses. Objective Here, we analyzed the potential for long‐term therapy by assessing a second follow‐up year of the previously published study. Methods The vaccine consisted of equine IL‐5 (eIL‐5) covalently linked to a cucumber mosaic virus‐like particle (VLP) containing a universal T cell epitope (CuMVTT) using a semi‐crossover design to follow vaccinated horses during a second treatment season. Thirty Icelandic horses were immunized with 300 μg of eIL‐5‐CuMVTT without adjuvant. Results The vaccine was well tolerated and did not reveal any safety concerns throughout the study. Upon vaccination, all horses developed reversible anti‐eIL‐5 auto‐antibody titers. The mean course of eosinophil levels was reduced compared to placebo treatment leading to significant reduction of clinical lesion scores. Horses in their second vaccination year showed a more pronounced improvement of disease symptoms when compared to first treatment year, most likely due to more stable antibody titers induced by a single booster injection. Hence, responses could be maintained over two seasons and the horses remained protected against disease symptoms. Conclusion Yearly vaccination against IL‐5 may be a long‐term solution for the treatment of IBH and other eosinophil‐mediated diseases in horses and other species including humans

Active vaccination against interleukin‐5 as long‐term treatment for insect‐bite hypersensitivity in horses

Background Insect‐bite hypersensitivity (IBH) in horses is a chronic allergic dermatitis caused by insect bites. Horses suffer from pruritic skin lesions, caused by type‐I/type‐IV allergic reactions accompanied by prominent eosinophil infiltration into the skin. Interleukin‐5 (IL‐5) is the key cytokine for eosinophils and we have previously shown that targeting IL‐5 by vaccination reduces disease symptoms in horses. Objective Here, we analyzed the potential for long‐term therapy by assessing a second follow‐up year of the previously published study. Methods The vaccine consisted of equine IL‐5 (eIL‐5) covalently linked to a cucumber mosaic virus‐like particle (VLP) containing a universal T cell epitope (CuMVTT) using a semi‐crossover design to follow vaccinated horses during a second treatment season. Thirty Icelandic horses were immunized with 300 μg of eIL‐5‐CuMVTT without adjuvant. Results The vaccine was well tolerated and did not reveal any safety concerns throughout the study. Upon vaccination, all horses developed reversible anti‐eIL‐5 auto‐antibody titers. The mean course of eosinophil levels was reduced compared to placebo treatment leading to significant reduction of clinical lesion scores. Horses in their second vaccination year showed a more pronounced improvement of disease symptoms when compared to first treatment year, most likely due to more stable antibody titers induced by a single booster injection. Hence, responses could be maintained over two seasons and the horses remained protected against disease symptoms. Conclusion Yearly vaccination against IL‐5 may be a long‐term solution for the treatment of IBH and other eosinophil‐mediated diseases in horses and other species including humans

The prospects of an active vaccine against asthma targeting IL-5

Allergen-specific T helper type 2 (Th2) responses followed by eosinophilic inflammation of the lung are important causes of allergic asthma. Interleukin-5 (IL-5) is a master regulator of eosinophil differentiation as well as activation. Blocking IL-5 using monoclonal antibodies (mAbs) against IL-5 is a powerful way to improve asthmatic symptoms in patients with an eosinophilic component of the disease. We have previously shown that vaccination against IL-5 can abrogate eosinophilic inflammation of the lung in allergic mice. More recently, we have demonstrated that eosinophil-mediated skin disease in horses with insect bite hypersensitivity can be strongly reduced by vaccination against IL-5. Here we would like to propose the development of a similar vaccine for the treatment of asthma in humans

Treating insect-bite hypersensitivity in horses with active vaccination against IL-5

Background Insect-bite hypersensitivity is the most common allergic dermatitis in horses. Excoriated skin lesions are typical symptoms of this seasonal and refractory chronic disease. On a cellular level, the skin lesions are characterized by massive eosinophil infiltration caused by an underlying allergic response. Objective To target these cells and treat disease, we developed a therapeutic vaccine against equine IL-5 (eIL-5), the master regulator of eosinophils. Methods The vaccine consisted of eIL-5 covalently linked to a virus-like particle derived from cucumber mosaic virus containing the tetanus toxoid universal T-cell epitope tt830-843 (CMVTT). Thirty-four Icelandic horses were recruited and immunized with 400 μg of eIL-5–CMVTT formulated in PBS without adjuvant (19 horses) or PBS alone (15 horses). Results The vaccine was well tolerated and did not reveal any safety concerns but was able to induce anti–eIL-5 autoantibody titers in 17 of 19 horses. This resulted in a statistically significant reduction in clinical lesion scores when compared with previous season levels, as well as levels in placebo-treated horses. Protection required a minimal threshold of anti–eIL-5 antibodies. Clinical improvement by disease scoring showed that 47% and 21% of vaccinated horses reached 50% and 75% improvement, respectively. In the placebo group no horse reached 75% improvement, and only 13% reached 50% improvement. Conclusion Our therapeutic vaccine inducing autoantibodies against self IL-5 brings biologics to horses, is the first successful immunotherapeutic approach targeting a chronic disease in horses, and might facilitate development of a similar vaccine against IL-5 in human subjects.</p