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Journal of Autoimmunity Feb 2016Autism spectrum disorders (ASD) are complex neurodevelopmental conditions that have been rising markedly in prevalence for the past 30 years, now thought to affect 1 in... (Review)
Review
Autism spectrum disorders (ASD) are complex neurodevelopmental conditions that have been rising markedly in prevalence for the past 30 years, now thought to affect 1 in 68 in the United States. This has prompted the search for possible explanations, and has even resulted in some controversy regarding the "true" prevalence of autism. ASD are influenced by a variety of genetic, environmental, and possibly immunological factors that act during critical periods to alter key developmental processes. This can affect multiple systems and manifests as the social and behavioral deficits that define these disorders. The interaction of environmental exposures in the context of an individual's genetic susceptibilities manifests differently in each case, leading to heterogeneous phenotypes and varied comorbid symptoms within the disorder. This has also made it very difficult to elucidate underlying genes and exposure profiles, but progress is being made in this area. Some pharmaceutical drugs, toxicants, and metabolic and nutritional factors have been identified in epidemiological studies as increasing autism risk, especially during the prenatal period. Immunologic risk factors, including maternal infection during pregnancy, autoantibodies to fetal brain proteins, and familial autoimmune disease, have consistently been observed across multiple studies, as have immune abnormalities in individuals with ASD. Mechanistic research using animal models and patient-derived stem cells will help researchers to understand the complex etiology of these neurodevelopmental disorders, which will lead to more effective therapies and preventative strategies. Proposed therapies that need more investigation include special diets, probiotics, immune modulation, oxytocin, and personalized pharmacogenomic targets. The ongoing search for biomarkers and better treatments will result in earlier identification of ASD and provide much needed help and relief for afflicted families.
Topics: Animals; Autism Spectrum Disorder; Autoimmunity; Brain; Disease Susceptibility; Environment; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Prevalence; Risk Factors
PubMed: 26725748
DOI: 10.1016/j.jaut.2015.11.003 -
Journal of the Academy of Nutrition and... Apr 2018
Topics: DNA Glycosylases; Diet, Mediterranean; Disease Susceptibility; Genetic Predisposition to Disease; Humans; Risk Factors
PubMed: 29305132
DOI: 10.1016/j.jand.2017.09.026 -
Journal of Magnetic Resonance (San... Jul 2018The ultimate goal of MRI is to provide information on biological tissue microstructure and function. Quantitative Susceptibility Mapping (QSM) is one of the newer... (Review)
Review
The ultimate goal of MRI is to provide information on biological tissue microstructure and function. Quantitative Susceptibility Mapping (QSM) is one of the newer approaches for studying tissue microstructure by means of measuring phase of Gradient Recalled Echo (GRE) MRI signal. The fundamental question in the heart of this approach is: what is the relationship between the net phase/frequency of the GRE signal from an imaging voxel and the underlying tissue microstructure at the cellular and sub-cellular levels? In the presence of external magnetic field, biological media (e.g. cells, cellular components, blood) become magnetized leading to the MR signal frequency shift that is affected not only by bulk magnetic susceptibility but by the local cellular environment as well. The latter effect is often termed the Lorentzian contribution to the frequency shift. Evaluating the Lorentzian contribution - one of the most intriguing and challenging problems in this field - is the main focus of this review. While the traditional approach to this problem is based on introduction of an imaginary Lorentzian cavity, a more rigorous treatment was proposed recently based on a statistical approach and a direct solution of the Maxwell equations. This approach, termed the Generalized Lorentzian Tensor Approach (GLTA), is especially fruitful for describing anisotropic biological media. The GLTA adequately accounts for two types of anisotropy: anisotropy of magnetic susceptibility and tissue structural anisotropy (e.g., cylindrical axonal bundles in white matter). In the framework of the GLTA the frequency shift due to the local environment is described in terms of the Lorentzian tensor L̂ which can have a substantially different structure than the susceptibility tensor χ̂. While the components of χ̂ are compartmental susceptibilities "weighted" by their volume fractions, the components of L̂ are additionally weighted by specific numerical factors depending on cellular geometrical symmetry. In addition to describing the GLTA that is a phenomenological approach largely based on considering the system symmetry, we also briefly discuss a microscopic approaches to the problem that are based on modeling of the MR signal in different regimes (i.e. static dephasing vs. motion narrowing) and in different cellular environments (e.g., accounting for WM microstructure).
Topics: Algorithms; Animals; Anisotropy; Disease Susceptibility; Heart; Humans; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging
PubMed: 29730126
DOI: 10.1016/j.jmr.2018.04.014 -
European Respiratory Review : An... Dec 2014
Topics: Diet; Disease Susceptibility; Fabaceae; Hispanic or Latino; Humans; Lung Neoplasms; Pulmonary Disease, Chronic Obstructive
PubMed: 25445939
DOI: 10.1183/09059180.00005414 -
Annual Review of Immunology Apr 2018Inflammatory bowel disease (IBD) defines a spectrum of complex disorders. Understanding how environmental risk factors, alterations of the intestinal microbiota, and... (Review)
Review
Inflammatory bowel disease (IBD) defines a spectrum of complex disorders. Understanding how environmental risk factors, alterations of the intestinal microbiota, and polygenetic and epigenetic susceptibility impact on immune pathways is key for developing targeted therapies. Mechanistic understanding of polygenic IBD is complemented by Mendelian disorders that present with IBD, pharmacological interventions that cause colitis, autoimmunity, and multiple animal models. Collectively, this multifactorial pathogenesis supports a concept of immune checkpoints that control microbial-host interactions in the gut by modulating innate and adaptive immunity, as well as epithelial and mesenchymal cell responses. In addition to classical immunosuppressive strategies, we discuss how resetting the microbiota and restoring innate immune responses, in particular autophagy and epithelial barrier function, might be key for maintaining remission or preventing IBD. Targeting checkpoints in genetically stratified subgroups of patients with Mendelian disorder-associated IBD increasingly directs treatment strategies as part of personalized medicine.
Topics: Animals; Biomarkers; Chronic Disease; Disease Management; Disease Models, Animal; Disease Susceptibility; Drug-Related Side Effects and Adverse Reactions; Dysbiosis; Gastrointestinal Microbiome; Genetic Predisposition to Disease; Humans; Inflammatory Bowel Diseases; Molecular Targeted Therapy; Translational Research, Biomedical
PubMed: 29677472
DOI: 10.1146/annurev-immunol-042617-053055 -
Annual Review of Animal Biosciences Feb 2024The study of adipose tissue (AT) is enjoying a renaissance. White, brown, and beige adipocytes are being investigated in adult animals, and the critical roles of small... (Review)
Review
The study of adipose tissue (AT) is enjoying a renaissance. White, brown, and beige adipocytes are being investigated in adult animals, and the critical roles of small depots like perivascular AT are becoming clear. But the most profound revision of the AT dogma has been its cellular composition and regulation. Single-cell transcriptomic studies revealed that adipocytes comprise well under 50% of the cells in white AT, and a substantial portion of the rest are immune cells. Altering the function of AT resident leukocytes can induce or correct metabolic syndrome and, more surprisingly, alter adaptive immune responses to infection. Although the field is dominated by obesity research, conditions such as rapid lipolysis, infection, and heat stress impact AT immune dynamics as well. Recent findings in rodents lead to critical questions that should be explored in domestic livestock as potential avenues for improved animal resilience to stressors, particularly as animals age.
Topics: Animals; Disease Susceptibility; Adipose Tissue; Inflammation; Livestock; Transcriptome
PubMed: 38064480
DOI: 10.1146/annurev-animal-021122-113212 -
Journal of Human Genetics Sep 2023Otosclerosis (OTSC) is a focal and diffuse bone disorder of the human middle ear characterized by abnormal bone growth and deposition at the stapes' footplate. This...
Otosclerosis (OTSC) is a focal and diffuse bone disorder of the human middle ear characterized by abnormal bone growth and deposition at the stapes' footplate. This hinders the transmission of acoustic waves to the inner ear leading to subsequent conductive hearing loss. The plausible convections for the disease are genetic and environmental factors with yet an unraveled root cause. Recently, exome sequencing of European individuals with OTSC revealed rare pathogenic variants in the Serpin Peptidase Inhibitor, Clade F (SERPINF1) gene. Here, we sought to investigate the causal variants of SERPINF1 in the Indian population. The gene and protein expression was also evaluated in otosclerotic stapes to ameliorate our understanding of the potential effect of this gene in OTSC. A total of 230 OTSC patients and 230 healthy controls were genotyped by single-strand conformational polymorphism and Sanger sequencing methods. By comparing the case controls, we identified five rare variants (c.72 C > T, c.151 G > A, c.242 C > G, c.823 A > T, and c.826 T > A) only in patients. Four variants c.390 T > C (p = 0.048), c.440-39 C > T (p = 0.007), c.643 + 9 G > A (p = 0.035), and c.643 + 82 T > C (p = 0.005) were found to be significantly associated with the disease. Down-regulation of SERPINF1 transcript level in otosclerotic stapes was quantified by qRT-PCR, ddPCR and further validated by in situ hybridization. Similarly, reduced protein expression was observed by immunohistochemistry and immunofluorescence in otosclerotic stapes that corroborate with immunoblotting of patients' plasma samples. Our findings identified that SERPINF1 variants are associated with the disease. Furthermore, reduced expression of SERPINF1 in otosclerotic stapes might contribute to OTSC pathophysiology.
Topics: Humans; Disease Susceptibility; Genotype; Otosclerosis; Polymerase Chain Reaction; Stapes
PubMed: 37308566
DOI: 10.1038/s10038-023-01158-w -
Reproduction (Cambridge, England) Dec 2014The phenomenon that adverse environmental exposures in early life are associated with increased susceptibilities for many adult, particularly metabolic diseases, is now... (Review)
Review
The phenomenon that adverse environmental exposures in early life are associated with increased susceptibilities for many adult, particularly metabolic diseases, is now referred to as 'developmental origins of health and disease (DOHAD)' or 'Barker' hypothesis. Fetal overnutrition and undernutrition have similar long-lasting effects on the setting of the neuroendocrine control systems, energy homeostasis, and metabolism, leading to life-long increased morbidity. There are sensitive time windows during early development, where environmental cues can program persistent epigenetic modifications which are generally assumed to mediate these gene-environment interactions. Most of our current knowledge on fetal programing comes from animal models and epidemiological studies in humans, in particular the Dutch famine birth cohort. In industrialized countries, there is more concern about adverse long-term consequences of fetal overnutrition, i.e. by exposure to gestational diabetes mellitus and/or maternal obesity which affect 10-20% of pregnancies. Epigenetic changes due to maternal diabetes/obesity may predispose the offspring to develop metabolic disease later in life and, thus, transmit the adverse environmental exposure to the next generation. This vicious cycle could contribute significantly to the worldwide metabolic disease epidemics. In this review article, we focus on the epigenetics of an adverse intrauterine environment, in particular gestational diabetes, and its implications for the prevention of complex disease.
Topics: Animals; Diabetes, Gestational; Disease Susceptibility; Epigenesis, Genetic; Female; Humans; Metabolic Diseases; Mice; Models, Animal; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Risk Factors
PubMed: 25187623
DOI: 10.1530/REP-14-0334 -
ELife May 2020Interactions between immune cell receptors and proteins that determine disease susceptibility shed light on how different arms of the immune system are involved in three...
Interactions between immune cell receptors and proteins that determine disease susceptibility shed light on how different arms of the immune system are involved in three viral infections and Crohn's disease.
Topics: Disease Susceptibility; Humans
PubMed: 32406819
DOI: 10.7554/eLife.56886 -
Preventive Veterinary Medicine Oct 2015The primary objectives of paratuberculosis control programs are reducing exposure of calves to Mycobacterium avium subspecies paratuberculosis (MAP), reducing herd... (Review)
Review
The primary objectives of paratuberculosis control programs are reducing exposure of calves to Mycobacterium avium subspecies paratuberculosis (MAP), reducing herd infection pressure and regular testing of cattle >36 months of age. Although control programs based on these principles have reduced prevalence of MAP infection in dairy herds, they have generally not eliminated the infection. Recent infection trial(s) have yielded new knowledge regarding diagnostic testing and age- and dose-dependent susceptibility to MAP infection. Calves up to 1 year of age are still susceptible to MAP infection; therefore, control programs should refrain from referring to specific ages with respect to susceptibility and prevention of new infections. Notwithstanding, lesions were more severe when calves were inoculated at 2 weeks versus 1 year of age. Furthermore, a high inoculation dose resulted in more pronounced lesions than a low inoculation dose, especially in young calves. Consequently, keeping infection pressure low should decrease the incidence of new MAP infections and severity of JD in cattle that do acquire the infection. It was also evident that early diagnosis of MAP infection was possible and could improve efficacy of control programs. Although its use will still need to be validated in the field, a combination of antibody ELISA and fecal culture in young stock, in addition to testing cattle >36 months of age when screening a herd for paratuberculosis, was expected to improve detection of dairy cattle infected with MAP. Although calves were inoculated using a standardized method in a controlled environment, there were substantial differences among calves with regards to immune response, shedding and pathology. Therefore, we inferred there were genetic differences in susceptibility. Important insights were derived from experimental infection trials. Therefore, it was expected that these could improve paratuberculosis control programs by reducing severity and incidence of JD by lowering infection pressure on-farm, and reducing exposure of young calves and older cattle. Furthermore, an earlier diagnosis could be achieved by combining ELISA and fecal shedding in young stock, in addition to testing cattle >36 months of age.
Topics: Animals; Cattle; Cattle Diseases; Disease Susceptibility; Incidence; Mycobacterium avium subsp. paratuberculosis; Paratuberculosis; Prevalence
PubMed: 26321657
DOI: 10.1016/j.prevetmed.2015.08.011