Scientific Hypotheses: Writing, Promoting, and Predicting Implications

Scientific hypotheses are essential for progress in rapidly developing academic disciplines. Proposing new ideas and hypotheses require thorough analyses of evidence-based data and predictions of the implications. One of the main concerns relates to the ethical implications of the generated hypotheses. The authors may need to outline potential benefits and limitations of their suggestions and target widely visible publication outlets to ignite discussion by experts and start testing the hypotheses. Not many publication outlets are currently welcoming hypotheses and unconventional ideas that may open gates to criticism and conservative remarks. A few scholarly journals guide the authors on how to structure hypotheses. Reflecting on general and specific issues around the subject matter is often recommended for drafting a well-structured hypothesis article. An analysis of influential hypotheses, presented in this article, particularly Strachan's hygiene hypothesis with global implications in the field of immunology and allergy, points to the need for properly interpreting and testing new suggestions. Envisaging the ethical implications of the hypotheses should be considered both by authors and journal editors during the writing and publishing process.

Interpretation of the hygiene and microflora hypothesis for allergic diseases through epigenetic epidemiology / 한국역학회지

The hygiene hypothesis (HH) proposed by Strachan in 1989 was expanded to explain the inverse association between the occurrence of allergy disorders and the risk of infectious diseases and parasite infestation. The microflora hypothesis (MH) suggests that gut microbial dysbiosis in early life might trigger hypersensitivity disorders. The sharing concept of both HH and MH is gene-environment interaction, which is also a key concept in epigenetics. The amalgamation of epidemiology and epigenetics has created a scientific discipline termed epigenetic epidemiology. To accomplish an era of gene-environment-wide interaction studies, it is necessary to launch a national human epigenome project.

Interpretation of the hygiene and microflora hypothesis for allergic diseases through epigenetic epidemiology / 한국역학회지

The hygiene hypothesis (HH) proposed by Strachan in 1989 was expanded to explain the inverse association between the occurrence of allergy disorders and the risk of infectious diseases and parasite infestation. The microflora hypothesis (MH) suggests that gut microbial dysbiosis in early life might trigger hypersensitivity disorders. The sharing concept of both HH and MH is gene-environment interaction, which is also a key concept in epigenetics. The amalgamation of epidemiology and epigenetics has created a scientific discipline termed epigenetic epidemiology. To accomplish an era of gene-environment-wide interaction studies, it is necessary to launch a national human epigenome project.

The Microbiome and Mental Health: Looking Back, Moving Forward with Lessons from Allergic Diseases

Relationships between gastrointestinal viscera and human emotions have been documented by virtually all medical traditions known to date. The focus on this relationship has waxed and waned through the centuries, with noted surges in interest driven by cultural forces. Here we explore some of this history and the emerging trends in experimental and clinical research. In particular, we pay specific attention to how the hygiene hypothesis and emerging research on traditional dietary patterns has helped re-ignite interest in the use of microbes to support mental health. At present, the application of microbes and their structural parts as a means to positively influence mental health is an area filled with promise. However, there are many limitations within this new paradigm shift in neuropsychiatry. Impediments that could block translation of encouraging experimental studies include environmental forces that work toward dysbiosis, perhaps none more important than westernized dietary patterns. On the other hand, it is likely that specific dietary choices may amplify the value of future microbial-based therapeutics. Pre-clinical and clinical research involving microbiota and allergic disorders has predated recent work in psychiatry, an early start that provides valuable lessons. The microbiome is intimately connected to diet, nutrition, and other lifestyle variables; microbial-based psychopharmacology will need to consider this contextual application, otherwise the ceiling of clinical expectations will likely need to be lowered.

Novel Risk Factors for Allergic Rhinitis in Korean Elementary School Children: ARCO-kids Phase II in a Community

PURPOSE: Allergic rhinitis (AR) is a multifactorial disease whose genetic and environmental risk factors have been studied for decades. Many pediatric studies have pointed out the familial history of allergy, hygiene hypothesis, breast-feeding, pet ownership, and diets as risk factors of AR. However, most of factors are still up for debate. This preliminary report aimed to confirm the known risk factors and find the novel risk factors for AR in the Korean pediatric population. METHODS: A bi-seasonal, winter and summer, study in 2 elementary schools included all students whose parents completed the questionnaire of medical and social histories, quality of life, infant and early-childhood history, and the living styles. Skin prick tests and endoscopic examinations were conducted on all participants. RESULTS: Among total 1,020 children, 338 participants had AR. The multivariate logistic regression analysis highlighted 6 factors: male gender (OR, 2.10; 95% CI, 1.32-3.33), older age (1.65; 1.03-2.65), previous history of allergic conjunctivitis (14.25; 4.99-40.74), asthma (2.73; 0.96-7.76) and pneumonia (0.39; 0.19-0.82), and an hour increase in daily playing time (0.90; 0.80-1.00). CONCLUSIONS: Lack of pneumonia in early childhood and short playing time are newly found risk factors for Korean pediatric AR in this study confirming male gender, older age and previous history of allergic conjunctivitis and asthma as the risk factors.

Clinical efficacy and mechanism of probiotics in allergic diseases / 소아과

A complex interplay between genetic and environmental factors partially contributes to the development of allergic diseases by affecting development during prenatal and early life. To explain the dramatic increase in the prevalence of allergic diseases, the hygiene hypothesis proposed that early exposure to infection prevented allergic diseases. The hygiene hypothesis has changed to the microbial hypothesis, in which exposure to microbes is closely linked to the development of the early immune system and allergic diseases. The intestinal flora may contribute to allergic disease through its substantial effect on mucosal immunity. Based on findings that exposure to microbial flora early in life can change the Th1/Th2 balance, thus favoring a Th1 cell response, probiotics may be beneficial in preventing allergic diseases. However, evidence from clinical and basic research to prove the efficacy of probiotics in preventing allergy is lacking. To date, studies have yielded inconsistent findings on the usefulness of probiotics in allergic diseases. It is difficult to demonstrate an exact effect of probiotics on asthma, allergic rhinitis, and food allergy because of study limitations, such as different first supplementation period, duration, different strains, short follow-up period, and host factors. However, many studies have demonstrated a significant clinical improvement in atopic dermatitis with the use of probiotics. An accurate understanding of the development of human immunity, intestinal barrier function, intestinal microbiota, and systemic immunity is required to comprehend the effects of probiotics on allergic diseases.

The Influence of IgE on Cultured Human Mast Cells

PURPOSE: The mast cell plays a pivotal role in the human immune response. Crosslinking of 2 IgE molecules bound to the high affinity IgE receptor (FcepsilonRI) on the surface of the mast cell results in mast cell degranulation and the release of several proinflammatory mediators. Patients with type-I allergy have increased levels of IgE in the blood compared to healthy individuals. METHODS: In a 6-week culture system of stem cells to human mast cells we investigated the effect of the concentration of IgE. The mast cells were cultured with different concentrations of IgE for the last 10 days of the maturation period. It was observed how the IgE concentration affects the histamine release, FcepsilonRI density on the mast cell surface and the concentration of other mediators. RESULTS: A clear correlation between IgE concentration in culture medium and the release of histamine upon activation was observed. It showed a bell-shaped dose response curve, with maximal response around an IgE-concentration of 250 ng/mL. Furthermore, the sensitivity of the mast cells and surface density of FcepsilonRI on mast cell surface was also influenced by the IgE concentration in the culture medium. CONCLUSIONS: IgE in the culture medium during the last 10 days of mast cell maturation influences the release of the preformed mediator histamine after mast cell activation and the density of FcepsilonRI on the mast cell surface. The release of the de novo synthetized mediator prostaglandin D2 and the expression of chymase and tryptase are not influenced by IgE in culture medium.

The Influence of IgE on Cultured Human Mast Cells

PURPOSE: The mast cell plays a pivotal role in the human immune response. Crosslinking of 2 IgE molecules bound to the high affinity IgE receptor (FcepsilonRI) on the surface of the mast cell results in mast cell degranulation and the release of several proinflammatory mediators. Patients with type-I allergy have increased levels of IgE in the blood compared to healthy individuals. METHODS: In a 6-week culture system of stem cells to human mast cells we investigated the effect of the concentration of IgE. The mast cells were cultured with different concentrations of IgE for the last 10 days of the maturation period. It was observed how the IgE concentration affects the histamine release, FcepsilonRI density on the mast cell surface and the concentration of other mediators. RESULTS: A clear correlation between IgE concentration in culture medium and the release of histamine upon activation was observed. It showed a bell-shaped dose response curve, with maximal response around an IgE-concentration of 250 ng/mL. Furthermore, the sensitivity of the mast cells and surface density of FcepsilonRI on mast cell surface was also influenced by the IgE concentration in the culture medium. CONCLUSIONS: IgE in the culture medium during the last 10 days of mast cell maturation influences the release of the preformed mediator histamine after mast cell activation and the density of FcepsilonRI on the mast cell surface. The release of the de novo synthetized mediator prostaglandin D2 and the expression of chymase and tryptase are not influenced by IgE in culture medium.

Immune Disorders and Its Correlation with Gut Microbiome

Allergic disorders such as atopic dermatitis and asthma are common hyper-immune disorders in industrialized countries. Along with genetic association, environmental factors and gut microbiota have been suggested as major triggering factors for the development of atopic dermatitis. Numerous studies support the association of hygiene hypothesis in allergic immune disorders that a lack of early childhood exposure to diverse microorganism increases susceptibility to allergic diseases. Among the symbiotic microorganisms (e.g. gut flora or probiotics), probiotics confer health benefits through multiple action mechanisms including modification of immune response in gut associated lymphoid tissue (GALT). Although many human clinical trials and mouse studies demonstrated the beneficial effects of probiotics in diverse immune disorders, this effect is strain specific and needs to apply specific probiotics for specific allergic diseases. Herein, we briefly review the diverse functions and regulation mechanisms of probiotics in diverse disorders.

Is Mode of Delivery Associated with an Increased Risk for Childhood Asthma? / 소아알레르기및호흡기학회지

Under the hygiene hypothesis, children born by cesarean section (CS) may consequently have an increased risk of asthma and other allergic diseases. CS has been shown to have a delayed and altered development in establishment of gut flora and altered cytokine production. Concerns about the relations between CS and the risk of children's asthma are rising due to the growing number of CS performed in many countries. However, finding the concrete evidence to correlate CS with higher risk of asthma is still controversial. There were significant covariate imbalance between groups of children born by CS vs. vaginal delivery that include the number of maternal age, gestational age, birth weight, complication during pregnancy, complication during labor, socioeconomic status, a parental history of atopy, and maternal smoking history. And there were considerable heterogeneity in methods and study subjects between the studies of delivery by CS and the offspring's risk of asthma and other allergic diseases. Therefore, as we proceed into the further study, researchers must refer to the literatures and look for the best way proving their hypothesis that are based on the methodological subject group. Of which should be accordance with the research purposes. Also, researchers have to search for identifying the core biological mechanism in order to know whether there is a causal relationship exists between the CS and asthma.

Update in the Pathogenesis of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a multifactorial disease characterized by abnormal immunologic responses to intestinal antigen, and its causes have not yet been clarified. IBD is known to be due to a complexity of environmental, genetic, and abnormal immunological responses. The hygiene hypothesis remains the key hypothesis for explaining the increase in the incidence of IBD, and smoking is the strongest of the known external environmental factors. Since the detection of the NOD2/CARD15 gene in 2001, rapid progress has occurred, and recently, an important relation between the IL23R gene and IBD has been established. Although studies of normal flora in IBD have some difficulties in methodology, the theory that the loss of immune tolerance to normal flora in the bowel results in IBD is still believed. Incomplete adaptation of innate and adaptive immunity is also one of the important pathogenesis. The toll-like receptor family and the NOD-like receptor family have a important role in the pathologic condition. As to adaptive immunity, in Crohn's disease, the Th1 phenotype is known to be involved, and in ulcerative colitis, the Th2 phenotype cytokines are known to be involved. However, recently, the roles of new cytokines and variable phenotypic lymphocytes have attracted interest. We can clarify the relations of inflammatory pathway-specific and molecular classification of the phenotypes of patients in 10~20 years if progress continues at the same rate as during the last 10 years. We also expected to develop a new therapeutic approach based on these efforts.

The Role of Suppressor T Cells in Mycobacterial Infection / 나학회지

Suppressor T cells (Ts cells) once became probably the most controversial topic in the field of immunology. However, recently the picture has changed dramatically. Suppressor T cells, now less provocatively renamed regulatory T cells (Treg cells) are isolated and can be expanded in vitro and in vivo and their role is the subject of intensive investigation. It is now well recognized that Treg cell is central components of fundamental immune functions such as self-tolerance, anti-tumor response, T cell homeostasis, allergic and autoimmune diseases, allograft transplantation and control of infection. Although regulatory T cells play a crucial role in the control of immune responses to bacteria, fungus, virus and parasites, little is known about the role of Treg cells in mycobacterial infections. Here, I briefly describe 1)the biology of Treg cells, 2)induction and expansion of pathogen-specific Treg cells, 3)beneficial and detrimental roles of Treg cells in infection and 4)"Old Friends" mechanism of hygiene hypothesis. This article also explores observations on Treg or Ts cells in mycobacterial infectious diseases such as leprosy and tuberculosis. I finally summarize the potential for Treg-targeted immunotherapy in infectious diseases allergic and autoimmune diseases as well as transplantation and anti-tumor immunity. The correct balance of effector/pathogenic and regulatory T cells for successful immunotherapeutic approach is also emphasized.

Epidemiology of childhood asthma in Asia / 천식및알레르기

Asthma is the most common chronic disease in childhood. Over the past 30 years, prevalence of childhood asthma has increased several folds throughout the world. In Asia, such increase has been observed in series of studies from South Korea, Taiwan, Thailand and Singapore as had been observed in industrialized countries. Available epidemiologic studies in Asia indicated that allergen exposure is the major risk factor for the development of childhood asthma. House dust mites and cockroaches are the major allergens sensitized by asthmatic children in Asia. Despite increasing evidence to support the popular 'Hygiene Hypothesis' in explaining the increase of allergic diseases in Europe and USA, results from limited studies in Asia are quite controversial. It is established that prevalence of childhood asthma is low among those residing in mainland China as compared to those living in Hong Kong. Nevertheless, recent studies on BCG vaccination from Hong Kong and Thailand did not indicate any difference in prevalence of allergic disease between children with/without significant tuberculin reactions. Limited information on smoking and breastfeeding exists from the region. A study from Japan indicated that breastfeeding was found not to exert a protective effect for the development of childhood asthma. In environment with multiple ethnicities such as in Asia, there is a great opportunity for a collaborative research on epidemiology of childhood asthma. The success of which will bring about further understanding on pathogenesis of asthma and on the increasing prevalence of allergic diseases in this region.

Relationship between total IgE and Epstein Barr virus infection during infancy and early childhood / 천식및알레르기

BACKGROUND: The 'hygiene hypothesis', the apparent inverse relationship between certain childhood infections and the subsequent development of asthma and atopy, has been gaining attention and is currently now considered one of the most plausible explanations for the cause of asthma and atopy currently. OBJECTIVE: We tried to evaluate the relationship between Epstein Barr virus infection in infancy and early childhood with total IgE, the hallmark of atopy. with these results, we observed the changing pattern of total IgE levels according to the ages that EBV infection occured. METHODS: The study population, a total of 75 patients were divided by age: under 2 years of age, under 3 years of age, under 4 years of age and then they were divided into the two groups : EBNA negative and EBNA positive groups. EBNA and IgE were measured by ELISA and CLA respectively. We analyzed the relationships between age, sex, family history, atopic predisposition, total eosinophils, log IgE, and positivity of EBNA stastically. RESULTS: Prevalence of EBNA positivity was 26% in children 1-3 years of age. Among the six variables, log IgE showed statistically significant difference in the two groups under 2 years of age and under 3 years of age. In the group of under 2 years of age, mean log IgE in EBNA positive group was 0.7 IU/mL and EBNA negative group was 1.3 IU/mL, these differences were significant statistically (p<0.05). In the group of under 3 years of age , mean log IgE in EBNA positive group was 0.8 IU/mL and EBNA negative group was 1.5 IU/mL, these differences were statistically significant(p<0.05). CONCLUSION: This study showed that Ebstein Barr virus infection before 3 years of age is associated with lower log IgE. This means that there is a possibility of a negative influence in the prevalence of allergic disease by EBV infection in children before 3 years of age.