Pathogenic mechanism for Blastocystis sp.: A review.

IgG4 autoimmune diseases are characterized by the presence of antigen-specific autoantibodies of the IgG4 subclass and contain well-characterized diseases such as muscle-specific kinase myasthenia gravis, pemphigus, and thrombotic thrombocytopenic purpura. In recent years, several new diseases were identified, and by now 14 antigens targeted by IgG4 autoantibodies have been described. The IgG4 subclass is considered immunologically inert and functionally monovalent due to structural differences compared to other IgG subclasses. IgG4 usually arises after chronic exposure to antigen and competes with other antibody species, thus “blocking” their pathogenic effector mechanisms. Accordingly, in the context of IgG4 autoimmunity, the pathogenicity of IgG4 is associated with blocking of enzymatic activity or protein–protein interactions of the target antigen. Pathogenicity of IgG4 autoantibodies has not yet been systematically analyzed in IgG4 autoimmune diseases. Here, we establish a modified classification system based on Witebsky’s postulates to determine IgG4 pathogenicity in IgG4 autoimmune diseases, review characteristics and pathogenic mechanisms of IgG4 in these disorders, and also investigate the contribution of other antibody entities to pathophysiology by additional mechanisms. As a result, three classes of IgG4 autoimmune diseases emerge: class I where IgG4 pathogenicity is validated by the use of subclass-specific autoantibodies in animal models and/or in vitro models of pathogenicity; class II where IgG4 pathogenicity is highly suspected but lack validation by the use of subclass specific antibodies in in vitro models of pathogenicity or animal models; and class III with insufficient data or a pathogenic mechanism associated with multivalent antigen binding. Five out of the 14 IgG4 antigens were validated as class I, five as class II, and four as class III. Antibodies of other IgG subclasses or immunoglobulin classes were present in several diseases and could contribute additional pathogenic mechanisms.

Permeability barrier disruption has been shown to induce immunological alterations (i.e., an "outside-to-inside" pathogenic mechanism). Conversely, several inflammatory and immunological mechanisms reportedly interrupt permeability barrier homeostasis (i.e., an "inside-to-outside" pathogenic mechanism). It is now widely recognized that alterations of even a single molecule in keratinocytes can lead to not only permeability barrier dysfunction but also to immunological alterations. Such a simultaneous, bidirectional functional change by keratinocytes is herein named an "intrinsic" pathogenic mechanism. Molecules and/or pathways involved in this mechanism could be important not only as factors in disease pathogenesis but also as potential therapeutic targets for inflammatory cutaneous diseases, such as atopic dermatitis, psoriasis, and prurigo nodularis. Elevation of skin surface pH following permeability barrier abrogation comprises one of the key pathogenic phenomena of the "outside-to-inside" mechanism. Not only type 2 cytokines (e.g., IL-4, IL-13, IL-31) but also type 1 (e.g. IFN-γ), and type 3 (e.g., IL-17, IL-22) as well as several other inflammatory factors (e.g. histamine) can disrupt permeability barrier homeostasis and are all considered part of the "inside-to-outside" mechanism. Finally, examples of molecules relevant to the "intrinsic" pathogenic mechanism include keratin 1, filaggrin, and peroxisome proliferator-activated receptor-α (PPARα).

Periodontitis is a chronic infectious inflammatory disease primarily caused by periodontal pathogenic bacteria, which poses a significant threat to human health. The pathogenic mechanisms associated with Porphyromonas gingivalis (P. gingivalis), a principal causative agent of periodontitis, are particularly complex and warrant thorough investigation. The extensive array of virulence factors released by this bacterium during its growth and pathogenesis not only inflicts localized damage to periodontal tissues but is also intricately linked to the development of systemic diseases through various mechanisms. The outer membrane vesicles (OMVs) produced by P. gingivalis play a key role in this process. These OMVs serve as important mediators of communication between bacteria and host cells and other bacteria, carrying and delivering virulence factors to host cells and distant tissues, thereby damaging host cells and exacerbating inflammatory responses. The ability of these OMVs to disseminate and deliver bacterial virulence factors allows P. gingivalis to play a pathogenic role far beyond the confines of the periodontal tissue and has been closely associated with the development of a variety of systemic diseases such as cardiovascular disease, Alzheimer's disease, rheumatoid arthritis, diabetes mellitus, non-alcoholic hepatitis, and cancer. In view of this, it is of great pathophysiological and clinical significance to deeply investigate its pathogenic role and related mechanisms. This will not only help to better understand the pathogenesis of periodontitis and its related systemic diseases but also provide new ideas and more effective and precise strategies for the early diagnosis, prevention, and treatment of these diseases. However, the current research in this field is still insufficient and in-depth, and many key issues and mechanisms need to be further elucidated. This article summarizes the recent research progress on the role of P. gingivalis OMVs (P. g-OMVs) in related diseases, with the aim of providing a theoretical basis and direction for future research and revealing the pathogenic mechanism of P. g-OMVs more comprehensively.

Mycoplasmas are unique prokaryotic pathogens distinguished by their lack of a cell wall. These microorganisms are widespread in nature and can cause severe infections, leading to substantial tissue damage. Recent advances in mycoplasmology, driven by developments in molecular biology and proteomics, have provided novel insights into their pathogenicity and pathogenic mechanisms. However, critical knowledge gaps remain in understanding their biology. Emerging evidence highlights the crucial role of protein post-translational modifications (PTMs) in regulating mycoplasma physiology, including virulence, metabolic adaptation, and persistence. Investigating mycoplasma PTMs in greater depth promises to expand our understanding of their pathogenic strategies and may reveal new targets for therapeutic intervention against mycoplasma-associated diseases.

Bacillus paranthracis, a species of the genus Bacillus, is a Gram-positive bacterium classified as an opportunistic pathogen that can cause foodborne diarrhea and other intestinal diseases in humans and various animals. To date, there has been limited research on B. paranthracis, and there are few records of this bacterium being isolated from animal intestines. In this study, a strain named Qf-1 was isolated and purified from faecal samples of mink. Through culturomics, 16S rRNA gene sequencing, whole-genome sequencing, and average nucleotide identity (ANI) analysis, the strain was confirmed to be B. paranthracis. Whole-genome sequencing revealed that the strain has a genome size of 5.27 Mb, comprising one chromosome (5,224,739 bp) and one plasmid (51,964 bp). Functional annotation of its genome identified multiple potential pathogenic factors associated with pneumonia, including the key genes AsbD and AsbF, which facilitate bacterial colonisation of the lungs and trigger inflammatory responses, as well as EsxB and EsxL, which exacerbate lung inflammation and promote infection spread. Comparative genomics analysis revealed that this strain shares a close evolutionary relationship with previously reported B. paranthracis strains. The structure and function of the bacterial genes were analyzed in depth using multi-omics methods. Through mouse pathogenicity experiments, it was found that this bacterium may cause pneumonia and enteritis in mice. We predict that it may also pose a threat to the health of the mink. These research findings contribute to the establishment of a stable experimental model between pathogens and mink hosts, laying the foundation for further elucidating their pathogenicity and pathogenic mechanisms. This is of great significance for the diagnosis and prevention of bacterial diseases in mink in the future.

Congenital heart defects (CHD) affect 50% of Down's syndrome (DS) cases. This review focusses on the pathogenic molecular mechanism leading to the formation of DS-associated CHD along with the advancement of the emerging diagnostic techniques available for such patients in past few decades. We have shed light on the causative genes of DS-associated CHD that are located either on chromosome 21 or outside chromosome 21. Along with locus-specific mutation, numerous SNP and CNV, miRNA, use of maternal folic acid during pregnancy and signalling pathways are also reported to contribute to the formation of CHD in patients with DS. With the help of both these our understanding of pathogenic mechanism causing CHD in DS cases along with the availability of emerging technologies has facilitated a novel discovery that has ultimately provided a better treatment and management for such cases. Accurate diagnosis and treatment are now available with the introduction of CNV detection and NGS based approaches such as WES, WGS, target sequencing and sequencing of foetal cell-free DNA by the medical geneticist and cardiologist have now allowed further identification of familial recurrence risk and relatives who are at risk through genetic counselling, thereby providing reproductive options and improving proper care of DS-associated CHD. Further, gene-editing studies explore novel pathogenic mechanisms and signalling pathways in DS-associated CHD.

Tea is one of the most popular beverages consumed across the world and is also considered a major cash crop in countries with a moderately hot and humid climate. Tea is produced from the leaves of woody, perennial, and monoculture crop tea plants. The tea leaves being the source of production the foliar diseases which may be caused by a variety of bacteria, fungi, and other pests have serious impacts on production. The blister blight disease is one such serious foliar tea disease caused by the obligate biotrophic fungus Exobasidium vexans. E. vexans, belonging to the phylum basidiomycete primarily infects the young succulent harvestable tea leaves and results in ~40% yield crop loss. It reportedly alters the critical biochemical characteristics of tea such as catechin, flavonoid, phenol, as well as the aroma in severely affected plants. The disease is managed, so far, by administering high doses of copper-based chemical fungicides. Although alternate approaches such as the use of biocontrol agents, biotic and abiotic elicitors for inducing systemic acquired resistance, and transgenic resistant varieties have been tested, they are far from being adopted worldwide. As the research on blister blight disease is chiefly focussed towards the evaluation of defense responses in tea plants, during infection very little is yet known about the pathogenesis and the factors contributing to the disease. The purpose of this chapter is to explore blister blight disease and to highlight the current challenges involved in understanding the pathogen and pathogenic mechanism that could significantly contribute to better disease management.

Spinocerebellar Ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease characterized by late onset, slowly progressive, mostly pure cerebellar ataxia. It is one of three allelic disorders associated to CACNA1A gene, coding for the Alpha1 A subunit of P/Q type calcium channel Cav2.1 expressed in the brain, particularly in the cerebellum. The other two disorders are Episodic Ataxia type 2 (EA2), and Familial Hemiplegic Migraine type 1 (FHM1). These disorders show distinct phenotypes that often overlap but have different pathogenic mechanisms. EA2 and FHM1 are due to mutations causing, respectively, a loss and a gain of channel function. SCA6, instead, is associated with short expansions of a polyglutamine stretch located in the cytoplasmic C-terminal tail of the protein. This domain has a relevant role in channel regulation, as well as in transcription regulation of other neuronal genes; thus the SCA6 CAG repeat expansion results in complex pathogenic molecular mechanisms reflecting the complex Cav2.1 C-terminus activity. We will provide a short review for an update on the SCA6 molecular mechanism.

Multiple sclerosis (MS) is a chronic disabling disease characterized by inflammation, demyelination, and axonal damage in the central nervous system (CNS), affecting both white and grey matter. Commonly observed symptoms are visual and balance disturbances, spasticity, bladder dysfunction, pain, and fatigue. At a later disease stage, paralysis may occur (Compston& Coles 2008; Sospedra& Martin 2005). For both exploratory and applied research into MS the use of a valid animal model is indispensable. The most widely used animal model for MS is experimental autoimmune encephalomyelitis (EAE), which is induced by active immunization with myelin derivatives formulated in adjuvant. EAE has been induced in a wide variety of species, including rabbits, guinea pigs, rats, mice, and non-human primates (Brok et al 2000; Genain et al 1995; Gold et al 2006; Massacesi et al 1995; Wekerle 2006). The EAE model in the common marmoset (Callithrix jacchus), a small-sized New World monkey, is exquisitely suitable for translational research into pathogenic mechanisms and therapy development for MS. A feature that distinguishes the model from classical rodent EAE models is that marmosets are exposed to the same environmental cues as humans, including those associated with MS susceptibility, i.e. viral pathogens. In this chapter, we will summarize our investigations into the core pathogenic autoimmune mechanisms underlying the development of pathology and clinical symptoms. In addition, we will discuss the separate and combined role of B cells and T cells, in this model. Finally, we will briefly discuss how the model can be used for testing new therapies.

Background:Primary Sjögren’s Syndrome (pSS) shares with SLE and RA a variety of features including their predominance in women, immunological characteristics and genetic risk background. For these reasons, to dissect the...

The dose-response relationships of scrapie strain 263K-infected hamster brain and spleen homogenates were compared to determine if intracerebral end-point titrations of infectivity in these homogenates were measures of the same pathogenic phenomenon. Analysis of the dose-response curves indicated that the average increase in incubation period per 10-fold dilution (i.e., the dilution kinetics) of brain infectivity was significantly different from that of spleen infectivity. This difference contradicted the assumption that the same pathogen or pathogenic mechanisms were responsible for producing disease in each titration. Therefore, the end-point titrations and infectivity titers of the brain and spleen homogenates were measures of two different phenomena. Subsequent passage of a scrapie-infected spleen homogenate demonstrated that the dose-response relationship of scrapie infectivity in this agent-host system was dependent on the organ titrated, not the tissue source or inoculation route of previous passage.

Patients with chronic mucocutaneous candidiasis (CMC) suffer persistent infections with the yeast Candida. CMC includes patients with autoimmune regulator (AIRE) gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, and dendritic cells (DCs), as central orchestrators, may underlie pathogenic disease mechanisms. In 29 patients with CMC (13 with APECED) and controls, we generated monocyte-derived DCs, stimulated them with Candida albicans, Toll-like receptor-2/6 ligand and lipopolysaccharide to assess cytokine production [interleukin (IL)-12p70, IL-23, interferon (IFN)-gamma, IL-2, tumour necrosis factor (TNF)-alpha, IL-6, transforming growth factor-beta, IL-10, IL-5, IL-13] and cell-surface maturation marker expression (CD83, CD86, human leucocyte antigen D-related). In both APECED and non-APECED CMC patients, we demonstrate impairment of DC function as evidenced by altered cytokine expression profiles and DC maturation/activation: (1) both groups over-produce IL-2, IFN-gamma, TNF-alpha and IL-13 and demonstrate impaired DC maturation. (2) Only non-APECED patients showed markedly decreased Candida-stimulated production of IL-23 and markedly increased production of IL-6, suggesting impairment of the IL-6/IL-23/T helper type 17 axis. (3) In contrast, only APECED patients showed DC hyperactivation, which may underlie altered T cell responsiveness, autoimmunity and impaired response to Candida. We demonstrate different pathogenic mechanisms on the same immune response pathway underlying increased susceptibility to Candida infection in these patients.

Diarrhea and constipation are common health concerns during childhood, with an estimated prevalence of 3% to 9% worldwide. Although numerous studies have identified strong association between gut microbiota and digestive-related diseases in children, little is known about the gut microbiota that simultaneously affects both diarrhea and constipation or their potential regulatory mechanisms. Here, we conducted a cohort study on 618 individuals (66 with diarrhea and 138 with constipation) via 16S rRNA sequencing of stool. Compared with healthy individuals, the significant reduction (n = 66, Chao1, ACE, p < 0.05) in the microbial diversity was observed in children with diarrhea, while a marked increase was observed in those with constipation (n = 138, Chao1, ACE, Shannon, and Simpson, p < 0.05). Importantly, we firstly determined a reversed effect from Clostridium and Ruminococcus illustrating significant synergistic changes [Clostridium levels decreased in the constipation group (p < 0.001) and increased in the diarrhea group (p = 0.005), while Ruminococcus levels increased in the constipation group (p = 0.033) and decreased in the diarrhea group (p = 0.006)] in the disease phenotypes compared with healthy control. Pathway analysis revealed significant correlation between the membrane transport and endocrine system pathways and the levels of both Clostridium and Ruminococcus, suggesting a potential shared regulatory mechanism in the pathogenesis of both diseases. In summary, this study reveals, for the first time, two core microbiota that might affect the steady intestinal balance in children, which provides important references for the potential diagnosis and treatment of constipation and diarrhea. IMPORTANCE Previous studies have explored the composition and structure of the gut microbiota in different disease states, but there has been little investigation on the potential pathogenic regulatory mechanisms and key microbial biomarkers for clinically similar or dissimilar diseases. This study compared the gut microbiota between children with diarrhea and healthy controls, as well as between children with constipation and healthy controls. We found that the impact of diarrhea and constipation on the gut diversity differed and that Clostridium and Ruminococcus were significantly associated with both diseases, suggesting their potential diagnostic value. Moreover, we identified two metabolic pathways, membrane transport and the endocrine system that were strongly correlated with both diseases indicating possible pathogenic mechanisms. These results provide a theoretical basis for the diagnosis and pathogenic mechanisms of childhood diarrhea and constipation.

BackgroundAmyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease with fast progression. ALS has heavy genetic components in which a series of genetic mutations have been identified. In 2013, Mutations of the CREST gene (also known as SS18L1), which functions as a calcium-regulated transcriptional activator, were found in sporadic ALS patients. However, the pathogenic causality and mechanisms of ALS-associated mutations of CREST remain to be determined.MethodsIn this study, we constructed CREST knockout and Q394X knock-in mice with CRISPR/Cas9 system. Using biochemical and imaging tools, we illustrated core pathological phenotypes in CREST mutant mice and claimed the possible pathogenic mechanisms. Furthermore, we also observed locomotion defects in CREST mutant mice with behavioural tests.ResultsWe demonstrate that ALS-related CREST-Q388X mutation exhibits loss-of-function effects. Importantly, the microglial activation was prevalent in CREST haploinsufficiency mice and Q394X mice mimicking the human CREST Q388X mutation. Furthermore, we showed that both CREST haploinsufficiency and Q394X mice displayed deficits in motor coordination. Finally, we identified the critical role of CREST-BRG1 complex in repressing the expression of immune-related cytokines including Ccl2 and Cxcl10 in neurons, via histone deacetylation, providing the molecular mechanisms underlying inflammatory responses within mice lack of CREST.ConclusionOur findings indicate that elevated inflammatory responses in a subset of ALS may be caused by neuron-derived factors, suggesting potential therapeutic methods through inflammation pathways.

Sudden infant death syndrome (SIDS) is described as the sudden and unexplained death of an apparently healthy infant younger than one year of age. Genetic studies indicate that up to 35% of SIDS cases might be explained by familial or genetic diseases such as cardiomyopathies, ion channelopathies or metabolic disorders that remained undetected during conventional forensic autopsy procedures. Post-mortem genetic testing by using massive parallel sequencing (MPS) approaches represents an efficient and rapid tool to further investigate unexplained death cases and might help to elucidate pathogenic genetic variants and mechanisms in cases without a conclusive cause of death. In this study, we performed whole-exome sequencing (WES) in 161 European SIDS infants with focus on 192 genes associated with cardiovascular and metabolic diseases. Potentially causative variants were detected in 20% of the SIDS cases. The majority of infants had variants with likely functional effects in genes associated with channelopathies (9%), followed by cardiomyopathies (7%) and metabolic diseases (1%). Although lethal arrhythmia represents the most plausible and likely cause of death, the majority of SIDS cases still remains elusive and might be explained by a multifactorial etiology, triggered by a combination of different genetic and environmental risk factors. As WES is not substantially more expensive than a targeted sequencing approach, it represents an unbiased screening of the exome, which could help to investigate different pathogenic mechanisms within the genetically heterogeneous SIDS cohort. Additionally, re-analysis of the datasets provides the basis to identify new candidate genes in sudden infant death.