Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon : Scientific Reports

Food-grade titanium dioxide (TiO2) containing a nanoscale particle fraction (TiO2-NPs) is approved as a white pigment (E171 in Europe) in common foodstuffs, including confectionary. There are growing concerns that daily oral TiO2-NP intake is associated with an increased risk of chronic intestinal inflammation and carcinogenesis. In rats orally exposed for one week to E171 at human relevant levels, titanium was detected in the immune cells of Peyer’s patches (PP) as observed with the TiO2-NP model NM-105. Dendritic cell frequency increased in PP regardless of the TiO2 treatment, while regulatory T cells involved in dampening inflammatory responses decreased with E171 only, an effect still observed after 100 days of treatment. In all TiO2-treated rats, stimulation of immune cells isolated from PP showed a decrease in Thelper (Th)-1 IFN-γ secretion, while splenic Th1/Th17 inflammatory responses sharply increased. E171 or NM-105 for one week did not initiate intestinal inflammation, while a 100-day E171 treatment promoted colon microinflammation and initiated preneoplastic lesions while also fostering the growth of aberrant crypt foci in a chemically induced carcinogenesis model. These data should be considered for risk assessments of the susceptibility to Th17-driven autoimmune diseases and to colorectal cancer in humans exposed to TiO2 from dietary sources.



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PLOS ONE: Gene Expression Profiles from Disease Discordant Twins Suggest Shared Antiviral Pathways and Viral Exposures among Multiple Systemic Autoimmune Diseases

Viral agents are of interest as possible autoimmune triggers due to prior reported associations and widely studied molecular mechanisms of antiviral immune responses in autoimmunity. Here we examined new viral candidates for the initiation and/or promotion of systemic autoimmune diseases (SAID), as well as possible related signaling pathways shared in the pathogenesis of those disorders. RNA isolated from peripheral blood samples from 33 twins discordant for SAID and 33 matched, unrelated healthy controls was analyzed using a custom viral-human gene microarray. Paired comparisons were made among three study groups—probands with SAID, their unaffected twins, and matched, unrelated healthy controls—using statistical and molecular pathway analyses. Probands and unaffected twins differed significantly in the expression of 537 human genes, and 107 of those were associated with viral infections. These 537 differentially expressed human genes participate in overlapping networks of several canonical, biologic pathways relating to antiviral responses and inflammation. Moreover, certain viral genes were expressed at higher levels in probands compared to either unaffected twins or unrelated, healthy controls. Interestingly, viral gene expression levels in unaffected twins appeared intermediate between those of probands and the matched, unrelated healthy controls. Of the viruses with overexpressed viral genes, herpes simplex virus-2 (HSV-2) was the only human viral pathogen identified using four distinct oligonucleotide probes corresponding to three HSV-2 genes associated with different stages of viral infection. Although the effects from immunosuppressive therapy on viral gene expression remain unclear, this exploratory study suggests a new approach to evaluate shared viral agents and antiviral immune responses that may be involved in the development of SAID

Scientists prove link between viral infection (cytomegalovirus) and autoimmune disease

Published in the leading journal Immunity, the Australian
research found that chronic cytomegalovirus (CMV) infection could lead
to the development of Sjogren's (SHOW-grins) syndrome.


CMV - a member of the herpes family - is a common viral infection
that causes mild flu-like symptoms in healthy people but can lead to
more serious illness in those with compromised immune systems.


Between 50 and 80 per cent of people in developed countries are
infected with CMV.  Although normally innocuous, given the right genetic
background, chronic viral infection with CMV can trigger autoimmunity.


"Sjogren's syndrome (SS) is the second most common autoimmune disease
in humans, affecting up to three per cent of the population or more
than four million people in the United States alone," Professor
Degli-Esposti said.

Genetic liability for schizophrenia predicts risk of immune disorders.

BACKGROUND:

Schizophrenia patients and their parents have an
increased risk of immune disorders compared to population controls and
their parents. This may be explained by genetic overlap in the
pathogenesis of both types of disorders. The purpose of this study was
to investigate the genetic overlap between schizophrenia and three
immune disorders and to compare with the overlap between schizophrenia
and two disorders not primarily characterized by immune dysregulation:
bipolar disorder and type 2 diabetes.

METHODS:

We performed a polygenic risk score analysis using results from the
schizophrenia Psychiatric GWAS consortium (PGC) (8922 cases and 9528
controls) and five Wellcome Trust Case Control Consortium (WTCCC) case
samples as target cases: bipolar disorder (n=1998), type 1 diabetes
(n=2000), Crohn's diseases (n=2005), rheumatoid arthritis (n=1999), and
type 2 diabetes (n=1999). The WTCCC British Birth Cohort and National
Blood Service samples (n=3004) were used as target controls.
Additionally, we tested whether schizophrenia polygenic risk scores
significantly differed between patients with immune disorder, bipolar
disorder, and type 2 diabetes respectively.

RESULTS:

Polygenic risk scores for schizophrenia significantly predicted disease status in
all three immune disorder samples (Nagelkerke-R² 1.1%-1.3%;
p<0.05). The polygenic risk of schizophrenia in patients with immune
disorders was significantly lower than in patients with bipolar disorder
(Nagelkerke-R² 6.0%; p<0.05), but higher than in type 2 diabetes patients (Nagelkerke-R² 0.5%; p<0.05).

CONCLUSIONS:

Our results suggest that genetic factors are shared between schizophrenia
and immune disorders. This contributes to an accumulating body of
evidence that immune processes may play a role in the etiology of
schizophrenia.

Scientists discover how to 'switch off' autoimmune diseases

Scientists have made an important breakthrough in the fight against debilitating autoimmune diseases such as multiple sclerosis by revealing how to stop cells attacking healthy body tissue. Rather than the body’s immune system destroying its own tissue by mistake, researchers at the University of Bristol have discovered how cells convert from being aggressive to actually protecting against disease.
Scientists were able to selectively target the cells that cause autoimmune disease by dampening down their aggression against the body’s own tissues while converting them into cells capable of protecting against disease. This type of conversion has been previously applied to allergies, known as ‘allergic desensitisation’, but its application to autoimmune diseases has only been appreciated recently.
The Bristol group has now revealed how the administration of fragments of the proteins that are normally the target for attack leads to correction of the autoimmune response.
Most importantly, their work reveals that effective treatment is achieved by gradually increasing the dose of antigenic fragment injected.



Here's the paper:-

Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy

'Wormy' pills might fend off autoimmune diseases | Futurity

Ancylostoma caninum, a type of hookworm, attached to the intestinal mucosa. Source:CDC's Public Health Image Library Image #5205 (Photo credit: Wikipedia)

Scientists have identified peptides from parasitic hookworms that can
calm the body’s immune response and perhaps pave the way to treat
autoimmune diseases.

Experts believe the peptide molecules could help explain why worm
infections can effectively treat diseases such as multiple sclerosis,
psoriasis, rheumatoid arthritis, and lupus.



 Here's the paper:-

Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases

The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)–related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar–micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7⁻ effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFNγ production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases

Research points way to 'holy grail' therapy for autoimmune diseases

"T cells are controlling cells of the immune response and are designed to attack
cells infected with viruses, bacteria, fungi, parasites and cancer cells,"
said Stephen Benedict, professor of molecular biology, who co-authored
the findings. "Self-reactive T cells are T cells that mistakenly can
attack normal things in our bodies. In the case of Type 1 diabetes, the
target of these cells is the beta cells of the pancreas."
To target only the self-reactive T cells, Benedict and his co-authors
interrupt the second of two signals T cells rely upon before attacking a
cell in the human body.
"Each T cell has a very specific molecule on its surface that guides
the cell to attack a beta cell, for example, or a specific
virus-infected cell and not to attack a normal heart cell or a different
virus, or a cell in the pancreas that is not a beta cell. This is
called the first signal, or signal 1," said Benedict. "But the cells
must receive a second signal to tell the T cell that it is really OK to
attack the target. In this case one of a few different protein molecules
on the T cell surface interact with a counterpart on the surface of the
target cells.
If this signal 2 takes place, the T cell is given permission to attack
the target. If the interaction does not take place, the T cell knows
that it should not attack and either backs away or it inactivates
itself, or it dies."

B-cells aggravate autoimmune diseases

In Germany, approximately 800,000 people suffer from rheumatoid arthritis. In this progressive disease, a person's own immune system attacks and destroys connective tissue. However, the most important factors governing the progress of the disease are still unknown. Now, scientists working with Michael Reth and David Medgyesi from the Max Planck Institute of Immunobiology and Epigenetics have identified a factor that may play a significant role. Using genetic engineering, they deactivated the PTP1B protein (PTPN1 protein tyrosine phosphatase, non-receptor type 1
) in B-cells in the immune systems of mice. The B-cells then became much more responsive to activating signals and, in turn, served to reactivate the other cells.

PTP1B could therefore have a monitoring function in the B-cell-mediated immune response. Until now, B-cells were mainly known for producing antibodies after coming into contact with pathogens. Only recently is more and more accepted by researchers that B-lymphocytes possess important regulatory function in the immune system. The current study now provides a new detail of this mechanism.

American Journal of Psychiatry | A Nationwide Study on the Risk of Autoimmune Diseases in Individuals With a Personal or a Family History of Schizophrenia and Related Psychosis

Objective
Previous research has found an increased risk of schizophrenia
in individuals with autoimmune diseases and smaller but significant
associations with a family history of autoimmune diseases. This study
investigates, for the first time, the association between schizophrenia
and subsequent autoimmune diseases (the reverse temporality) and also
considers the effect of infections, a possible risk factor for both
schizophrenia and autoimmune diseases.

Method
Danish nationwide registers were linked to establish a cohort of
3.83 million people, identifying 39,364 individuals with
schizophrenia-like psychosis and 142,328 individuals with autoimmune
disease. Data were analyzed using survival analysis and adjusted for
calendar year, age, and sex.

Results
Individuals with schizophrenia had an elevated risk of
subsequent autoimmune diseases, with an incidence rate ratio of 1.53
(95% CI=1.46–1.62). Among persons without hospital contacts for
infections, the effect of having schizophrenia was smaller, with an
increased incidence rate ratio of 1.32 (95% CI=1.22–1.43) for autoimmune
diseases. For individuals with schizophrenia as well as hospital
contacts for infections, the combined risk of autoimmune diseases was
2.70 (95% CI=2.51–2.89). A family history of schizophrenia slightly
increased the overall risk of developing autoimmune diseases (incidence
rate ratio=1.06, 95% CI=1.02–1.09). Autoimmune diseases developed
subsequently in 3.6% of people with schizophrenia, and 3.1% of people
with autoimmune diseases had a family history of schizophrenia.

Conclusions
The increased risk of subsequent autoimmune diseases in
individuals with schizophrenia may involve neuropsychiatric
manifestations from the undiagnosed autoimmune disease, medical
treatment or lifestyle associated with schizophrenia, or common
etiological mechanisms, such as infections and shared genetic factors.

Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits

DNA variants (SNPs) that predispose to common traits often localize within noncoding regulatory elements such as enhancers. Moreover, loci identified by genome-wide association studies (GWAS) often contain multiple SNPs in linkage disequilibrium (LD), any of which may be causal. Thus, determining the effect of these multiple variant SNPs on target transcript levels has been a major challenge. Here, we provide evidence that for six common autoimmune disorders (rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, lupus, and ulcerative colitis), the GWAS association arises from multiple polymorphisms in LD that map to clusters of enhancer elements active in the same cell type. This finding suggests a “multiple enhancer variant” hypothesis for common traits, where several variants in LD impact multiple enhancers and cooperatively affect gene expression. Using a novel method to delineate enhancer–gene interactions, we show that multiple enhancer variants within a given locus typically target the same gene. Using available data from HapMap and B lymphoblasts as a model system, we provide evidence at numerous loci that multiple enhancer variants cooperatively contribute to altered expression of their gene targets. The effects on target transcript levels tend to be modest and can be either gain- or loss-of-function. Additionally, the genes associated with multiple enhancer variants encode proteins that are often functionally related and enriched in common pathways. Overall, the multiple enhancer variant hypothesis offers a new paradigm by which noncoding variants can confer susceptibility to common traits.

Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder.

 It is believed that in utero environmental factors contribute to autism spectrum disorder (ASD). The goal of this study was to demonstrate, using the largest cohort reported so far, that mothers of an ASD child have an elevated frequency of anti-brain antibodies and to assess whether brain reactivity is associated with an autoimmune diathesis of the mother. We screened plasma of 2431 mothers of an ASD child from Simon Simplex Collection and plasma of 653 unselected women of child-bearing age for anti-brain antibodies using immunohistology on mouse brain. Positive and negative plasma from mothers with an ASD child were analyzed for anti-nuclear antibodies and for autoimmune disorders. Mothers of an ASD child were four times more likely to harbor anti-brain antibodies than unselected women of child-bearing age (10.5 vs 2.6%). A second cohort from The Autism Genetic Resource Exchange with multiplex families displayed an 8.8% prevalence of anti-brain antibodies in the mothers of these families. Fifty-three percent of these mothers with anti-brain antibodies also exhibited anti-nuclear autoantibodies compared with 13.4% of mothers of an ASD child without anti-brain antibodies and 15% of control women of child-bearing age. The analysis of ASD mothers with brain-reactive antibodies also revealed an increased prevalence of autoimmune diseases, especially rheumatoid arthritis and systemic lupus erythematosus. This study provides robust evidence that brain-reactive antibodies are increased in mothers of an ASD child and may be associated with autoimmunity. The current study serves as a benchmark and justification for studying the potential pathogenicity of these antibodies on the developing brain. The detailed characterization of the specificity of these antibodies will provide practical benefits for the management and prevention of this disorder.

Epidemiologic Evidence Linking Autoimmune Diseases and Psychosis.

 This review summarizes the epidemiologic evidence linking autoimmune diseases and psychosis. The associations between autoimmune diseases and psychosis have been studied for more than a half century, but research has intensified within the last decades, since psychosis has been associated with genetic markers of the immune system and with excess autoreactivity and other immune alterations. A range of psychiatric disorders, including psychosis, have been observed to occur more frequently in some autoimmune diseases, such as systemic lupus erythematosus and multiple sclerosis. Many autoimmune diseases involve multiple organs and general dysfunction of the immune system, which could affect the brain and induce psychiatric symptoms. Most studies have been cross-sectional, observing an increased prevalence of a broad number of autoimmune diseases in people with psychotic disorders. Furthermore, there is some evidence of associations of psychosis with a family history of autoimmune disorders and vice versa. Additionally, several autoimmune diseases, individually and in aggregate, have been identified as raising the risk for psychotic disorders in longitudinal studies. The associations have been suspected to be caused by inflammation or brain-reactive antibodies associated with the autoimmune diseases. However, the associations could also be caused by shared genetic factors or common etiologic components such as infections. Infections can induce the development of autoimmune diseases and autoantibodies, possibly affecting the brain. Autoimmune diseases and brain-reactive antibodies should be considered by clinicians in the treatment of individuals with psychotic symptoms, and even if the association is not causal, treatment would probably still improve quality of life and survival.

Turning to parasites as potential disease fighters

(Medical Xpress)—There is a new weapon in the fight against autoimmune diseases such as Type 1 diabetes, rheumatoid arthritis, Crohn's disease and lupus, the common trait of which is an immune system that attacks its own organs and tissues.William Gause, an immunologist at Rutgers New Jersey Medical School, is among those leading the charge against these diseases by studying how the human body reacts to worms. The worms Gause studies, or helminths , are small parasites that live in human intestines, especially in the developing world.

Dueling infections: Parasitic worms limit the effects of giardia, and vice versa

"If the idea of hookworms makes you shudder, consider this: Those pesky intestinal parasites may actually help your body ward off other infections, and perhaps even prevent autoimmune and other diseases."

Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation: PNAS

Deletion of lyn, a Src-family tyrosine kinase expressed by B, myeloid, and dendritic cells (DCs), triggers lupus-like disease in mice, characterized by autoantibody production and renal immune complex deposition leading to chronic glomerulonephritis. B cells from these mice are hyperactive to antigen-receptor stimulation owing to a loss of inhibitory signaling mediated by Lyn kinase. The hyperactive B-cell responses are thought to underlie the development of autoimmunity in this model. Lyn-deficient mice also manifest significant myeloexpansion. To test the contribution of different immune cell types to the lupus-like disease in this model, we generated a lynflox/flox transgenic mouse strain. To our surprise, when we crossed these mice toCd11c-cre animals, generating DC-specific deletion of Lyn, the animals developed spontaneous B- and T-cell activation and subsequent production of autoantibodies and severe nephritis. Remarkably, the DC-specific Lyn-deficient mice also developed severe tissue inflammatory disease, which was not present in the global lyn−/− strain. Lyn-deficient DCs were hyperactivated and hyperresponsive to Toll-like receptor agonists and IL-1β. To test whether dysregulation of these signaling pathways in DCs contributed to the inflammatory/autoimmune phenotype, we crossed the lynf/f Cd11c-cre+ mice to myd88f/f animals, generating double-mutant mice lacking both Lyn and the adaptor protein myeloid differentiation factor 88 (MyD88) in DCs, specifically. Deletion of MyD88 in DCs alone completely reversed the inflammatory autoimmunity in the DC-specific Lyn-mutant mice. Thus, we demonstrate that hyperactivation of MyD88-dependent signaling in DCs is sufficient to drive pathogenesis of lupus-like disease, illuminating the fact that dysregulation in innate immune cells alone can lead to autoimmunity.

Humans experiencing increased exposure to aluminium and its predicted to get worse

 "Aluminium - the most abundant metal and third most abundant element of the Earth’s crust - has no known biological function and is a recognised environmental toxin. Human exposure to aluminium is implicated in a number of chronic diseases, including bone disease, auto-immune conditions, cancer and neurodegenerative diseases."

Futurity.org – Gut bacteria make some autoimmune diseases skew female

Women are more likely to get a number of autoimmune diseases like lupus. The way gut microbes interact with sex hormones could be why. -

Researcher finds way to convert blood cells into autoimmune disease treatment

 "Chang Kim, a professor of comparative pathobiology, has created a way to direct the differentiation of T-cells, a white blood cell that is a key player in the body's immune system. The method uses naïve T-cells, immature cells from which all T-cells develop, and induces them to become suppressive T-cells that block the development of painful inflammation associated with autoimmune diseases."

Negligible impact of rare autoimmune-locus coding-region variants on missing heritability : Nature : Nature Publishing Group

Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect

Hunger-spiking neurons could help control autoimmune diseases

 "Neurons that control hunger in the central nervous system also regulate immune cell functions, implicating eating behavior as a defense against infections and autoimmune disease development, Yale School of Medicine researchers have found in a new study published in the Proceedings of the National Academy of Sciences (PNAS)."

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