PolygenicBlog: lupus

Showing posts with label lupus. Show all posts

Commensal Microbes May Initiate and Drive Immune Responses in Lupus | Taconic Biosciences

At the end of March, researchers at Yale University published a paper entitled "Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus"
in the journal Science Translational Medicine in which the authors
demonstrated that Ro60 orthologs exist in commensal bacteria commonly
found in or on the human body.

Greiling et al. demonstrated in human and mouse studies that
these bacterial orthologs of Ro may generate autoimmune responses that
drive lupus. The authors revealed that a high level of homology exists
between the major T and B cell epitopes within human Ro60 (hRo60) and
commensal Ro60 orthologs. Antibodies from anti-Ro60 positive lupus
patients, but not negative control patients preferentially
coimmunoprecipitated Ro60 ribonucleoproteins (RNPs) from a Ro60
ortholog-containing commensal organism. Further demonstrating the
cross-reactivity of orthologous Ro60, hRo60-reactive T cell clones, and
freshly isolated anti-Ro60-positive memory T cells responded to epitopes
derived from commensal Ro60 in vitro.

Could lupus raise dementia risk?

The researchers identified 4,886 individuals who had received a
diagnosis of systemic lupus erythematosus , and these were matched by age and sex in a 1:5 ratio
to 24,430 people without the condition (the controls). The incidence of
dementia was assessed for each group.
The study revealed that people with SLE were 51 percent more
likely to develop dementia than people without SLE, and this association
persisted across all age groups.
Based on their results, the researchers conclude that "systemic lupus erythematosus is significantly associated with dementia."

Microbiome Seems to Have a Role in Triggering Lupus

"Systemic lupus erythematosus (SLE) is caused by a combination of genetic and environmental factors. A team of researchers from New York City believes that clinical SLE disease is associated with microbiome imbalances, specifically with decreases in the diversity and blooms of specific operational taxonomic units in the the intestine.

In an abstract presented at the 2015 American College of Rheumatology Annual Meeting in San Francisco, CA, Greg Silverman, MD, and colleagues at the NYU School of Medicine noted that animal models in other studies of inflammatory and autoimmune disease have shown intestinal bacteria play a role in the development of these tissues. They looked at a group of 67 SLE adult patients and 16 healthy controls, analyzing bacteria in fecal samples. They found the patients with SLE had microbiota that were less diverse. SLE patients displayed a significant increase in Proteobacteria and a decrease in Firmicutes. Also, the SLE patients had increased representation of specific operational taxonomic units. "Interestingly the anaerobic species Prevotella copri, recently linked to new-onset RA, was expanded in a subset of SLE patients but not in healthy controls," they noted.

'via Blog this'

DNA methylation of human endogenous retrovirus in systemic lupus erythematosus : Journal of Human Genetics

Previous studies have reported that T cells from active systemic lupus erythematosus (SLE) patients contained global hypomethylation and demethylation at the promoter of several genes, which may contribute to the pathogenesis of the disease. Currently there are scarce data on methylation of retroelements in patients with SLE. We estimated and compared the methylated levels of human endogenous retroviruses (HERV)-E and HERV-K in normal and SLE CD3+CD4+ T lymphocytes, CD8+ T and B lymphocytes by using combined bisulfite restriction analysis-interspersed repetitive sequences (COBRA-IRS). HERV-E LTR2C methylation level in CD3+CD4+ T lymphocytes of active SLE was significantly lower than inactive SLE and normal controls (P=0.023 and 0.035, respectively). Surprisingly, HERV-K LTR5_Hs hypomethylation was significantly detected in CD3+CD4+ T lymphocytes from patients with inactive SLE when compared with the active SLE and normal controls (P=0.027 and 0.002, respectively). Demethylation of HERV-K LTR5_Hs in B cells was also detected when compared with the normal controls (P=0.048). Furthermore, the hypomethylation of HERV-E LTR2C in CD3+CD4+ T lymphocytes was positively correlated with lymphopenia in active SLE, whereas the hypomethylation of HERV-K LTR5_Hs was significantly correlated with complement activity and Systemic Lupus Erythematosus Disease Activity Index score. In summary, for each lymphocyte subset in patients with SLE, IRS hypomethylation was found to be type specific. Further studies are needed to confirm and explain these observations.

(Thanks Daniel)

JCI - Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus

Autoantibodies against cytokines, chemokines, and growth factors inhibit normal immunity and are implicated in inflammatory autoimmune disease and diseases of immune deficiency. In an effort to evaluate serum from autoimmune and immunodeficient patients for Abs against cytokines, chemokines, and growth factors in a high-throughput and unbiased manner, we constructed a multiplex protein microarray for detection of serum factor–binding Abs and used the microarray to detect autoantibody targets in SLE. We designed a nitrocellulose-surface microarray containing human cytokines, chemokines, and other circulating proteins and demonstrated that the array permitted specific detection of serum factor–binding probes. We used the arrays to detect previously described autoantibodies against cytokines in samples from individuals with autoimmune polyendocrine syndrome type 1 and chronic mycobacterial infection. Serum profiling from individuals with SLE revealed that among several targets, elevated IgG autoantibody reactivity to B cell–activating factor (BAFF) was associated with SLE compared with control samples. BAFF reactivity correlated with the severity of disease-associated features, including IFN-α–driven SLE pathology. Our results showed that serum factor protein microarrays facilitate detection of autoantibody reactivity to serum factors in human samples and that BAFF-reactive autoantibodies may be associated with an elevated inflammatory disease state within the spectrum of SLE.

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.

A New Target for Lupus Treatment: Scripps

A team at The Scripps Research Institute (TSRI) has made a discovery that may lead to better treatments for lupus, a debilitating autoimmune disease that affects tens of millions of people all over the world.
Therapies for lupus do exist, but they do not directly target its underlying causes, primarily because the origins of the condition are not entirely known. The condition appears to arise from both genetic and environmental factors and involves complex autoimmune processes. A key feature of the disease is the activity of antibodies – also known as "autoantibodies" – that attack the patient's own cellular proteins, including DNA and RNA. "In this new study, TSRI researchers determined that the absence of a certain type of immune cell – or a key signaling molecule within the cell ( SLC15A4 )– could protect against lupus. In a mouse model of the disease, patients without the cell or signaling molecule showed little impairment of their normal immune functions.

Scientists Find A Key Element Of Lupus, Suggesting Better Drug Targets

MNT: Beutler's special mice lack a working gene for a protein called SLC15A4, and as a result of this mutation, the pDCs in these mice develop normally, but are largely unable to produce type I interferons in response to the usual stimuli. Such cells normally produce large amounts of interferons after detecting viral or bacterial genetic material. For this detection, they use a class of internal receptors called TLRs (toll-like receptors). Beutler received the 2011 Nobel Prize in Physiology or Medicine for his work on TLRs. His SLC15A4-mutant mice specifically lack the ability to respond to stimuli that would normally be detected by two of these receptors, TLR7 and TLR9. These same TLRs have been implicated in lupus - they apparently mistake self-nucleic acids for viral nucleic acids.

Working with Beutler, the TSRI team applied the SLC15A4 mutation to a strain of lupus mice to see if it would protect them from autoimmunity. And it did. "The usual lupus-like signs significantly decreased, and survival was extended," said Baccala.

Lupus: Peptide P140/LupuzorTM effectiveness confirmed

A clinical trial with 149 patients suffering from the very disabling autoimmune disease systemic lupus erythematosus, has shown the effectiveness of a synthetic peptide developed by a team of researchers led by CNRS biologist Slyviane Muller at the Institut de Biologie Moleculaire (IBMC) in Strasbourg, France."

'via Blog this'

Uranium exposure linked to high lupus rates in community living near a former refinery

ScienceDaily (Nov. 10, 2012) — High rates of systemic lupus erythematosus have been linked to living in proximity to a former uranium ore processing facility in Ohio, according to new research findings presented this week at the American College of Rheumatology Annual Meeting in Washington, D.C.

IgGs containing λ- and κ-type light chains and of all subclasses (IgG1-IgG4) from the sera of patients with autoimmune diseases and viral and bacterial infections hydrolyze DNA.

We present the first evidence demonstrating that small fractions of IgGs of all four subclasses (IgG1-IgG4) from patients with viral (tick-borne encephalitis), bacterial infections (streptococcal infection or erysipelas), and suppurative surgical infections caused by epidermal staphylococci as well as from patients with autoimmune diseases (systemic lupus erythematosus and multiple sclerosis) are catalytically active in the hydrolysis of supercoiled DNA. The hydrolysis of DNA was analyzed by agarose gel electrophoresis. The catalytic activities of nonfractionated IgGs increased in the following order: tick-borne encephalitis < suppurative surgical infection < streptococcal infection < multiple sclerosis < systemic lupus erythematosus, whereas IgGs of healthy donors were inactive. However, the pools of antibodies corresponding to any particular disease were characterized by a specific ratio of IgGs of all four subclasses (IgG1-IgG4) and IgGs containing λ- and κ-type light chains, and each of these subfractions of immunoglobulins demonstrated characteristic relative DNase activity. The relative activities of IgGs containing λ-type light chains may on average be higher, lower, or comparable with those for IgGs with κ-type light chains. The relative contributions of IgGs of different subclasses to the total activity of IgGs also varied widely in the case of various diseases: IgG1 (7%-45%), IgG2 (0.4%-73%), IgG3 (0%-12%), and IgG4 (9%-66%). Thus, immune systems of patients with different diseases can generate a variety of anti-DNA abzymes of different types and with different catalytic properties, which can play an important role in the pathogenesis or protection from the development of these diseases.

Helicobacter pylori serology in autoimmune diseases - fact or fiction?

The pathogenesis of autoimmunity is presumed to be a complex process including genetic predisposition, hormonal balance and environmental factors such as infectious agents. Helicobacter pylori, a common bacterial infectious agent has been associated with a variety of autoimmune disorders. However, this bacteria is also thought to play a protective role in the development of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD). We tested various links between anti-H. pylori (anti-HP) antibodies and a wide profile of autoimmune diseases and autoantibodies. Methods: A total of 1290 patients diagnosed with 14 different autoimmune diseases from two geographical areas (Europe and Latin America) and two groups of healthy matching controls (n=385) were screened for the presence of H. pylori IgG antibodies by "pylori detect" kit. In parallel, a large profile belonging to three groups of autoantibodies was tested in all sera (anti-nuclear antibodies, autoantibodies associated with thrombophilia and gastrointestinal diseases). Results: Our data demonstrate associations between anti-HP antibodies and anti-phospholipid syndrome, giant cell arteritis, systemic sclerosis and primary biliary cirrhosis. Our data also support a previously known negative association between the prevalence of anti-HP antibodies and IBD. Additionally, links were made between seropositivity to H. pylori and the presence of anti-nuclear antibodies, dsDNA, anti-Ro and some thrombophilia-associated antibodies, as well as negative associations with gastrointestinal-associated antibodies. Conclusions: Whether these links are epiphenomenal or H. pylori does play a causative role in the autoimmune diseases remains uncertain. The negative associations could possibly support the notion that in susceptible individuals infections may protect from the development of autoimmune diseases.

Vitamin D supplements may benefit lupus patients

A new clinical study published in BioMedCentral's open access journal Arthritis Research and Therapy provides preliminary evidence that vitamin D supplementation could be considered an immunomodulatory agent for systemic lupus erythematosus (SLE), a debilitating autoimmune disease characterized not only by skin, joint, neurological and renal symptoms, but also by inflammation of tissue linings in the body.

Chronic exposure to staph bacteria may be risk factor for lupus, study finds

Chronic exposure to even small amounts of staph bacteria could be a risk factor for the chronic inflammatory disease lupus, Mayo Clinic research shows. Staph, short for Staphylococcus aureus, is a germ commonly found on the skin or in the nose, sometimes causing infections. In the Mayo study, mice were exposed to low doses of a protein found in staph and developed a lupus-like disease, with kidney disease and autoantibodies like those found in the blood of lupus patients.

Virus protects against lupus

To the surprise of investigating researchers, an animal model of Epstein Barr virus protected lupus-prone mice against development of the autoimmune disease. Earlier work had suggested that EBV might promote the development of autoimmunity.

A genetic accelerator hits the gas on autoimmune diseases

A "genetic accelerator" is responsible for the most severe cases of Lupus (systemic lupus erythemathosus), an autoimmune disease: the accelerator, called enhancer HS1.2, (within an immunoglobulin gene) speeds up the activity of some critical genes of the immune system involved in the disease.

A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap

Systemic Lupus Erythematosus

Related articles

PolygenicBlog