What began as a chat between husband and wife has evolved into an intriguing scientific discovery. The results show a ‘highly significant’ correlation between periodic solar storms and incidences of rheumatoid arthritis (RA) and giant cell arteritis (GCA), two potentially debilitating autoimmune diseases. The findings by a rare collaboration of physicists and medical researchers suggest a relationship between the solar outbursts and the incidence of these diseases that could lead to preventive measures if a causal link can be established.

RA and GCA are autoimmune conditions in which the body mistakenly attacks its own organs and tissues. RA inflames and swells joints and can cause crippling damage if left untreated. In GCA, the autoimmune disease results in inflammation of the wall of arteries, leading to headaches, jaw pain, vision problems and even blindness in severe cases.

Inspiring this study were conversations between Simon Wing, a Johns Hopkins University physicist and first author of the paper, and his wife, Lisa Rider, deputy unit chief of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences in the National Institutes of Health, and a coauthor. Rider spotted data from the Mayo Clinic in Rochester, Minnesota, showing that cases of RA and GCA followed close to 10-year cycles. ‘That got me curious,’ Wing recalled. ‘Only a few things in nature have a periodicity of about 10-11 years and the solar cycle is one of them.’

Wing teamed with physicist Jay Johnson of the U.S. Department of Energy’s Princeton Plasma Physics Laboratory, a long-time collaborator, to investigate further. When the physicists tracked the incidence of RA and GCA cases compiled by Mayo Clinic researchers, the results suggested ‘more than a coincidental connection,’ said Eric Matteson, chair of the division of rheumatology at the Mayo Clinic, and a coauthor. This work drew upon previous space physics research supported by the DOE Office of Science.

The findings found increased incidents of RA and GCA to be in periodic concert with the cycle of magnetic activity of the sun. During the solar cycle, dramatic changes that can affect space weather near Earth take place in the sun. At the solar maximum, for example, an increased number of outbursts called coronal mass ejections hurl millions of tons of magnetic and electrically charged plasma gas against the Earth’s magnetosphere, the magnetic field that surrounds the planet. This contact whips up geomagnetic disturbances that can disrupt cell phone service, damage satellites and knock out power grids. More importantly, during the declining phase of the solar maximum high-speed streams develop in the solar wind that is made up of plasma that flows from the sun. These streams continuously buffet Earth’s magnetosphere, producing enhanced geomagnetic activity at high Earth latitudes.

The research, which tracked correlations of the diseases with both geomagnetic activity and extreme ultraviolet (EUV) solar radiation, focused on cases recorded in Olmsted County, Minnesota, the home of the Mayo Clinic, over more than five decades. The physicists compared the data with indices of EUV radiation for the years 1950 through 2007 and indices of geomagnetic activity from 1966 through 2007. Included were all 207 cases of GCA and all 1,179 cases of RA occurring in Olmsted County during the periods and collected in a long-term study led by Sherine Gabriel, then of the Mayo Clinic and now dean of the Rutgers Robert Wood Johnson Medical School.

Correlations proved to be strongest between the diseases and geomagnetic activity. GCA incidence — defined as the number of new cases per capita per year in the county — regularly peaked within one year of the most intense geomagnetic activity, while RA incidence fell to a minimum within one year of the least intense activity. Correlations with the EUV indices were seen to be less robust and showed a significantly longer response time.

The findings were consistent with previous studies of the geographic distribution of RA cases in the United States. Such research found a greater incidence of the disease in sections of the country that are more likely to be affected by geomagnetic activity. For example, the heaviest incidence lay along geographic latitudes on the East Coast that were below those on the West Coast. This asymmetry may reflect the fact that high geomagnetic latitudes — areas most subject to geomagnetic activity — swing lower on the East Coast than on the opposite side of the country. While Washington, D.C., lies just 1 degree farther north than San Francisco geographically, for example, the U.S. capital is 7 degrees farther north in terms of geomagnetic latitude.

Although the authors make no claim to a causal explanation for their findings, they identify five characteristics of the disease occurrence that are not obviously explained by any of the currently leading hypotheses. These include the east-west asymmetries of the RA and GCA outbreaks and the periodicities of the incidences in concert with the solar cycle. Among the possible causal pathways the authors consider are reduced production of the hormone melatonin, an anti-inflammatory mediator with immune-enhancing effects, and increased formation of free radicals in susceptible individuals. A study of 142 electrical power workers found that excretion of melatonin — a proxy used to estimate production of the hormone — was reduced by 21 percent on days with increased geomagnetic activity.

Confirming a causal link between outbreaks of RA and GCA and geomagnetic activity would be an important step towards developing strategies for mitigating the impact of the activity on susceptible individuals. These strategies could include relocating to lower latitudes and developing methods to counteract direct causal agents that may be controlled by geomagnetic activity. For now, say the authors, their findings warrant further investigations covering longer time periods, additional locations and other autoimmune diseases. Princeton Plasma Physics Laboratory

Scientists at King’s College London have identified a single blood protein that may indicate the development of Mild Cognitive Impairment (MCI) years before symptoms appear, a disorder that has been associated with an increased risk of Alzheimer’s disease or other dementias.

The new research used data from over 100 sets of identical twins from TwinsUK, the biggest adult twin cohort in the UK. The use of twins in the study indicated that the association between the blood protein and a ten year decline in cognitive ability was independent of age and genetics, both of which are already known to affect the risk of developing Alzheimer’s disease, the most common form of dementia.

The study, the largest of its kind, measured over 1,000 proteins in the blood of over 200 healthy individuals, using a laboratory test called a SOMAscan, a protein biomarker discovery tool which allows a high volume of proteins to be measured simultaneously. Using a computerised test, the researchers then assessed each individual’s cognitive ability, and compared the results with the measured level of each protein in the blood.
For the first time, they found that the blood level of a protein called MAPKAPK5 was, on average, lower in individuals whose cognitive ability declined over a ten year period.

There are currently no treatments available proven to prevent Alzheimer’s disease, and prevention trials for Alzheimer’s disease can be problematic because to be effective, they must involve individuals at risk of the disease, who can be hard to identify. Studies using Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) brain scans have been shown to display visible signs of the disease before the onset of symptoms, but these types of scans are both timely and costly.

To date, few other studies have looked at the blood of individuals with very early stages of cognitive decline and therefore most appropriate for a prevention study. Identifying blood markers such as MAPKAPK5, which may indicate a person’s future risk of Alzheimer’s disease, could contribute towards the better design of prevention trials. King’s College London

A genetic mutation responsible for a debilitating childhood neurological condition known as Aicardi syndrome has been identified by the Translational Genomics Research Institute (TGen).

In a study researchers identified mutations to a gene known as TEAD1, which not only affects formation of the brain but also the retina, the part of the eye responsible for helping turn light into nerve impulses.

In addition, the TGen study found that – contrary to previous studies – Aicardi syndrome may also occur in boys, as well as girls.

Within five months of birth, children with Aicardi syndrome experience: spasms or seizures; ice-cream-scoop-like divots in the retina known as chorioretinal lacunae; and a partial or complete absence of a key brain structure called the corpus callosum, which normally connects the two sides, or hemispheres, of the brain.

‘Discovering the first gene mutation associated with Aicardi syndrome is a revolutionary finding with many implications about how children with this disorder might be best identified and treated in the future,’ said Dr. Matt Huentelman, Co-Director of TGen’s Center for Rare Childhood Disorders and the study’s senior author.

To identify genetic factors in the cellular pathways involved in AIC, TGen researchers sequenced the genomes of 10 children with the disorder, as well as their parents. By screening the billions of pieces of genetic information, they discovered a mutation in TEAD1.

‘Discovery of a specific genetic change associated with AIC will help improve diagnosis, provide a better understanding of the disease biology, and lead to better treatment approaches,’ said Dr. Vinodh Narayanan, Medical Director of TGen’s Center for Rare Childhood Disorders and one of the study’s authors.
TEAD1 has previously been associated with Sveinsson’s syndrome, an inherited progressive weakening of the eye’s retina and choroid, a layer of nerves and blood vessels that connects the retina to the optic nerves. The TGen study suggests that TEAD1 mutations can lead to other chorioretinal complications, such as chorioretinal lacunae.

The TGen study also found that the children in this study also share a potential pathogenic, or disease-causing, mechanism: the altered expression of genes associated with neuronal development; retinal development; cell-cycle control; and synaptic plasticity, the ability of synapses to strengthen or weaken over time in response to increases or decreases in their activity.

Most surprising was the finding that AIC might also be more common among boys than previously thought because the TEAD1 mutation is on an autosome, a chromosome not linked to sex.

AIC had been strongly presumed by geneticists to be an X-linked-dominant disorder occurring almost exclusively in females. However, no gene on the X chromosome has ever been conclusively associated with AIC.

‘Our study strongly challenges this notion by demonstrating a deleterious mutation of TEAD1 on an autosome,’ said Dr. Isabelle Schrauwen, a Research Assistant Professor in Dr. Huentelman’s lab and the lead author of the study. ‘These findings are of clinical importance because they demonstrate AIC linked to autosomal mutations, and therefore for the first time rule-in a likely much higher frequency of AIC in boys.’ Translational Genomics Research Institute (TGen)

An analysis of five families has revealed a previously unknown genetic immunodeficiency, says an international team led by researchers from Boston Children’s Hospital. The condition, linked to mutations in a gene called DOCK2, deactivates many features of the immune system and leaves affected children open to a unique pattern of aggressive, potentially fatal infections early in life.

As the researchers—led by Kerry Dobbs and Luigi Notarangelo, MD, of Boston Children’s Division of Allergy and Immunology—reported today in the New England Journal of Medicine, DOCK2 deficiency may be detectable by newborn screening and is curable with a hematopoietic stem cell transplant (HSCT).

Genetic immunodeficiencies, such as X-linked severed combined immunodeficiency (X-SCID) or Wiskott-Aldrich syndrome (WAS), are a group of devastating conditions where mutations to specific genes cause either functional defects in or interfere with production of T-cells and other components of a patient’s immune system. These defects increase a patient’s susceptibility to a range of severe infections at an early age.

Conditions for which the causative genes are known, such as X-SCID, can be screened for at birth, allowing for early detection and, when appropriate, curative treatment with a hematopoietic stem cell transplant.

‘Until recently, a correct diagnosis for babies born with SCID or other combined immunodeficiencies, such as DOCK2 deficiency, could be made only after these babies had developed serious infections, which could lead to death or compromise the efficacy of an HSCT,’ said Notarangelo, who is a professor of pediatrics at Harvard Medical School. ‘Newborn screening for these diseases is now available for most babies with SCID born in the USA, and this gives increased chances of definitive cure by performing the transplant while the baby is still well.’

In the current study, Notarangelo, Dobbs and their colleagues at the Rockefeller University and the Center for Molecular Medicine in Austria, conducted genetic, genomic and immunological analyses on five patients from Lebanon, Finland, Turkey and Honduras/Nicaragua who early in life demonstrated symptoms indicating a severe but distinctive immunodeficiency, one that left patients susceptible to a broad range of infections but particularly vulnerable to viruses. Three out of the five patients were born of closely related parents, and three were successfully treated by HSCT.

The team discovered through whole exome sequencing that all five patients harboured mutations in DOCK2, mutations that rendered the DOCK2 protein inactive. The mutations had profound effects on multiple aspects of the patients’ immune systems, causing a profound decrease in T-cells and defects in T-, B- and natural killer (NK) cell function.

The study data show that defects in DOCK2, which helps immune cells react to external chemical signals, can have a profound effect on several aspects of immunity, including unforeseen affects on how non-immune cells (such as cells of the skin) respond to viruses.

Notarangelo noted that the data expand the field’s understanding of the basic molecular mechanisms underlying human immunity, while adding a new diagnostic target for newborn screening. Boston Children’s Hospital