Can autoimmune diseases be prevented?

This past week I was at the American College of Rheumatology's annual meeting in Washington D.C. where I attended a session on the prevention of autoimmune diseases. While the conference was focused mostly on rheumatic disease like rheumatoid arthritis and lupus, this particular session discussed the possibilities of prevention of autoimmune diseases in general.

To orient us, it's helpful to think of autoimmune diseases using the following paradigm where a person has an initial genetic risk, followed by a pre-clinical phase of autoimmunity, which can eventually progress to a clinically apparent autoimmune disease. The following figure comes from a paper published by Deane, Norris, and Holers pertaining to rheumatoid arthritis. But we believe that this model of disease development applies to other autoimmune diseases.

This figure suggests that there is an existing genetic risk and some environmental factor such as smoking triggers an autoimmune response. This autoimmune response is usually asymptomatic and might be present for years and might never progress to clinically apparent disease. Some people might even lose their pre-clinical autoimmunity. In some cases, eventually another factor such as another environmental exposure (maybe the person never stopped smoking) causes the progression to clinically apparent disease.

This paradigm presents us with interesting prevention strategies where we can target individuals with a genetic predisposition to a disease, and if we know what environmental factors might cause autoimmunity, we can eliminate these exposures to prevent autoimmunity. We might also try and prevent progression to clinically apparent disease by eliminating exposures or treatment with mild immunosuppressives to prevent disease manifestation. Unfortunately for this prevention paradigm, many autoimmune diseases are not well understood and can have a complex etiology.

A question to consider would be if prevention of disease such as avoidance of gluten to prevent Celiac's disease is even feasible, given the unknown etiology?
Or would it be more effective to just treat clinical autoimmune diseases such as insulin use for type 1 diabetics?

 I remain optimistic and believe that advancing scientific evidence will eventually shed light on the etiology of many autoimmune diseases, allowing us to consider such prevention strategies.

Sources:
Deane KD, Norris JM, Holers VM. Preclinical Rheumatoid Arthritis: Identification, Evaluation, and Future Directions for Investigation. Rheumatic Disease Clinics of North America 2010;36:213–41.

HIV invasion into the Brain

  Human Immunodeficiency virus is a retrovirus.  Retroviruses have an enzyme, reverse transcriptase that can transcribe RNA into DNA.  HIV has been shown to have a profound effect on the brain of patients infected by the virus.  It causes HAD (HIV associated dementia) in Aids patients.  The damage to the brain from this virus is caused by the virus crossing through the blood brain barrier (BBB).   The blood brain barrier is a barrier composed of epithelial cells that are tightly connected by proteins forming tight junction complexes.  Early in the onset of AIDS, HIV is thought to use activated monocytes to infect cells in the brain.  The virus supposedly uses regular biological mechanisms for crossing the blood brain barrier.

  In the later stages of AIDS the blood brain barrier (BBB) is mechanically altered, thus allowing for an increase in infected monocyte and macrophage to invade the brain.  Many mechanisms have been proposed for how HIV is able to alter the blood brain barrier.  One mechanism is that cytokines released by infected cells or activated epithelial cells disrupts the BBB allowing for infected cells to infiltrate into the brain.  Cytokines (cell-signaling proteins) can cause epithelial cells to secrete proteins that thin the basal lamina (the lining of proteins between the epithelial cells and other cells in the blood).  Another mechanism proposed is the viral protein such as Tat and gp120 are secreted from infected cells could alter the blood brain barrier. Tat has been shown in animal models to cause disorganization of the tight junction complexes in the blood brain barrier. Also, gp120 has been shown in animal models to cause degradation of both the basal lamina and the protein that makes up the tight junction complexes between the epithelial cells.  Another belief in the research community is HIV can infect the endothelial cells in the blood brain barrier leading to infection in the brain.  If the endothelial cells can be infected with HIV, the cells could secrete Tat or other proteins that could cause the degradation of the basal lamina and tight junctions.  The epithelial cells could also die due to infection leading to the infiltration of infected cells into the brain.

  After the blood brain barrier has been altered infected monocytes and macrophages can enter the brain at a higher rate.  As more monocytes (t-cells) enter the brain they recruit macrophages by secreting cytokines activating more cells which leads to inflammation and oxidative stress in the brain.  The microglia and astrocytes (brain cells) become infected and can replicate the virus to infect more cells in the brain.  All these events contribute to the cause of HAD. 

 

  One question that arises from my research done on this topic is: what would be the target for drug treatment to prevent the progression of HAD? 

References:

Grass G and Kaul M.  Molecular Mechanisms of neuroinvasion by monocytes-macrophages in HIV-1 infection.  Retrovirology 2010.  7:30.

Miller F, Afonso P, Gessain A and Ceccaldi P.  Blood-brain barrier and retroviral infections.  Virulence 2012.  3:222-229.

Valcour V, Shiramizu B and Shikuma C.  HIV DNA in circulating monocytes as a mechanism to dementia and other complication.  Journal of Leukocyte Biology 2010. 87:621-626.

Histones aid the immune system?

Histones are present in large numbers in most animal cells.  They function to compact 3 meters of DNA so it can fit inside the nucleus.   That, however, appears to not be their only job.  Strangely enough, there is some evidence that histones can protect cells against bacteria.  How on earth can a DNA-bound protein aid the immune system to mount an antibacterial response?? And how can a nuclear protein attack bacteria that, from what I know, multiply in the cytosol not in the nucleus?  Additionally, I thought free histones could be damaging to cells?  Too many questions!  Turns out our cells may have found a way around these limitations.  Namely, histones bound to intracellular lipids.  A group from the University of California Irvine isolated lipid droplets from Drosophila embryos and showed that it is these lipid-bound histones that can be released to kill bacteria.  They tested this antibacterial ability of histones by injecting bacteria into wild-type Drosophila embryos, containing lipid-bound histones, and into lipid-bound histone knockout embryos. Turns out, the knockouts were 14 times more likely to die of the bacterial infection.  Is this just in flies?  No.  It appears some data shows that this antibacterial role of histones may be present in mice.  Researchers have also identified lipid-bound histones in human cells as well.  What does this mean for humans?  Could histones be manipulated to aid in the immune response?  

Anand et. al., A novel role for lipid droplets in the organismal antibacterial response. eLife 2012. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491588/pdf/elife00003.pdf

Bee Stings, Coconut Oil, and Chile Peppers?!

There are many natural remedies for pain associated with inflammation. We've already talked about bee stings and coconut oil but are there other anecdotal treatments out there? The answer is yes. A recent NBC article highlights eight natural ways to fight pain associated with arthritis, immune disorders and acute post surgical swelling. Among capcaisin (what makes peppers hot), found to relieve arthritis and certain neuropathies, other natural products like aquamin (component in red seaweed) have been shown to pain management to people wary to try medications. Fish oil, already a popular supplement, has been shown to break down into prostaglandins, providing inflammation relief. When tested among arthritic patients who took non-steroidal anti-inflammatory drugs (NSAIDS), fish oil allowed them to cut their NSAID use by more than a third and some were able to stop NSAID use altogether by the end of the study. Another natural treatment, arnica also appears in this article. The component of a European flower, arnica can be used to treat post-surgical acute inflammation. This supplement can be used in a variety of ways such as a lactose tablet, in ointment, or as an additive to traditional pain medication.

Although these alternative treatments sound less invasive that NSAIDS and other traditional drug therapies, caution should be practiced and consulting a physician before beginning alternative treatment is a must. Until research on these treatments can show conclusive evidence that they do in fact provide therapeutic effects, traditional anti-inflammatory treatments should be continued.

NBC-
http://www.msnbc.msn.com/id/26136767/ns/health-alternative_medicine/t/youre-pain-you-want-relief-naturally/#.UKgoLmhSSeA

RSV in infancy and Asthma

Respiratory Syncytial Virus (RSV) also known as bronchiolitis is an infection in the upper respiratory tract that typically happens before the age of 2. Some children get a more severe form and develop lower airway symptoms as well. Typically only 1-2% of infants are hospitalized with RSV when infection occurs. This disease can leave kids wheezing for several years after the infection has occurred. There is little evidence at this time suggesting if RSV is nonallergenic or if it is an onset of IgE associated asthma. RSV primes the memory T-cells that make Interferon-c (INF-c) and are also associated with IL-4 producing T-cells that are activated during RSV infections. There are many studies that show that there is a strong relationship between RSV and asthma or allergies.

With a normal child a RSV infection is mild and they develop a predominant Th1 antiviral response that clears the infection. The memory T-cells are dominated by IFN-c production rather than IL-4. In children that develop a more severe form of RSV (when hospitalization is needed) a strong INF-c response occurs along with an IL-4 response which leads to the accumulation of antiviral-T cells in the lungs causing an impairment of the respiratory tract. Post infection both IL-4 and IFN-c T-cells are maintained as memory cells that recirculate in the blood. There is some evidence that children who are administered a polyclonal antiviral antibody therapy have a delay in RSV infection and show improved lung function.

There are several different mechanisms that can explain the association between asthma and RSV. Experiments with animals suggest that RSV may contribute to post bronchiolitic symptoms and when inhaled allergens are delivered to these animals the effects are enhanced by a RSV infection. In these studies they link IL-4 production and a type 2 cytokine response with enhanced lung disease during the viral infection--this is also a common feature in asthma and atopy.  This mechanism has yet to be proven in humans.

Results in infant peripheral blood mononuclear cells can be used to show that RSV increases the risk of atopy and provides an IL-4 rich environment in which encountering airborne allergens can create an increased memory T-cell response. Other studies suggest that there is an increase of Th2 response which is medicated by overexpression of the IL-4 which only provides preliminary evidence for a genetic link between RSV and asthma. The last suggestion is that there is a genetic defect that is associated with the delay in postnatal maturation of Th1 function that gives susceptibility to both severe viral infection in the lungs as well as allergies and asthma in childhood.

Eosinophil cationic protein is created in the serum of children with asthma and with children with bronchiolitis. This suggests the degranulation of the eosinophil’s in both conditions. This increase in antigen specific enhancement of IL-4 production may be able to explain the link between RSV and asthma as well as chronic wheezing during childhood.

Referances

Severe Respiratory Syncytial Virus Bronchiolitis in Infancy and Asthma and Allergy at Age 13. http://ajrccm.atsjournals.org/content/171/2/137.full.pdf

 

Enhanced IL-4 responses in children with a history of respiratory

syncytial virus bronchiolitis in infancy P. http://erj.ersjournals.com/content/20/2/376.full.pdf

 

Why are Jewish children more susceptible to pediatric neurodegenerative diseases?

Most of the neurodegenerative diseases that we have been studying are those affecting mostly the elderly, however I was curious about neurological disorders that affect children and how they develop.  I came across a devastating disease called Mucolipidosis Type IV which is a genetic neurodegenerative disease resulting in progressive vision loss and delayed mental and motor skills.  However, even though this disease is fairly rare, about 70% of those affected individuals have Ashkenazi Jewish ancestry. Why?

ML4 is an autosomal recessive lysosomal storage disorder caused by a mutation on the MCOLN1 gene.  This gene is responsible for creating the protein mucolipin-1 which is found in membranes of lysosomes and endosomes.  Mucolipin-1 is responsible for (although not completely understood) transporting fats and proteins between lysosomes and endosomes that proves necessary for the development and support of the brain and retina.  A mutated mucolipin-1 causes nonfunctional transfer and communication which leads to a buildup of substances inside the lysosomes, which is why it is called a lysosomal storage disorder.

Unfortunately, about 1 in 100 Ashkenazi Jews are carriers of the defected MCOLN1 gene but the carrier rate in the general population is unknown.  Children born with this gene will develop no further than a 15-month old in language and motor function.  In addition to neural and vision problems, those affected will also experience digestive problems because mucolipin-1 also plays a role in the production of digestive acids.

However, there is hope! With early intervention and intense therapy, children may show less degeneration and more independence.  For example, the 5-year old girl in the following picture was diagnosed with ML4 was able to sit up on her own with minimal support and had no obvious vision problems.

http://ghr.nlm.nih.gov/condition/mucolipidosis-type-iv
http://www.ml4.org
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824620/ (picture)
http://www.jewishgeneticdiseases.org/diseases/mucolipidosis-type-4/

Alzheimer's and Parkinson's

Two common forms of neurodegeneration are Alzheimer’s disease and Parkinson’s disease. Over 5 million Americans are living with Alzheimer’s and about 50,000 new cases of Parkinson’s disease are diagnosed each year.

Alzheimer’s disease is the most common form of dementia, leading to a loss of memory and mental function, worsening over time. It is currently hypothesized that the root of this disease is due to a buildup beta-amyloid plaques. The plaques clump outside neurons, which then alter tau protein folding, which disrupts normal neuron function. The symptoms generally appear after the patient is over the age of 60. Onset of the symptoms is slow, starting first with getting lost and taking longer to complete normal everyday chores, then slowly lacking the ability to recognize friends and family. More severe symptoms include hallucinations, paranoia, weight loss, and seizures. While there is no cure, there are many medications available to slow the progression of symptoms. The most common treatment is a cholinesterase inhibitor, which boosts cell communication. Experimental treatment being developed focuses on inhibiting beta-amyloid buildup.

Parkinson’s disease is the result of loss of dopamine-producing cells in the brain. Dopamine influences movement and initiation. When the cells stop producing this neurotransmitter, it results in very apparent symptoms associated with Parkinson’s disease, including tremor, muscle stiffness, bradykinesia (slow movement), dyskinesia (jerking of the muscles), and impaired balance and coordination. Other symptoms include difficulty swallowing, chewing and speaking, as well as emotional changes. The onset of symptoms is again progressive and associated with age, with most patients being senior citizens. The loss of the brain cells is still idiopathic, but it is associated with Lewy bodies, clumps of protein alpha-synuclein. Parkinson’s is diagnosed with a MRI, CT, or PET scan when the Lewy bodies are seen in the midbrain or brain stem. There is no cure for Parkinson’s disease, but several treatments to alleviate symptoms. The most common is levodopa, a drug which helps nerve cells make dopamine. Unfortunately its effectiveness is reduced as a result of overuse. Generally after 3 years, patients have to switch medications.

Most patients of both Parkinson’s and Alzheimer’s need caregivers. Caregivers are a necessity to patients who begin to lack the ability to perform daily tasks on their own. For Alzheimer’s patients, having a constant figure in their life is great when they can no longer adapt to change. Caregivers also help regulate their schedules, keeping patients eating, taking their medication, and going to the bathroom regularly. For Parkinson’s patients, caregivers are not there to keep their minds in check, just to help them perform tasks for them such as feeding them or escorting them when they walk.

Although both of these diseases are common in elderly citizens, it is not a natural process of aging. Both represent irreversible degenerative clinical processes.

“About Alzheimer’s Disease: Symptoms” Alzheimer’s Disease Education and Referral Center. National Institute on Aging: National Institutes of Health, April 2011. http://www.nia.nih.gov/alzheimers/topics/symptoms

“Alzheimer’s Disease.” Center for Disease Control and Prevention, 13 October 2011 http://www.cdc.gov/aging/aginginfo/alzheimers.htm

“Alzheimer’s Disease.” Mayo Clinic: Mayo Foundation for Medical Education and Research, 18 January 2011. http://www.mayoclinic.com/health/alzheimers-disease/DS00161

“NINDS Parkinson’s Disease Information Page.” National Institute of Neurological Disorders and Stroke, 14 November 2012. http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease.htm

“Parkinson’s disease – Causes.” National Health Service, 5 October 2012. http://www.nhs.uk/Conditions/Parkinsons-disease/Pages/Causes.aspx

“Parkinson’s Disease Overview” National Parkinson Foundation, 2012. http://www.parkinson.org/parkinson-s-disease.aspx

“What is Alzheimer’s disease?” Alzheimer’s Society: National Institute for Health and Clinical Excellence, 2012. http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=100

“What is Parkinson’s Disease?” Parkinson’s Disease Foundation, 2012. http://www.pdf.org/en/about_pd