Monthly Archives: November 2012

Background.  Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune vesicobullous disorders with IgG autoantibodies directed against desmoglein (Dsg)1 and 3, which lead to intraepidermal acantholysis.

Aim.  To characterize the clinical and immunological profile of patients with PF or PV with umbilical involvement.

Methods.  In total, 10 patients (7 women, 3 men; age range 24–70 years, disease duration 3–16 years) diagnosed with either PV (n = 5) or mucocutaneous PF (n = 5) were assessed according to their clinical features, histopathology and immunological findings .

Results.  Erythema, erosions, crusts and vegetating skin lesions were the main clinical features of the umbilical region. DIF of the umbilical region gave positive results for intercellular epidermal IgG and C3 deposits in eight patients and for IgG alone in the other two. Indirect immunofluorescence with IgG conjugate showing the typical pemphigus pattern was positive in all 10 patients, with titres varying from 1 : 160 to 1 : 2560. ELISA with recombinant Dsg1 gave scores of 24–266 in PF and 0–270 in PV. Reactivity to recombinant Dsg3 was positive in all five patients with PV (ELISA 22–98) and was negative in all PF sera.

Conclusions.  All 10 patients with pemphigus with umbilical presentation had the clinical and immunopathological features of either PF or PV. This peculiar presentation, not yet completely elucidated, has rarely been reported in the literature. A possible explanation for this unique presentation may be the presence of either novel epitopes or an association with embryonic or scar tissue located in the umbilical-cord region.

Full article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2230.2012.04468.x/abstract

High-dose intravenous immunoglobulin (IVIG) therapy is used in patients with severe autoimmune blistering diseases that are refractory to standard immunosuppressive therapy. To determine the efficacy and frequency of adverse events of IVIG therapy, we retrospectively analysed data for 16 patients with pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid and paraneoplastic bullous pemphigoid. Frequency of adverse reactions and efficacy of IVIG were analysed over time with a scoring system for every 6 months of IVIG therapy. Headache (43.8%) and fatigue (43.8%) were the most common side-effects recorded; serious adverse reactions did not occur. There was good overall efficacy, as measured by clinical response rates using a clinical score, as well as indicated by a mean reduction of 75.8% in the starting steroid dose.

Full article available at: http://www.ncbi.nlm.nih.gov/pubmed/23073990?dopt=Abstract

Background  Hailey-Hailey disease (HHD) or familial benign chronic pemphigus is a rare autosomal dominant inherited skin disorder, characterized by flaccid vesicles and erosions on the intertriginous areas. Current treatments are not particularly effective. We report 6 cases dramatically improving with doxycycline.

Case reports  6 patients, aged from 33 to 77 years old, presented with a variable 4 to 40 year history of severe treatment-resistant HHD. All 6 patients were then treated successfully with doxycycline 100 mg per day for at least 3 months.

Discussion  An improvement was observed in all 6 patients from 1 week to 3 months after the beginning of treatment. Relapses were observed after various periods. Maintenance half-dose therapy seemed to be beneficial in patients experiencing recurrence. Only one patient developed gastro-intestinal intolerance. No other side effects were reported. Currently, 2 patients have improved and present a decreased number of exacerbations, 2 others are in complete remission after more than 5 years of follow-up. Treatment efficiency is difficult to evaluate in HHD as it is a rare condition. No controlled studies have been published. Local treatments may improve inflammation but do not treat the underlying cause, targeted systemic therapies exist but there is little evidence supporting their use, physical treatments are cumbersome. Besides their antibiotic potential, tetracycline antibiotics also have anti-inflammatory properties and anticollagenase activity via inhibition of matrix metalloproteinases.

Conclusions  Doxycycline appears to be an interesting therapeutic option in Hailey-Hailey disease.

Full article available at: http://onlinelibrary.wiley.com/doi/10.1111/jdv.12016/abstract;jsessionid=8314ECF44FF542D304546752C44E6B24.d02t03

The molecular basis of disease heterogeneity in autoimmune conditions such as Pemphigus vulgaris is poorly understood. Although desmoglein 3 (Dsg3) has been well established as a primary target of immunoglobulin (Ig) autoantibodies in PV, there remain several questions regarding the overall distribution of anti-Dsg3 Ig subtypes among patient subsets and considerable controversy regarding whether an isotype switch can be observed between phases of disease activity. To systematically address the outstanding questions related to Ig-isotype specificity in PV, we analyzed IgA, IgM, IgG1, 2, 3 and 4 anti-Dsg3 levels by ELISA in 202 serum samples obtained from 92 patients with distinct clinical profiles based on a set of defined variable (activity, morphology, age, duration) and constant (HLA-type, gender, age of onset) clinical parameters, and 47 serum samples from HLA-matched and -unmatched controls. Our findings provide support for earlier studies identifying IgG4 and IgG1 as the predominant antibodies in PV with significantly higher levels in active than remittent patients. We do not see evidence for an isotype switch between phases of disease activity and remission, and both IgG4 and IgG1 subtypes remain elevated in remittent patients relative to controls. We do, however, find IgG4 to be the sole subtype that further distinguishes PV patient subgroups based on different disease morphologies, disease duration, and HLA-types. These data provide further insight into the immune mechanisms responsible for phenotypic expression of disease, and contribute to the broader effort to establish comprehensive immunoprofiles underlying disease heterogeneity to facilitate increasingly specific and individualized therapeutic interventions.

Full article available at: http://www.ncbi.nlm.nih.gov/pubmed/22779708

An autoimmune disease develops when the body’s immune system fails to recognize normal body tissues and attacks and destroys them as if they were foreign, rather than attacking an outside organism. The cause is not fully understood, but in some cases it is thought that autoimmune diseases are triggered by exposure to microorganisms or other environmental causes, especially in people with a genetic predisposition to the disorder. A single organ or multiple organs and tissues may be affected.

There are many autoimmune diseases with symptoms that range from mild rashes to life-threatening conditions that attack major organ systems. Though each disease is different, immune-system malfunction is present in all of them. Disease symptoms vary depending on which tissue is targeted for destruction. Symptoms common to all autoimmune disorders include fatigue, dizziness, malaise, and low-grade fever.

Autoimmune disorders are frequently classified into organ-specific disorders and non-organ-specific types. Organs and tissues frequently affected include the endocrine gland, such as thyroid, pancreas, and adrenal glands; components of the blood, such as red blood

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cells; and the connective tissues, skin, muscles, and joints.

In organ-specific disorders, the autoimmune process is directed mostly against one organ. But patients may experience several organ-specific diseases at the same time. In non-organ-specific disorders, autoimmune activity is widely spread throughout the body. This includes Rheumatoid Arthritis (joints), Systemic Lupus Erythematosus, and Dermatomyositis (connective tissue).

According to the American Autoimmune Related Diseases Association, about 75 percent of autoimmune disease cases occur in women, particularly those who have had children. The cause is not fully understood, but in some cases it is thought to be triggered by exposure to microorganisms especially in people with a genetic predisposition to the disorder.

Common types of localized autoimmune disorders:

  • Addison’s disease (adrenal)
  • Autoimmune hepatitis (liver)
  • Celiac disease (GI tract)
  • Crohn’s disease (GI tract)
  • Graves’ disease (overactive thyroid)
  • Guillain-Barre syndrome (central nervous system)
  • Hashimoto’s thyroiditis (lowered thyroid function)
  • Multiple sclerosis
  • Raynaud’s phenomenon (fingers, toes, nose, ears)
  • Type 1 Diabetes Mellitus (pancreas islets)
  • Ulcerative colitis (GI tract)Common types of systemic autoimmune diseases:
  • Lupus [Systemic Lupus Erythematosus] (skin, joints, kidneys, heart, brain, red blood cells, other)
  • Polymyalgia Rheumatica (large muscle groups)
  • Rheumatoid arthritis (joints; less commonly lung, skin, and Juvenile rheumatoid arthritis)
  • Scleroderma (skin, intestine, less commonly lung)
  • Sjogren’s syndrome (salivary glands, tear glands, joints)
  • Systemic Sclerosis
  • Temporal Arteritis / Giant Cell Arteritis (arteries of the head and neck)

The types of autoimmune disease treated at SCCA with stem cell transplants include:

  • Multiple Sclerosis
  • Systemic Sclerosis
  • Systemic Lupus Erythermatosus
  • Rare neurologic diseases

Other autoimmune diseases treated at SCCA include:

  • Autoimmune Cerebellar Degeneration
  • Autoimmune Peripheral Neuropathies
  • Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
  • Gait Ataxia with Late Age Onset Polyneuropathy (GALOP)
  • Lambert Eaton Myasthenic Syndrome
  • Myasthenia Gravis
  • Opsoclonus/Myoclonus (Anti-Ri)
  • Rasmussen’s Encephalitis
  • Stiff Person Syndrome
  • Tropical Spastic Paraperesis HTLV-1 Associated Myelopathy (TSP/HAM)

Autoimmune diseases that affect blood cells are discussed under Blood Disorders.

  • Immune thrombocytopenia purpura (ITP)
  • Autoimmune hemolytic anemia
  • Autoimmune neutropenia

Inflammation is a key component of immune responses to infection, but when uncontrolled can lead to autoimmune diseases like Crohn’s disease, rheumatoid arthritis, type I diabetes, ankylosing spondylitis, lupus, psoriasis and multiple sclerosis. In these diseases inflammation is mediated by molecules of the immune system called cytokines and cells that respond to these cytokines called T cells. Autophagy is an ubiquitous process whereby cells degrade their own internal components, either to release valuable nutrients in times of starvation, or to remove damaged or noxious intracellular components. The work by Dr Harris and colleagues showed that autophagy also control release of the inflammatory cytokines and cells that have been implicated in the pathology of autoimmune diseases. The findings suggest that autophagy represents a potent target for new anti-inflammatory therapies, which could be beneficial in a range of autoimmune disorders. The group, in combination with Professor Kingston Mills, now hopes to apply these findings to specific models of autoimmune disease. The work is funded by Science Foundation Ireland as part of a Strategic Research Cluster (SRC) award based in The Trinity Biomedical Sciences Institute. “Autophagy is a common cellular process that is important for the maintenance of normal cell functions. Our work has shown that this process is

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important in the control of inflammation and, as such, could represent a particularly efficacious target for new drugs against inflammatory conditions. There are over 80 different autoimmune diseases, most of which are chronic and debilitating and can be difficult and expensive to treat. Any research which helps us to better understand the underlying mechanisms behind the control of inflammation will ultimately lead to better treatments,” explained Dr James Harris.

Read more at: http://medicalxpress.com/news/2012-10-important-role-autophagy-self-eating-cells.html#jCp

 

An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases could be co-marketed with the Thomas Rockwell’s children’s classic How to Eat Fried Worms. It begins with the author, Moises Velasquez-Manoff, recounting his border-crossing to Tijuana to infect himself with Necator americanus—hookworms—in an attempt to cure the asthma, hay fever, food allergies, and alopecia that had plagued him since childhood. In the next three hundred pages, the author very cogently explains the idea that led him to willingly infect himself with a parasite known to cause severe diarrhea, anemia, and mental retardation in children.

Velasquez-Manoff marshals the reams of evidence researchers have accumulated to support said concept: the hygiene hypothesis, but with an updated, parasitic twist. The ideas he presents haven’t been accepted by many in the medical community, and there’s little high-quality evidence, in the form of well controlled trials, that exposure to parasites could have positive effects on human health. So, even if the author is thorough, it’s important to keep in mind that the evidence he’s presenting is primarily in the form of correlations.

The Hygiene Hypothesis

A simplistic view of the hygiene hypothesis is that in the absence of something dangerous to fight against—the cholera toxin, for example—immune cells get confused, or bored, and fight against harmless stimuli like dust mites and peanuts instead. But there is a more nuanced view. Our immune systems co-evolved with an enormous community of microbes, and were in fact shaped by them. Many became established, long-term, and vital residents in our guts; the importance, and in fact the very existence, of these commensals has only recently been realized.

Constant exposure to all of these bugs, as a unit, enhanced the regulatory arm of the immune system, modulating responses so that we could tolerate the filthy environment in which we lived while at the same time (hopefully) fighting off those pathogens that posed a mortal threat and not destroying our own bodies in that process. In the martial analogy that is inevitable in discussing immunology, ancient human immune cells that were always surrounded by microbes were like battle-hardened old soldiers who have learned the ability to watch warily when encountering something new, waiting to see whether or not it is dangerous; modern immune cells raised in our hyper-sanitized environment are like new recruits just given their first gun, testy and jumpy at the first hint of a threat and liable to blow up their surroundings in inappropriately directed and outsized force. Experience has not taught them moderation.

Seeing worms everywhere

Yes, he includes autism in the list of modern diseases caused by our out-of-whack immune systems. Along with other cases where immune dysfunction hasn’t been established, like obesity, cardiovascular disease, type 2 diabetes, and cancer.

There are some serious problems with blaming all of these on immune dysfunction, but we’ll focus on a single example: autism. Just as the absence of worms’ mediating effects on our immune system causes some people to have an allergic response to harmless ingested proteins and others to attack their own tissues, the argument goes, chronic inflammation in the womb generates fetuses with autism.

The rest of this article can be read here: http://arstechnica.com/science/2012/10/book-review-an-epidemic-of-absence-takes-on-the-worms-youre-missing/

A new study in mice where researchers replicated a rare type of immune cell in the lab and then infused it back into the body, is raising hope for a new treatment for severe autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

The researchers, from Duke University Medical Center in the US, write about their work on a type of B cell, in a paper that was published online in Nature at the weekend.

B Cells

B cells are immune cells that create antibodies to attack unwanted pathogens like bacteria and viruses.

The type that the researchers on this study focused on are known as regulatory B cells or B10, after interleukin-10 (IL-10), a cell-signalling protein that the cells use.

B10 cells help control immune response and limit autoimmunity, which is where the immune system attacks the body’s own healthy tissue as if it were an unwanted pathogen.

Although there aren’t many of them, B10 cells play a key role in controlling inflammation: they limit normal immune response during inflammation, thus averting damage to healthy tissue.

Regulating Immune Response Is a Highly Controlled Process

Study author Thomas F. Tedder is a professor of immunology at Duke. He says in a statement that we are only just beginning to understand these recently discovered B10 cells.

He says these regulatory B cells are important because they “make sure an immune response doesn’t get carried away, resulting in autoimmunity or pathology”.

“This study shows for the first time that there is a highly controlled process that determines when and where these cells produce IL-10,” he adds.

What they Did

For their study, Tedder and colleagues used mice to study how B10 cells produce IL-10. For IL-10 production to start, the B10 cells have to interact with T cells, which are involved in switching on the immune system.

They found B10 cells only react to certain antigens. They found that binding to these antigens makes the B10 cells turn off some of the T cells (when they come across the same antigen). This stops the immune system from harming healthy tissue.

This was a new insight into the function of B10 cells that spurred the researchers to see if they could take this further: what if it were possible to use this cellular control mechanism to regulate immune responses, particularly in respect of autoimmunity?

Replicating Large Numbers Outside the Body

B10 cells however are not common, they are extremely rare. So Tedder and colleagues had to find a way to make a ready supply of them outside the body.

They found a way to isolate the B10 cells without damaging their ability to control the immune responses. And they found a way to replicate them in large numbers, as Tedder explains:

“Normal B cells usually die quickly when cultured, but we have learned how to expand their numbers by about 25,000-fold.”

“However, the rare B10 cells in the cultures expand their numbers by four-million-fold, which is remarkable. Now, we can take the B10 cells from one mouse and increase them in culture over nine days to where we can effectively treat 8,000 mice with autoimmune disease,” he adds.

Influencing Autoimmunity

The next stage was to try out the new B10 cells: could they influence autoimmunity sufficiently to affect disease symptoms?

They found when they introduced a small number of B10 cells into mice bred to have a disease similar to multiple sclerosis, their symptoms lessened significantly.

“B10 cells will only shut off what they are programmed to shut off,” explains Tedder.

If you have rheumatoid arthritis, you would want cells that would only go after your rheumatoid arthritis,” he adds.

Implications

He and his colleagues suggest their work shows there is potential to remove regulatory cells, replicate them in their millions, and put them back in the body of a person with an autoimmune disease and it will effectively “shut down the disease”, as Tedder describes it:

“This may also treat transplanted organ rejection,” he adds.

The researchers call for more studies to learn how to replicate human B10 cells, and find out how they behave in humans.

Autoimmune diseases are complex, so making a single therapy that targets several diseases without causing immunosuppression is not easy, Tedder explains.

“Here, we’re hoping to take what Mother Nature has already created, improve on it by expanding the cells outside of the body, and then put them back in to let Mother Nature go back to work,” he says.

Grants from the National Institutes of Health, the Lymphoma Research Foundation, and the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, helped pay for the study.

Article from: http://www.medicalnewstoday.com/articles/251507.php

Written by Catharine Paddock PhD
Copyright: Medical News Today

Background  Bullous skin diseases are known to be associated with significant morbidity and mortality. There have been no studies on mortality from severe bullous skin diseases in Canada.

Methods  We used mortality data from the Statistics Canada website from 2000 to 2007 for three major bullous skin diseases: bullous pemphigoid; pemphigus; and toxic epidermal necrolysis (TEN). Crude and age-standardized mortality rates were calculated and compared with the corresponding US mortality rates. Linear regression was used to assess time trend and effect of gender and age on mortality rates.

Results  During the period of eight years, there were 115 deaths attributed to pemphigoid, 84 to pemphigus, and 44 to TEN. The crude annual mortality rate was the highest for pemphigoid (0.045 per 100,000), followed by pemphigus (0.033), and TEN (0.017). None of these conditions demonstrated significant time trends in mortality rates over the eight-year period, although a trend towards decreasing pemphigus mortality was observed (P = 0.07). No gender difference in mortality was observed, but advanced age was associated with mortality in all three conditions.

Conclusion  Among bullous skin diseases, pemphigoid is the leading cause of mortality in Canada. This is in contrast to the USA, where TEN is the leading cause of mortality from bullous skin diseases. It is not clear whether differences in healthcare systems explain these findings.

Full article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-4632.2011.05227.x/abstract;jsessionid=FAE06EFE4AF802D50261B2992F71D91D.d02t01?systemMessage=Wiley+Online+Library+will+be+disrupted+on+27+October+from+10%3A00-12%3A00+BST+%2805%3A00-07%3A00+EDT%29+for+essential+maintenance

OBJECTIVES:

Thymomas are relatively rare tumors. In this study, we investigated the clinical features of patients who underwent surgical resection for thymoma.

PATIENTS AND METHODS:

This study clinicopathologically evaluated 54 consecutive patients who underwent a surgical resection of thymoma in our department between 1994 and 2006.

RESULTS:

A complete resection was performed in 52 patients, while two patients underwent an incomplete resection due to pleural dissemination. Combined resection with adjacent organs was performed for the lung (n=6), pericardium (n=5), and large vessels (brachiocephalic vein in three, superior vena cava in two). The concomitant autoimmune diseases were observed in 20 patients (37%), and they included myasthenia gravis in 17 patients, macroglobulinemia in one, pemphigus vulgaris in one, and stiff person syndrome in one patient. The histologic types of the World Health Organization classification diagnosed as type A in four patients, type AB in 14, type B1 in eight, type B2 in 15, and type B3 in 11. There were 27, 17, eight, and two patients with Masaoka stages I, II, III, and IV, respectively. Four patients died, and the causes of death included recurrence of thymoma in two, gastric carcinoma in one, and respiratory failure due to myasthenia gravis in one patient. The overall survival rate at 10 years was 94.6% in patients with stages I and II disease and 77.1% in patients with stages III and IV disease.

CONCLUSIONS:

Long-term survival can be expected not only for patients at early stages, as well as for patients with stages III and IV disease if surgical resection is completed macroscopically.

Full article available at: http://www.ncbi.nlm.nih.gov/pubmed/23063086?dopt=Abstract