Yearly Archives: 2012

 

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

Pemphigus is a chronic, muco-cutaneous autoimmune blistering disorder; two main variants being pemphigus vulgaris (PV) and pemphigus foliaceus (PF). PV is the most common subtype, varying between 75 to 92% of total pemphigus patients. Although no community based studies are undertaken to estimate the incidence of pemphigus in India, it is relatively common. A questionnaire based survey in Thrissur district of south India estimated pemphigus incidence to be 4.4 per million population. Mortality due to pemphigus has decreased remarkably with the aggressive and widespread use of corticosteroids, prior to which it was as high as 90%. High dose corticosteroids were once used in combination with other immunosuppressants with good improvement, but such high doses of corticosteroids were often associated with severe side effects, and were responsible for the death of nearly 10% of the patients. With the aim of reducing the adverse effects of long term, high dose steroid administration dexamethasone cyclophosphamide pulse (DCP) therapy was introduced in 1984. Since then DCP or oral corticosteroids with or without adjuvant immunosuppressants (azathioprine, cyclophosphamide, mycophenolatemofetil, and cyclosporine) have been the corner-stone of therapy for these disorders in India. Despite the benefits associated with DCP therapy compared to high dose oral steroids, it cannot be denied that even DCP therapy with or without adjuvants can lead to numerous adverse events, which account for majority of deaths in pemphigus. Moreover there are few patients who fail to improve with these conventional treatments or have contraindications for their usage. Thus there has been a constant search for newer therapeutic modalities in pemphigus. Rituximab (Reditux. Dr. Reddy’s, Hyderabad, India and MabThera TM , Roche, Basel, Switzerland), a monoclonal chimeric IgG1 antibody targeting the B cell specific cell-surface antigen CD20, is one such newer novel therapy for pemphigus (an off-label indication for its use. It has so far been approved by FDA for use only in CD 20+ B cell non-Hodgkin’s lymphoma, treatment resistant rheumatoid arthritis, Wegener’s granulomatosis and microscopic polyangiitis).

There is currently no consensus on the optimal dosage and schedule of rituximab in treatment of pemphigus. The various treatment protocols followed include:

  1. Lymphoma protocol- Most commonly followed protocol. Rituximab is administered at a dose of 375mg/m 2 body surface area weekly for four weeks.
  2. Rheumatoid arthritis protocol- Two doses of rituximab 1g is administered at an interval of 15 days. Increasingly used by dermatologists and is the protocol currently followed in our institute. Advantage over the lymphoma protocol include less cost and fewer infusions.
  3. Combination therapy- Rituximab has been used in combination with IVIG, immunoadsorption and dexamethasone pulse therapy
  4. Long-term rituximab treatment with regular infusions every 4 or 12 weeks following an induction cycle of infusions every week

Full article can be viewed at: http://www.ijdvl.com/article.asp?issn=0378-6323;year=2012;volume=78;issue=6;spage=671;epage=676;aulast=Kanwar

Background:  Desquamative gingivitis refers to a clinical manifestation associated with several mucocutaneous disorders. The most common are mucous membrane pemphigoid, pemphigus vulgaris and lichen planus. Their specific diagnosis is better established by histopathological and immunofluorescence evaluation.

Objective:  To examine cases of desquamative gingivitis using reflectance confocal microscopy and compare the findings with those of normal gingiva. Moreover, confocal microscopy findings in desquamative gingivitis were compared to conventional histopathology of the biopsied lesions, in order to establish criteria for this non-invasive diagnostic technique.

Methods:  Cases suspected of mucous membrane pemphigoid, pemphigus vulgaris and lichen planus were included, totalizing twenty-five cases. Reflectance confocal microscopy was performed the gingival of a healthy person and on gingival lesions. All lesions were biopsied in order to perform a reflectance confocal microscopy- histopathologic correlation.

Results:  Reflectance confocal microscopy exam of the gingival lesions suspected of mucous membrane pemphigoid revealed a separation at the level of dermal-epidermal junction, filled with small bright structures interpreted as blood cells. Histopathological and immunofluorescence aspects confirmed the diagnosis. For pemphigus vulgaris, reflectance confocal microscopy aspects were of intraepithelial cleft with round detached cells interpreted as acantholytic keratinocytes, similar to the histopathological features. Hyperkeratosis and spongiosis associated with infiltration of inflammatory cells, recognized as small bright cells intermingling the honeycomb keratinocyte epithelial structure, were seen in lichen planus. Mild bright round structures interpreted as necrotic keratinocytes and mild bright stellate structures, interpreted as melanophages in the dermis were also seen. These features were present in histopathology, confirming the diagnosis of lichen planus.

Conclusion:  We propose the use of reflectance confocal microscopy as a useful tool to help distinguish between the three most common causes of desquamative gingivitis.

full article available at: http://onlinelibrary.wiley.com/doi/10.1111/bjd.12021/abstract

Background  The classic treatment for pemphigus vulgaris is prednisolone. Immunosuppressive drugs can be used in association.

Objective  To compare the efficacy of Azathioprine in reducing the Disease Activity Index (DAI).

Patients and methods  A double blind randomized controlled study was conducted on 56 new patients, assigned to two therapeutic groups: (i) prednisolone plus placebo; (ii) prednisolone plus Azathioprine. Patients were checked regularly for 1 year. ‘Complete remission’ was defined as healing of all lesions after 12 months, and prednisolone <7.5 mg daily, (DAI ≤ 1). Analysis was done by ‘Intention To Treat’ (ITT) and ‘Treatment Completed Analysis’ (TCA).

Results  Both groups were similar in age, gender, disease duration, and DAI. Primary endpoint: By ITT and TCA, the mean DAI improved in both groups with no significant difference between them. The difference became significant for the last trimester (3 months; ITT:P = 0.033, TCA: P = 0.045). Secondary endpoint: The total steroid dose decreased significantly in both groups, with no significant difference between them, except for the last trimester (ITT: P = 0.011, TCA: P = 0.035). The mean daily steroid dose decreased gradually in both groups becoming statistically significant in favour of azathioprine, in the last trimester, especially at 12th months (ITT: P = 0.002, TCA:P = 0.005). Complete remission was significant at 12 months only for TCA (AZA/Control: 53.6%/39.9%, P = 0.043).

Limitations  Sample size was rather small to demonstrate all differences. Other limitations include the choice of primary and secondary endpoints and the unavailability to measure thiopurine methyltransferase activity.

Conclusion  Azathioprine helps to reduce prednisolone dose in long-run.

Full article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-3083.2012.04717.x/abstract;jsessionid=4F8C646E8902BB54AC0026B542EF91FD.d03t01

Pemphigus foliaceus, the most common autoimmune skin condition in dogs and cats, is characterized by pustules, erosions, and crusts. In this article, we focus on the diagnosis and treatment of pemphigus foliaceus in dogs and cats.

The signs of an attack on keratinocyte adhesion structures are clinically evident. When the tight bonds between superficial keratinocytes are affected, it manifests as vesicles and pustules. When the tight bonds between basilar keratinocytes and the skin’s basement membrane are affected, it manifests as bullae (large blisters) and ulcers.

In pemphigus foliaceus in people, the most common target of autoantibodies is the desmoglein 1 (DSG1) glycoprotein in the desmosome. The autoantibody response primarily involves IgG (IgG4 subclass). Initial studies in dogs with pemphigus foliaceus only rarely detected an IgG autoantibody response, but more recent work using different substrates in indirect immunofluorescence testing confirms that IgG autoantibodies are important in canine pemphigus foliaceus. However, DSG1 is not commonly targeted in pemphigus foliaceus in dogs ; it is not yet known which part of the desmosome is targeted in most canine pemphigus foliaceus cases. Early immunoblotting studies revealed that the target was a 148 kDa or 160 kDa protein. Immunoelectron microscopy shows that the site of autoantibody binding is in the extracellular region of the desmosome.

Genetic factors can influence the development of pemphigus foliaceus. In dogs, it is more frequently diagnosed in two breeds with closely related genotypes, Akitas and chows. Pemphigus foliaceus has also been reported in littermates. No breed disposition has been noted in feline pemphigus foliaceus. Sex and age appear to be unrelated to the development of pemphigus foliaceus in dogs and cats. The age of onset is variable and ranges from 1 to 16 years in dogs and less than 1 year of age4 to up to 17 years of age in cats.

Background  Pemphigus foliaceus (PF) is a chronic cutaneous autoimmune blistering

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disease that is characterized by superficial blistering of the skin, and according to the current perspective is caused by autoantibodies directed against desmoglein (Dsg) 1.

Objectives  To examine early acantholysis in the skin of patients with PF at an ultrastructural level.

Methods  Two Nikolsky-negative (N−), five Nikolsky-positive (N+) and two lesional skin biopsies from immunoserologically defined patients with PF were studied by light and electron microscopy.

Results  We found no abnormalities in N− PF skin, whereas all the N+ skin biopsies displayed intercellular widening between desmosomes, a decreased number of desmosomes and hypoplastic desmosomes in the lower epidermal layers. Acantholysis was present in two of five N+ biopsies, but only in the upper epidermal layers. The lesional skin biopsies displayed acantholysis in the higher epidermal layers. Hypoplastic desmosomes were partially (pseudo-half-desmosomes) or completely torn off from the opposing cell.

Conclusion  We propose the following mechanism for acantholysis in PF: initially PF IgG causes a depletion of nonjunctional Dsg1, leading to intercellular widening between desmosomes starting in the lower layers and spreading upwards. Depletion of nonjunctional Dsg1 impairs the assembly of desmosomes, resulting in hypoplastic desmosomes and a decreased number of desmosomes. In addition, antibodies might promote disassembly of desmosomes. In the upper layers of the epidermis, where Dsg3 is not expressed and cannot compensate for Dsg1 loss, ongoing depletion of Dsg1 will finally result in a total disappearance of desmosomes and subsequent acantholysis.

Full article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2133.2012.11173.x/abstract;jsessionid=624E75DA95767387AA80E95C275F4100.d02t01

MedWire News: Researchers have identified the primary target of the autoantibodies found in the serum of patients with the blistering skin disorder pemphigus vulgaris (PV).

PV patients develop antibodies against the proteins desmoglein (DSG)1 and 3, which help epidermal cells stick together and maintain the integrity of the skin, causing painful blistering on the skin and mucus membranes.

Giovanna Zambruno (Istituto Dermopatico dell’Immacolata, Rome, Italy) and colleagues found that the cis-adhesive interface of the DSG3 extracellular domain (EC)1 is the main target of the PV autoantibody (A)224 generated in the serum of patients with PV.

Existing therapies for the condition target the whole immune system, but this can cause problems with side effects and can result in patients being vulnerable to infections.

To pinpoint the trigger of the autoantibody production in PV more specifically, Zambruno and team isolated 15 immunoglobulin (Ig)G antibodies specific for DSG3 from two patients with the disorder.

Of these, three disrupted layers of skin cells in the laboratory and two were pathogenic when expressed in a murine passive transfer model.

The epitopes recognized by the pathogenic PV antibodies were isolated to the DSG3 EC1 and EC2 subdomains and a specific serologic assay was used to pinpoint the target of the PVA224 as being the cis-adhesive interface on EC1.

The researchers suggest that the autoreactivity seen in PV is due to somatic mutations that are generated by an antigen other than DSG3, as binding to DSG3 disappeared when the somatic mutations reverted to the germline sequence.

“The identification of an immunodominant region targeted by pathogenic antibodies has implications for diagnosis of PV and opens new perspectives toward the establishment of therapeutic approaches for treatment of PV patients,” write Zambruno and team in the Journal of Clinical Investigation.

“Finally, the germlined version of the PV autoantibodies may lead to the identification of the antigens that eventually lead to development of this life-threatening disease.”

medwireNews (www.medwire-news.md) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

Read at: http://www.medwire-news.md/66/101414/Dermatology/Therapeutic_targets_for_pemphigus_vulgaris_discovered.html