Metabolic syndrome is a cluster of conditions — increased blood pressure, a high blood sugar level, excess body fat around the waist, and abnormal cholesterol levels — that occur together, increasing the risk of heart disease, stroke, and diabetes. Metabolic syndrome is closely linked to obesity, which is now viewed by many scientists as an autoimmune, inflammatory disorder. However, the various immune-mediated mechanisms that participate to the development of obesity are not well characterized. An advanced understanding of these mechanisms — and their interactions — would open up the exciting possibility of developing immuno-modulatory therapeutic strategies for the treatment of obesity and obesity-associated complications.
Now, results from a new study advance our understanding of how the immune response is linked to metabolic syndrome and obesity. The study (Perforin-Positive Dendritic Cells Exhibit an Immuno-regulatory Role in Metabolic Syndrome and Autoimmunity) was carried out using a mouse model and focused on a specific type of immune cells — a rare subpopulation of newly discovered dendritic cells that release a toxic molecule called perforin.
Perforin is contained in granules present within two specialized type of T cells — called cytotoxic T lymphocytes and natural killer cells — which destroy cells infected with viruses. It opens up pores on the surface of the cells to be killed, allowing other killer molecules to enter these cells and induce cell death. Senior study author Yair Reisner and his collaborators had previously identified dendritic cells rich in granules containing perforin — they named these cells perf-DCs.
Dendritic cells are stellate or tree-like cells that capture antigens, convert them into small pieces, and display these small pieces on their cell surfaces in a process called antigen presentation. The dendritic cells then travel to lymph nodes or the spleen where they stimulate other cells of the immune system to respond to invading microbes.
In the past few years, scientists have discovered that dendritic cells play additional roles in the immune response. The unexpected discovery of granules containing perforin in a population of dendritic cells directed Reisner and his collaborators to understand the role played by this population.
The scientists hypothesized that perf-DCs could be able to kill normal cells in certain autoimmune diseases. To test their hypothesis, the scientists developed mice that lacked perf-DCs. Surprisingly, they found that these mice gained weight and exhibited features of metabolic syndrome even when they consumed a standard diet. In addition, these mice presented — in their fat tissue — different types of the T lymphocytes that normally direct the immune response. Once these T lymphocytes were removed from the mice, lack of perf-DCs had no effect on the development of obesity and metabolic syndrome.
“Notably, mice lacking these regulatory dendritic cells were also found to be more prone to develop another form of autoimmunity with symptoms similar to those found in multiple sclerosis,” Reisner said in a press release.
Thus, perf-DCs may normally function to keep certain populations of T lymphocytes under control in order to avoid autoimmune responses. In other words, perf-DCs may contribute to immune tolerance by deleting potentially harmful T lymphocytes. Immune tolerance is a process that silences dangerous immune cells, and prevents them from attacking the body’s own tissues or innocuous materials present in the body. Lack of perf-DCs does not allow silencing of T lymphocytes involved in the development of metabolic abnormalities and weight gain.
Reisner told Science: “We are now working in human cells to see if there is something similar going on there. I think this is the beginning of a new focus on a new regulatory cell.” However, he said in the press release: “It is hard to predict how this might impact patient care.” Indeed, immunologist Vishwa Deep Dixit, who was not involved in the work, told Science: “Talking about therapeutics at this point would be a bit of a stretch.”
Therapeutics or not, we’re moving towards an improved understanding of the immune-mediated mechanisms at the basis of obesity and metabolic syndrome.
The revelation of “Perforin containing Dendritic Cells” and its role in the development of Metabolic Syndrome changes the manner in which we understand Obesity, Diabetes, and even the subject of Immunology. This shines a new light on those experiencing Diabetes, Obesity and other Metabolic Syndrome related deficiencies, as being subject to an actual disease rather then not being able to control their own physical condition. Typically, treatment for Metabolic Syndrome includes weight loss surgery, physical exercise, a heart-healthy diet, medications such as statin, and even sometimes, hormonal treatment. The role of regulatory cells as modes of treatment for those experiencing Metabolic Syndrome and related conditions, could perhaps find a role in treatment for conditions such as Diabetes and Obesity.
In Dr. Yair Resiner’s publication titled “Perforin-Positive Dendritic Cells Exhibit an Immunoregulatory Role in Metabolic Syndrome and Autoimmunity”, he and his colleagues were able to demonstrate that perf-DC’s are able to control inflammatory T-Cells and play a crucial role in the regulation of Metabolic Syndrome. However, perf-DC’s also exhibited a role in the onset of Multiple Sclerosis, a debilitating autoimmune disorder that effects the central nervous system, as a result of its interaction with inflammatory T-Cells.
Given that these experiments have thus far have mostly been carried out on mice, the exact result and role of perf-DC’s in the human body, with a human immune system cannot be certain. However moving forward, it would be interesting to see whether or not scientists and physicians can harness this knowledge of perf-DC’s and inflammatory T-cells to help treat conditions in humans such as multiple sclerosis, metabolic syndrome, and other possible autoimmune disorders that are affected by perf-DC’s as a regulatory cell.
Work Cited:
Zlotnikov-Klionsky et al., 2015, Immunity 43, 776–787 October 20, 2015 ª2015 Elsevier Inc. http://dx.doi.org/10.1016/j.immuni.2015.08.015
While going through the press release by Reisner and the study which discovered the presence of pref-DC, a sudden streak of thought that came to my mind was Atherosclerosis.
Atherosclerosis is a process of formation of plague in the arteries, which is related to the level of cholesterol (mainly LDL) in the plasma. As LDL crosses the lumen of the artery, it is subjected to oxidative stress and damage which triggers the monocytes to come for the rescue. As monocytes comes into play and gets transformed into macrophages, it leads to the development of foam cells and triggered immune response which recruits interleukins, interferons, T-lymphocytes and cytokines. Depending on the site of plague formation it can lead various diseases can occur like heart attacks, strokes, chronic kidney disease etc.
Apart from lifestyle and genetic reasons, inflammatory and immune responses also play an important role in the formation of plague and its related diseases. The properties of perf-DC especially the immune- tolerance activity and metabolic control could reduce the risk of development of atherosclerosis. The further studies could possibly be a breakthrough in the field of immunology and therapeutics for major metabolic disorders.
Obesity is associated with disorders that are mediated by the immune system, such as atheroscelerosis and non-alcoholic steatohepatitis (NASH). Oxidative stress is related to both of these diseases. Nonalcholoc fatty liver disease is caused by obesity and may evolve into NASH. Oxidative stress has a very important role in the evolution of NAFLD to NASH. Antigens that are generated through oxidative stress and originated within fatty livers stimulate both humoral and cellular adaptive immunity. Responses of the immune system that are stimulated by antigens related to oxidative stress have the ability to strengthen the progression of experimental NASH. This takes place through the Th-1 activation of CD4+ T cells. The CD4+ T cells then stimulate macrophages as well as the recruitment of liver CD8 cells and NK cells. Further research on NASH may lead to the discovery of aspects of NASH that are similar with other diseases that impair the regulation of the immune system where NASH therapy may be applied to treat these diseases as well.
(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491900/)
Metabolic disorders are results of imbalance in biochemical function of the body cells. A very important aspect of our immune system is discrimination between self and non-self-antigens. When self-antigens are attacked by immune cells, it results in autoimmune diseases. Dendritic cells acts as a bridge between innate and adaptive immune response. Function of Dendritic cells is to present antigen so that specific T cells gets activated. Perf- dendritic cells with a large number of granules are aggressive form of dendritic cells in killing their target cells. It has been seen that over expression of inflammatory genes are associated with obesity and metabolic disorders. Due to inflammation, level of circulatory cytokines are increased in blood and in turn alters the biochemical signaling pathway resulting in metabolic dysfunction.
According to this article, mice lacking Perf- dendritic cells in their adipose tissue have different types of T cells accumulation that causes immune response and those mice are prone to develop other forms of autoimmunity as well. Studies have shown that mice lacking perforin dendritic cells have high cholesterol, sign of insulin resistance and presence of biomarkers indicating heart disease and high blood pressure. But, the good news is that metabolic disorders can be prevented by the more disciplined and healthy life style.
References
Zabelina VD, Zemskov VM, Mkrtumian AM, Balabolkin MI, Antonova OA. [Characteristics of immune system in patients with metabolic syndrome].Ter Arkh. 2004; 76(5):66-72.
Min Chen, Kumar Felix, and Jin Wang. Critical role for perforin- and Fas-dependent killing of dendritic cells in the control of inflammation. Blood First Edition Paper, pre published online October 31, 2011; DOI 10.1182/blood-2011-06-363994
So is it autoimmunity which triggers metabolic changes in obesity or its other way around? That is what pop up in my head while I was reading the article. The popular quote about obesity reversal ‘Eat less, exercise more’ seems dubious with more focused research on obesity. It’s proven in so many research that obesity is not just a disease, but it is more of a syndrome. It is associated with so many conditions such as hypertension, diabetes mellitus, worsened asthma and COPD etc. That is why the term obesity vaguely converts to metabolic syndrome. Although dietary regulation still plays a big role in its management but approaches such as autoimmunity associated with obesity provide a new angle to the whole scenario. It is quite fascinating to imagine that how dendritic cells deal with autoimmunity. As mentioned by Dr. Reisner that certainty of perforin in autoimmunity yet to be addressed in human therapeutics, but it will be interesting to see how perforin going to play a role if administer exogenously. But there is strong evidence to consider the role of perforin for human trials. One of the study I came across where the author explained how genetic variation in perforin gene leads to chronic inflammatory pathology. Which shows how important perforin expression is for immune interactions. Although it’s released from dendritic cells, but it expands its role in both innate as well as acquired immunity. As it helps in integration of immunity, so a lot of factors need to consider before trying it on metabolic syndrome patient.
Reference: S. Buttini, G. Cappellano, P. Ripellino, C. Briani et al 2015. Variations of the perforin gene in patients with chronic inflammatory demyelinating polyradiculoneuropathy: Genes and Immunity; 16; 99–102. doi:10.1038/gene.2014.59
Wow, the findings in this recent study are amazing! The fact that there are a rare sub-population of our well-known dendritic cells, containing granules which contain the toxic compound, perforin shows how important the immune system is and how the smallest duties make such large effects in the body. Metabolic syndrome (METs), Type 2 diabetes and cardiovascular disease, are very common health problems, and have been the focus of several studies. Metabolic syndrome has been characterized by insulin resistance and chronic low-grade inflammation, in which conditions are the consequences of the complex interaction between adipocytes and immune cells, linking it to an altered immune response1. Past studies are support to the innovative claim that perforin-containing dendritic cells (perf-DCs) are capable of killing normal cells in certain autoimmune diseases. This study strikes my interest in such a way and I think these perf-DCs should be studied more in depth, especially in relation to obesity.
This toxic molecule could potentially explain some of the many cases of obese indivuduls, that are on standard diets, while their weight causes implications that they are eating, excessively. I would definitely like to see more studies, using human cells from METs patients, to gain a beter understanding of the role of the perf-DCs, with later potential of creating some type of vaccine or therapy for metabolic syndrome related issues. If obesity, is an autoimmune disorder, as scientists are claiimg, the disease may be a little more challenging, however, the clear understanding will provide a way of gathering better ways of targeting the disorder. The function of perf-DCs can be key players in regulating the immune response, which indirectly, connects the lack thereof, to altered functionality of certain immune cells, such as, T-lymphocytes.
Works Cited
Paragh, G., Seres, I., Harangi, M., and Fülöp P. “Dynamic interplay between metabolic syndrome and immunity. .” Adv Exp Med Biol. 824 (2014): 171-90.
Aisha’s point in regards to the creation of a vaccine to fight certain conditions, while employing dendritic cells, was something I had thought of as I was reading through the article and posts below. I came across an insightful study that expanded into this exact topic. It was conducted by Dr. Catharina Gross and Dr. Wiendl Heinz. The study begins by discussing how Autoimmune diseases are a consequence of a misconfigured regulatory apparatus. Gross and Heniz further elaborate on how Tolerogenic Dendritic Cells are significant actors in this network by way of creating and preserving both central and peripheral tolerance. In light of the information expanded upon in the study, experiments conducted outside of actual organisms created Tolgerogenic Dendritic Cells, which could be thought of as vaccines to re-introduce tolerance in order to fight specific autoimmune disorders. Still, Tolerogenic Dendritic cells according to Dr. Gross exemplify a diverse array of dendritic cells that are located in different tissues and maintain tolerance through a wide spectrum of different mechanisms. A host of different animal models as illustrated in the study have exhibited their ability to restore antigen-specific tolerance in large part assisted by the induction of antigen-specific T cell anergy and or bolstering regulatory T cells. Obstacles in the study that will have to be addressed include the selection of antigens, dendritic cell generation protocols, and of course appliance procedures. Clearly, a lot more research must be invested into this topic in order for more affirmative results to be yielded.
Work Cited:
Gross, Catharina C., and Heinz Wiendl. “Dendritic cell vaccination in autoimmune disease.” Current opinion in rheumatology 25.2 (2013): 268-274.
Popular knowledge says the only point in the T lymphocyte lifecycle where self-reactive cells may be identified and eliminated in the thymus. T regulatory cells, although they can identify and suppress self-reactive lymphocytes do not truly eliminate the potentially autoimmune cells in circulation. Once in circulation autoreactive cells always retain the potential to become activated and wreck havoc or so was thought. The existence of a type of perforin secreting resident cell capable of rooting out self-reactive lymphocytes shows that there are multiple points of time and places where the body may eliminate the cells responsible for autoimmunity.
It is also known that the intestinal environment, including its microbial composition may affect the development of resident cells and cytokine production. Under healthy conditions, the intestinal microbiota stimulates the development and proliferation of intestinal dendritic cells, which intern appear to develop a tolerance for mutualistic flora. However, should the normal flora be eliminated through diet or antibiotics, intestinal dendritic cell development is compromised, and the intestine becomes inflammation prone.
If the discovery of perf-DC is considered in the context of what we know about microbiota and diet, is it not possible that processed meat and food additives known for inducing inflammation through mechanisms not fully understood may do so in part by altering the efficacy of Perf-Dendritic cells? If either through directly acting on dendritic receptors with the effect of reducing activity, or more likely distorting the composition of the intestinal microbiota with the ultimate result of reducing the proliferation of dendritic cells, Perf-DC included. If so, then understanding ways to manipulate this network of cell development, even if only through modest means such as altering the microbiome may be an avenue for prophylactic and therapeutic intervention.
Bibliography: 1. Wu H, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes. 2012;3(1):4-14. doi:10.4161/gmic.19320.
Bibliography: 2. Chistiakov D, Bobryshev Y, Kozarov E, Sobenin I, Orekhov A. Intestinal mucosal tolerance and impact of gut microbiota to mucosal tolerance. Front Microbiol. 2015;5. doi:10.3389/fmicb.2014.00781.
Bibliography: 3. Chassaing B e. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. – PubMed – NCBI. Ncbinlmnihgov. 2015. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25731162. Accessed November 18, 2015.
I find the study along with the support of evidence of obesity as an autoimmune disease quite intriguing. However, nearly two-thirds of the American population is overweight (clinical.diabetesjournal.org) and I personally don’t believe that all of those people lack perforin dendritic cells (perf-DCs). The study done by Reisner and the overlapping study done by Daniel Winer in Canada (news.sciencemag.org) looked at obesity caused by a lack of perf-DCs while consuming a normal diet and lack of perf-DCs while consuming a high fat diet. What I did not find evidence of is a study of obesity caused by lack of perf-DCs, but also included consistent exercise while consuming a normal/low fat diet. What if there is a portion of the population that lacks perf-DCs but is not obese because they eat a nutritious diet and exercise regularly? Could that mean that lack of perf-DCs just increase the likelihood of obesity without a proper diet and without adequate exercise? And not necessarily that if a person lacks perf-DCs that they will undoubtedly be overweight/obese? I undoubtedly believe that these studies are a step towards therapeutics for obesity. However, I think that researchers should consider other possible causes of obesity in conjunction with lack of perf-DCs.
Works cited:
Perforin-Positive Dendritic Cells Exhibit an Immuno-regulatory Role in Metabolic Syndrome and Autoimmunity
Yael Zlotnikov-Klionsky2, Bar Nathansohn-Levi2, Elias Shezen, Chava Rosen, Sivan Kagan, Liat Bar-On, Steffen Jung, Eric Shifrut, Shlomit Reich-Zeliger, Nir Friedman, Rina Aharoni, Ruth Arnon, Oren Yifa, Anna Aronovich, Yair Reisner.
I agree, Torrellas Beasley, obesity is a big problem here in the United States. Obesity can lead to high blood pressure, stroke, heart problems, diabetes, high cholesterol, and even put you at a high risk for certain cancers. It is highly unlikely that here in the United States obesity and metabolic syndrome stems from a lack of perf-DCs. Studies have shown Americans consume high amounts of fat, sugar, sodium and carbohydrates. The American Heart Association recommends no more than 6-9 teaspoons of added sugar per day while the average American consumes 20 teaspoons or more of added sugar. U.S. Food and Drug Administration calculates on average Americans consume 3,300 milligrams of sodium everyday which is 1,000 milligrams over the recommended amount of sodium. Also, the average American consumes more than 1,800 milligrams of sodium over what is recommended for those over 50 years of age, African-Americans of all ages, those who have high blood pressure, diabetes or chronic kidney disease. Also, it should be considered what is a normal healthy diet for mice is not a normal diet for humans, so having a lack of perf-DCs in humans may not have an effect because a healthy diet of fruits and vegetables offer antioxidants that strengthen the immune system. In addition, perf-DCs should be tested in vivo with human immune cells because there may be a difference in concentration and perf-DCs in humans may have different immunological targets. Also, the different T-lymphocytes in human fat cells may be able to control perf-DCs.
I found the association between metabolic syndrome, obesity, autoimmunity, and dendritic cells quite fascinating. Initially, I thought a dendritic cell’s role was to carry the antigen from the infection site, and present the antigen to the lymph node to elicit an adaptive immune response. However, given these new findings, it suggest the some dendritic cells are responsible for releasing perforin to induce cell death. Further experiments with mice indicated that perforin- dendritic cells are responsible for regulating T lymphocytes to avoid autoimmune responses, by deleting potentially harmful lymphocytes. These new findings are helpful with correlating obesity with metabolic syndrome, because the lack of perforin dendritic cells causes the T lymphocytes involved with metabolic abnormalities and weight gain to remain present in an individual. Therefore, the lack perforin dendritic cells are more prone and susceptible to developing metabolic syndrome and obesity. Although, the findings were produced through mice studies, I think the next step is to conduct in experiment with humans. We should compare the amount of perforin dendritic cells in obese individuals and in healthy individuals to identify any correlation between the two subjects. Given that these results are consistent with the mice findings, I think it would be beneficial to screen children at an early age to detect there perforin dendritic cells, to help prevent obesity in children that are more susceptible.
References:
Perforin-Positive Dendritic Cells Exhibit an Immuno-regulatory Role in Metabolic Syndrome and Autoimmunity Yael Zlotnikov-Klionsky2, Bar Nathansohn-Levi2, Elias Shezen, Chava Rosen, Sivan Kagan, Liat Bar-On, Steffen Jung, Eric Shifrut, Shlomit Reich-Zeliger, Nir Friedman, Rina Aharoni, Ruth Arnon, Oren Yifa, Anna Aronovich, Yair Reisner.
I agree, the knockout-chimeric mouse models like the ones utilized by Reisner do not recreate the exact sort of lifestyle and mechanisms behind obesity in normal humans and it most likely the study did not seek to. Nevertheless, Reisner’s did use the presence or absence of Perf-DC as an independent variable and with as much control as you could get from bone grafts, did show that a lack of Perf-DCs do have a causal relationship to more self-reactive lymphocytes, and more inflammation and both of those conditions do have a well-known relation to metabolic syndrome.
Most people suffering from obesity probably aren’t null mutants for perforin Dendritic Cells, but we do know from studies like the ones carried out by Wu that healthy makeup of intestinal microbiota or lack of thereof is enough to create a deficiency in resident Dendritic cells. Combine that with studies that show the additives in processed food can distort the makeup of a healthy microbiome and induce intestinal inflammation and it isn’t a stretch that with all other things held equal, impaired dendritic cell function will contribute to metabolic syndrome.
I also agree with your point of view Juan regarding the healthy makeup of intestinal microbial or lack thereof is enough to create a deficiency in resident Dendritic cells in combination with how additives in process foods distort a healthy microbial environment digestive gut. Furthermore, poor diet and nutrition is also a leading factor with the development of obesity. So even though individuals who lack Perf-DCs are more prone and susceptible to developing metabolic syndrome and obesity, I feel it is ultimately the responsibility of the individual or parent’s of the individual to take care of their body, exercise, and develop eating habits to prevent or lower the risk of disease.
I find the discovery of the potential linkage of Perf-DCs and obesity as being quite fascinating. Lower levels of Perf-DCs in mice have been found to be associated with higher rates of metabolic syndrome causing obesity. I do however, feel that more research should be done to ascertain that higher than normal Perf-DC levels are not negative for the immune system due to the possible over regulation of harmful T lymphocytes. It may be possible that the body needs to maintain a limited amount of “bad” lymphocytes in order for it to not attack itself. In addition to not exactly knowing how much inherent regulation of the T lymphocytes is necessary when comparing mice to humans, I find it to be very important to confirm that added Perf-DCs to human hosts cannot work counter-productively. I fear that a potential treatment developed that increases Perf-DC count could actually cause greater autoimmunity than the amount it was intended to prevent. If too much Perf-DC is present, there could be a severe enough deficiency of the harmful T lymphocytes where excess perforin is inadvertently used on healthy immune cells. Since Perf-DCs rely on antigens in order to eliminate the bad T cells, it will also be very important to not desensitize the dendritic cell-antigen interaction by creating an overabundance of DCs that cannot interact or correctly perform their functions (Nat Rev Immunol). These are critical considerations that I feel research should account for when developing ways to apply Perf-DCs to the human immune system.
Bird, L. (2015). Dendritic cells: Perforin protection. Nat Rev Immunol Nature Reviews Immunology, (15), 666-667. doi:10.1038/nri3926
I find the study along with the support of evidence of obesity as an autoimmune disease quite intriguing. However, nearly two-thirds of the American population is overweight (http://clinical.diabetesjournals.org/content/22/1/1.full) and I personally don’t believe that all of those people lack perforin dendritic cells (perf-DCs). The study done by Reisner and the overlapping study done by Daniel Winer in Canada (http://news.sciencemag.org/biology/2015/09/some-obesity-may-be-caused-faulty-immune-system) looked at obesity caused by a lack of perf-DCs while consuming a normal diet and lack of perf-DCs while consuming a high fat diet. What I did not find evidence of is a study of obesity caused by lack of perf-DCs, but also included consistent exercise while consuming a normal/low fat diet. What if there is a portion of the population that lacks perf-DCs but is not obese because they eat a nutritious diet and exercise regularly? Could that mean that lack of perf-DCs just increase the likelihood of obesity without a proper diet and without adequate exercise? And not necessarily that if a person lacks perf-DCs that they will undoubtedly be overweight/obese? I undoubtedly believe that these studies are a step towards therapeutics for obesity. However, I think that researchers should consider other possible causes of obesity in conjunction with lack of perf-DCs.
Works cited:
Yael Zlotnikov-Klionsky2, Bar Nathansohn-Levi2, Elias Shezen, Chava Rosen. “Perforin-Positive Dendritic Cells Exhibit an Immuno-regulatory Role in Metabolic Syndrome and Autoimmunity.” 20 October 2015. Volume 43, Issue 4, p776–787.
http://news.sciencemag.org/biology/2015/09/some-obesity-may-be-caused-faulty-immune-system
http://clinical.diabetesjournals.org/content/22/1/1.full
I agree with your premise that Perf-DCs alone cannot be the sole contributor to obesity or metabolic syndrome in the population. However, I believe the article simply intended to inform people as to what are other potential factors that could pre-dispose an individual to obesity not stating that there was a direct cause necessarily. I find it important that research continues to find correlations and associations because these findings over time lead to discoveries that in fact identify biological causation. I feel researchers did consider the other possible causes of obesity but they wanted to bring light to the potentially large effect of Perf-DC’s when both their presence and function had previously been unknown by many. And while the results do not show direct causation yet, they did account for varying diets in mice which whether standard or not lead to an increase in the mice’s weight and showed signs of the metabolic syndrome. I would agree with those that argue that mice are not biologically identical to humans, but the article still did a good job in highlighting what could be a very important relationship between Perf-DCs and autoimmunity.
I find it interesting the connection to multiple sclerosis since this autoimmune disease has also been linked to vitamin D deficiency. This important vitamin is a fat soluble molecule that also travels through the lymphatic system after being absorbed in the small intestine until it is stored in adipose tissue. As discussed in Wortsman et al “Decreased bioavailability of vitamin D in obesity”, increase body fat decreases the serum vitamin D concentrations and they concluded that this molecule is less likely to be released from adipose tissue when needed. Their study also showed an increase in the plasma levels of parathyroid hormone. In Abdallah Sassine Geara et al article, “Effects of parathyroid hormone on immune function”, the review of various research on parathyroid hormone (PTH) and its effect on immunological function was discussed and most notable was that different immune cells have PTH receptors including T lymphocytes and that hyperparathyroidism lead to an increase in CD8 cells. All these interactions could lead to an interesting avenue of study for both metabolic syndrome as well as new areas of study in the treatment of multiple sclerosis.
References:
Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. American Journal of Clinical Nutrition. 2000;72(3):690–3.
http://ajcn.nutrition.org/content/72/3/690.long
Abdallah Sassine Geara, Mario R. Castellanos, Claude Bassil, et al., “Effects of Parathyroid Hormone on Immune Function,” Clinical and Developmental Immunology, vol. 2010, Article ID 418695, 10 pages, 2010. doi:10.1155/2010/418695
http://www.hindawi.com/journals/jir/2010/418695/cta/
Obesity is apparently a complex, challenging disorder to tackle. For example, adipocytes are able to produce pro-inflammatory cytokines, making it hard to determine whether the inflammation causes the weight gain or the opposite. People now believe that our immune system is able to handle adipocytes and fatty acids in a way similar to that in dealing with invaders, including phagocytosis, antigen presentation and cytotoxicity. Yair Reisner and collaborators work shows the correlation between the lack of Perforin positive dendritic cells and the accumulation of pro-inflammatory T cells in the adipose tissue in mice developing metabolic syndrome, suggesting their regulating function. Other researchers reported that perf-DCs may contribute to immune tolerance possibly by deleting potentially harmful T cells in an antigen-dependent manner, and these perf-DCs may commit suicide by “degranulation”, releasing the perforin to themself. However, most of these experiments are conducted with EAE model, but normally the autoreactive T cells are supposed to be eliminated during negative selection. The relationship between the development of metabolic syndrome and autoimmunity is still not clear.
Findings like the Perf-DCs makes the Immune system a tad bit confusing better yet interesting. From prior understanding it was only regular DCs. Knowing that some of the DCs contain perforin is remarkable. Perforin is known to be contained in granules of cytotoxic T lymphocytes and NK cells that destroy virus infected cells. The perf-DCs are linked with metabolic syndrome and autoimmunity. It was discovered that rats which lacked perf-DCs gained weight and exhibited metabolic syndrome. This discovery basically connects the immune system with health issues such as obesity, diabetes, abnormal cholesterol levels etc. What leads to production of perf-DCs in comparison to regular DCs? Does exercising and being lead to production of perf-DCs? Does genetics play a role in perf-DC production? Questions like these come to mind because effects of metabolic syndrome such as obesity can be improved by exercising. I’m also aware that some people find it hard to lose weight even when exercising due to genetic problems.
Knowing the complete production process of perf-DCs and its entire function will be very helpful in finding therapies for health issues associated with metabolic syndrome and autoimmunity. This was an educating article because it expands the role of DC and also creates a mystery as to what else the immune system is linked with.
I think that linking a lack of perf-DC’s to obesity as a whole may be premature, particularly as there has yet to be any human trials. I am doubtful that we can conclude that these statements pertain to all incidence of obesity. The study found that mice deficient of these subset of dendritic cells can be implicated in a decrease in metabolic activity and therefore an increase in weight. While I do not doubt these findings I do have to wonder whether this is true in all cases or if this is just one particular modality. Hypothyroidism also leads to obesity but not all who are obese suffer from this condition. Genetic factors have also shown to be contributors to some incidence, but here again not all who are obese have these either. Further studies in humans are needed before such a claim can be made.
What I did find interesting, however, is the link to autoimmunity. In rheumatoid arthritis and lupus, autoimmune disorders, research has shown that there is a decrease in mature dendritic cells as well as in regulatory T cells, which act as suppressors of chronic inflammation. There is also an increase in CD4+ T cells that express CD25 and Foxp3 (Ishikawa, Shoenfeld, & Sartori, 2014). While further research would be needed to draw a correlation between the findings of this study to that of these autoimmune disorders, one has to wonder if perf-DCs might also play a role in suppression of these overactive T cells.
Ishikawa, L. W., Shoenfeld, Y., & Sartori, A. (2014). Immunomodulation in human and experimental arthritis: including vitamin D, helminths and heat-shock proteins. Lupus, 23(6), 577-587.
Like many others, I agree that lacking perf DCs is probably not the only the cause of obesity. According to the International Diabetes Foundation, nearly one quarter of the adults in the world have metabolic syndrome. Perhaps in other countries, the lack of perf DC cells could potentially be more of a contributing factor, but I think that here in the US, we should be more concerned about our choices regarding eating and physical activity habits. Saying that the discovery of these new DCs is going to going change the way we treat obesity is like saying that we have found the magic solution to what are largely lifestyle related conditions. To me, this seems like a reason to blame biology for eating too many cookies while spending too much time on the couch.
On a serious note, I do wonder if any of the typical treatments for metabolic disorders such as bariatric surgery for example, could influence the number of perf DCs, the numbers of T cells on which the perf DCs act, or any other immune cells for that matter. There have been studies that show that just the drastic reduction in caloric intake after gastric bypass surgery can affect the immune system and it’s ability to defend the body, despite the reduction in inflammation post surgery. Additionally, there other factors such as changes in gut microbiota, bile, and hormone secretion to consider.
http://www.idf.org/metabolic-syndrome
http://msutoday.msu.edu/news/2009/msu-professor-studies-links-between-gastric-bypass-immune-system/
http://www.nature.com/news/weight-loss-surgery-a-gut-wrenching-question-1.15560
I like the idea to present the obesity as a multifactorial syndrome rather than pinpointing on the autoimmunity. As mentioned in the previous comment that it may be a contributing factor but not a prime determinant of the obesity. A sedentary lifestyle and unhealthy eating habits seem major culprits in obesity. Sitting for the long hour is becoming a big problem. ‘Sitting is a new smoking’ is being promoted as a new tagline to bring awareness on this issue. Why I find autoimmunity just one of a contributing factor because there can be the countless reason for obesity. As we can blame to genetics (African American are more tend to put on weight than other races), hormonal imbalances, metabolic dysregulation, psychiatric and psychological factor or a sedentary lifestyle so on the autoimmunity. Although the idea of obesity due to dendritic cell dysregulations seems interesting, yet it still has a long way to go by crossing human trial hurdles and then reach to the therapeutic level. Even if the correlation with autoimmunity is justified, but its fate in the therapeutics may be questionable; as obesity usually associated with many other factors. But this whole assumption about DCs may be possible as autoimmune pathologies somewhat co-exist with obesity; chronic inflammation may be the reason behind it. As hypothesis still in the naïve stage; so in most of the cases eat less, exercise more is the best approach along with a relevant pharmacological intervention.
Reference: Ricordi C, Garcia-Contreras M, Farnetti S 2015. Diet and Inflammation: Possible Effects on Immunity, Chronic Diseases, and Life Span. Journal of American College of Nutrition; 34 Suppl 1:10-3. doi: 10.1080/07315724.2015.1080101.
I agree that obesity is a multifactorial syndrome, but most people don’t see it that way. This study states that metabolic syndrome and obesity have been linked together and is viewed as an autoimmune, inflammatory disorder. In addition to researching the role perf-DCs play, I think it is important to observe hormone concentrations to see the overall picture. The hypothalamus is involved in a number of physiological processes needed to maintain homeostasis. The hypothalamus is involved in energy balance homeostasis or maintaining stable body weight by balancing energy intake with energy expenditure. Leptin is secreted by adipocytes in direct proportion to a person’s body fat percentage. Leptin decreases feeding and increases metabolism to keep body weight at a certain set point. However, obese people seem to have normal to high levels of leptin suggesting leptin may not be very effective for them. Another hormone that plays a role in energy balance is ghrelin. Ghrelin is a hormone released from the stomach when its empty and it stimulates feeding. I think future research on obesity should be focused on the immune system and homeostatic energy balance mechanisms to get a bigger picture of what obesity really is.
Bear MF, Connors BW, Paradiso MA (2016) Exploring the Brain. In: Neuroscience, 4 Edition, pp 498-503: Wolters Kluwer.
Dendritic cells are key elements in relating the innate immune system to the adaptive immune system. They acting as antigen-capturing cells and give their response quickly to the foreign antigens to initiate an adaptive response through the use of T cell and B cell stimulation. Obesity can be known to weaken the innate immune system and can impact the adaptive immune system. Obese dendritic cells will alter T-cell stimulating abilities and cytokine production in comparison to non-obese dendritic cells. Perforin-positive dendritic cells (perf-DCs) can help to keep T lymphocyte population under control to prevent autoimmune responses. The article showed that mice that lack perf-DCs gained weight and showed metabolic syndrome. The perf-DCs can be up regulated and down regulated to control our immune responses specifically with obesity. Along with the Perforin there are other factors that can add to obesity. Studies show that dendritic cells also are involved with CD86 and CD83 in obese. Dendritic cells in obese express much lower levels of CD86, a co-stimulator for a full T-cell response, and lower levels of CD83, a dendritic cell maturation marker with T-cell and B-cell response. It also shows that if levels of CD83 are reduced on obese dendritic cells then they are more vulnerable to viral infection and even defective responses to vaccinations. Dendritic cells that are supposed to be circulating were decreased in numbers in the obese compared to the lean cohort. This study explained that diet-induced obese mice had altered T-cell response to influenza infection. It also says that up-regulation in CD83 was much less in the obese cohort specifically with viral response. It concluded that obesity negatively effect dendritic cells to mature and deliver correct messages, which in return affects T-cell responses and affects the host against viral responses. With the perf-DCs, CD86, and CD83 control, obese organisms can have a better immune response and prevent them for catching higher disease. If further studied, this can also be used to improve the over all immune system of a healthy organism and not just obese.
O’Shea, D., Corrigan, M., Dunne, M. R., Jackson, R., Woods, C., Gaoatswe, G., & … Hogan, A. E. (2013). Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection. International Journal Of Obesity, 37(11), 1510. doi:10.1038/ijo.2013.16
Metabolic syndrome or obesity is the byproduct of our today’s busy lifestyle. What makes obesity really problematic that it affects each physiological function of our body. Not only just adipocytes but every cell get its own share of stress with obesity. I find it quite interesting that how dendritic cells are associated with autoimmunity and obesity. Strange enough but leptin is also elevated in most of the obese people. Why it is strange because leptin is known to reduce appetite and keep one slim but as person start gaining weight, our body try to control weight by releasing more leptin. But a chronically elevated level of leptin decreases the sensitivity of its receptors and they become resistant like the insulin receptor in type 2 diabetes. The elevated leptin also associated with ectopic deposition of fats. So it is more of a vicious cycle, happen due to the faulty metabolism of our body. But as apart from providing satiety the leptin also acts as an immunomodulator by its proinflammatory action. So while I was thinking about it, I was intrigued by following paper on the role of leptin (along with ghrelin) on the maturation of dendritic cells; DOI: 10.1134/S001249661503014X. Ghrelin is a physiological antagonist to leptin in our body. Authors hypothesized that how leptin and ghrelin together regulate dendritic cell maturation. They maintained a specific ratio of immature to mature DC, these immature DCs releases tolerogenic cytokines such as IL-10, TGF-beta 1 etc. So overall help to maintain the tolerogenic effect and prevent the autoimmunity. But as in obesity there is disturb ratio of leptin to ghrelin in one’s body, so that may be the rationalization behind autoimmunity. As disturb leptin to ghrelin ratio further upsets the equilibrium between immature to mature dendritic cells, so weakened the tolerogenic effect from immature DCs and leads to autoimmunity.
Reference: E. G. Orlova, S. V. Shirshev, and O. A. Loginova 2015. Leptin and Ghrelin Regulate Dendritic Cell Maturation
and Dendritic Cell Induction of Regulatory TCells. Doklady Biological Sciences; 462(1); 171-174. DOI: 10.1134/S001249661503014X.
The discovery of perforin-positive dendritic cells is very interesting. I would like to learn more about the lineage of this subset of DCs. DCs express MHC Class II and lack CD3, CD19/CD20, CD16, and CD56. However, there are other markers to distinguish DCs. Myeloid DCs express CD11c and are similar to monocytes, while plasmacytoid DCs express CD123 and physically resemble plasma cells.
Is there a population of myeloid and plasmacytoid DCs expressing perforin as well? Or do only one of these subsets express perforin? And additionally, in what parts of the body are these perforin positive cells expressed? Flow cytometry analysis can answer these questions. It will be exciting to learn more about this new subset of cells.
Source:
Collin M, et al. Human dendritic cell subsets. Immunology. 2013 September; 140(1): 22-30.
The Perforin-positive dendritic cells are very interesting to study. I agree there are other markers to distinguish these cells. They can be regulated to control our immune systems with obesity. How cool would it be to do that? Try and eliminate obesity being a huge problem in the United States? It is not only the Perforin-positive dendritic cells that deal with obesity but multiple other factors like dendritic cells themselves deal with it also. In obese individuals the expression of co-stimulators on Perforin-positive cells are much lower causing an incomplete response from the T-cells. From class, we learned that T cell activation requires the co-stimulator signal and antigen-specific signal. Co-stimulators such as B7 on dendritic cells need to have a high affinity to run the antigen to the T cell and create an immune response and if that is affected then we have an issue. Interestingly enough, Treg cells can also display Perforin-dependent cytotoxicity and dependent on the CD18. Some natural killer cells also have these cytolytic proteins. The point is for it to bind to the target cells to kill infection which brings to the conclusion that perf-DC are critical in our bodies to protect from autoimmunity and metabolic syndromes.
Quite Interesting. The discovery of what’s been expressed on Perf-DCs surfaces will help us distinguish it from regular dendritic cells. It would also give us an insight on the precursor of its formation and whether or not regular dendritc cells can differentiate into Perf-DCs.
Other question I have is besides reducing obesity, are there other vital roles Perf-DCs play in humans?
Studying it’s markers will definitely shed more light on its potential roles.
Because the overall and successful function of the body requires the cohesiveness of different systems of the human body, after reading the article, my first thoughts were on how the endocrine system may possibly affect the immune system in the same way that the perf-DCs do; how hormones may mediate the deletion of potentially harmful T lymphocytes. Different interactions between adipose tissue (that is an endocrine organ), the endocrine system and the immune system lead to different outcomes. Because adipose tissue is the store of nutrients, which are depleted during starvation and replenished when food sources are abundant, it functions as the primary sensory mechanism of an organism’s nutrient availability.
The sensory adipose receptor in adipose tissue, when activated by accumulation of fat in its adipose cell, sends a signal that communicates to the body the current nutrient availability in the body through hormones called adipokines that mediate immune cell activity. Under normal conditions, a stable balance between different adipokines ensures that immune cells respond efficiently and are not activated excessively. The metabolic disorders described in the article are usually associated with an unstable balance of different adipokines that leads to the excessive activation of immune cells. In contrast, during starvation, an unstable balance of different adipokines leads to inhibition of the activation of cells as well as reduced nutrient consumption by immune cells that promote infections.
(http://www.sciencedirect.com/science/article/pii/S1044532315000706)