Wednesday, July 13, 2011

The profile of Ruslan medzhitov, a pioneer in Immunology

I came across the profile of Ruslan Medzhitov in HHMI website. I am reproducing this for the readers. His passion for science and immunology makes him break many myths in Immunology.
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Sometimes a little sweet talk goes a long way. A silver tongue catapulted Ruslan Medzhitov from Tashkent to Yale, where he's helped revolutionize our understanding of the immune system.
The early 1990s were a bleak time for science in the Soviet Union. As the empire crumbled, scientific resources drained away, until just a single battered copy of the weekly journals made the rounds at Moscow University. As a graduate student there, Medzhitov yearned to keep up with the latest advances, and his weekly hour with Science and Nature wasn't enough. So he headed to the Academy of Natural Sciences, which was then engaged in its own detente with the university. For various bureaucratic reasons, university students weren't allowed access to the library. "So I had to go and flirt with the librarians—there were several of them—and eventually they all knew me and let me in secretly and told me not to tell anyone," says Medzhitov.
There, in the stacks, the young biology student stumbled on a copy of Cold Spring Harbor Symposia. In it was the paper that launched his career. Written by the late Yale immunologist Charles Janeway (an HHMI investigator), the article sketched a new theory for how the immune system recognizes and responds to pathogens. Little was known then about the so-called innate immune system and how it identifies and reacts to invaders. Janeway's ideas ignited Medzhitov, sending him to his university's sole e-mail terminal. "I was able to send messages once a week," says Medzhitov. "And my first message was to Charlie." Medzhitov asked the professor for more details about his ideas. To Medzhitov's delight, Janeway responded, and the pair exchanged several more messages.
"Charlie's paper was the only paper that made sense of a lot of things," says Medzhitov. "That was the point I first thought about being a researcher in immunology. As an undergraduate student, I never had a course on immunology."
With a career path now in mind, Medzhitov landed a fellowship at the University of California, San Diego. There, working with protein evolution pioneer Russell Doolittle, Medzhitov contacted local immunologist Richard Dutton, who knew Janeway and recommended Medzhitov for a postdoctoral position in Janeway's lab. Janeway said yes. "I felt very lucky," says Medzhitov.
When he arrived at Yale—after a detour to Moscow to defend his thesis and sweat out a government coup and six months of uncertainty—Medzhitov felt overwhelmed. "Janeway's lab was very famous, and I imagine competition to get in was very high. And I was coming from just a few e-mail exchanges and a recommendation. My challenge was, not only did I not speak English well, I also had never done any experiments. In Russia, there was no money to do anything. All I could do was sit in the library. So I arrived without any experience, basically zero. I had to learn as quickly as I could."
It turns out that lack of experience helped Medzhitov in another way. Janeway's theory of how innate immunity acted, by recognizing bits of invading organisms, was "extremely speculative." And that meant it was risky to work on. But, being "oblivious to concerns about career," Medzhitov jumped in on the project. "I was just happy to be in a place where I could do science," he says.
In 1996, after just a few years working together, Janeway and Medzhitov made a breakthrough. They discovered receptors that alerted the second arm of the immune system, the more familiar T cells and B cells that attack pathogens. Studying these proteins, dubbed Toll-like receptors, quickly became one of the hottest areas in biology. "That was an extremely exciting time," says Medzhitov. "We didn't realize how much would come out of it eventually, that it would become such a huge area of research."
In the decade-plus since then, Medzhitov has piled one discovery after another upon the first, dramatically expanding our understanding of the key roles Toll-like receptors play in infection control, chronic inflammation, and even the growth of tumors. At the same time, he's branched off in a dozen directions: One example of many, Medzhitov is learning how commensal bacteria—which live in our guts and help us digest food—also help protect our intestines from injury.
Medzhitov now thinks that Toll-like receptors and related proteins may trigger the chronic inflammation that leads to coronary artery disease, Alzheimer's, and diabetes—some of our biggest killers. "I like a lot of areas of biology and it's hard for me to focus on only one," he says. Now, with plenty of journals to read and experiments to conduct, he doesn't have to.

Dr. Medzhitov is also Professor of Immunobiology at Yale School of Medicine.

Friday, May 14, 2010

Th9 mystery: Is it finally solved?

In the recent article by Kaplan group, the authors have dissected the mechanisms by which Th9 cells develop. The Th9 cells are described as CD4+IL9+IL10+ T cells by Stockinger and Kuchroo groups in nature Immunology 2008. Previously, immunologists felt that IL9 secretion is part of Th2 function. IL9 is an important cytokine secreted by Th2 cells which has an effect on mast cell function. However, there is ambiguity in secretion of IL9 by Th2 polarised cells.
Kaplan group have identified PU.1 as the transcription factor that drives Th9 polarisation. PU.1 is expressed by sub-population of Th2 populations expressing low IL4. In addition, PU.1 deficient cells secrete less IL9 compared to the cells that have PU.1. The authors also show that IL10 secretion is not characteristic feature of Th9 cells as reported by Stockinger and Kuchroo groups before. The authors identify the chromatin modifications on il9 locus  by PU.1 by ChIP assays. Finally, by analyzing allergic patients and also the allergic asthma model, the authors show the obligatory role of  IL9 and PU.1 in the manifestation of asthma.
By this study, the authors have made the knowledge of Th cells more complex. The T cells are now known to be plastic. The regulatory T cells and the Th17 cells share common but contrasting developmental pathways. Similiarly, Th2 cells develop in presence of IL4 while the Th9 cells need IL4 and TGFb1 for their development.Also, PU.1 and GATA-3 interact with each other similar to FoxP3 and RORg which answers the plasticity among the Th subsets.These raise important issues about the role of Th cells in innate immune responses where there is need for spontaneous immune responses.

Recommended reading:
1. H. C. Chang, S. Sehra, R. Goswami, W. Yao, Q. Yu, G. L. Stritesky, R. Jabeen, C. McKinley, A. N. Ahyi, L. Han, E. T. Nguyen, M. J. Robertson, N. B. Perumal, R. S. Tepper, S. L. Nutt, and M. H. Kaplan. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat.Immunol., 2010.

2.V. Dardalhon, A. Awasthi, H. Kwon, G. Galileos, W. Gao, R. A. Sobel, M. Mitsdoerffer, T. B. Strom, W. Elyaman, I. C. Ho, S. Khoury, M. Oukka, and V. K. Kuchroo. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat.Immunol. 9 (12):1347-1355, 2008. 
3.W. Elyaman, E. M. Bradshaw, C. Uyttenhove, V. Dardalhon, A. Awasthi, J. Imitola, E. Bettelli, M. Oukka, Snick J. Van, J. C. Renauld, V. K. Kuchroo, and S. J. Khoury. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc.Natl.Acad.Sci.U.S.A 106 (31):12885-12890, 2009. 
4. E. E. Forbes, K. Groschwitz, J. P. Abonia, E. B. Brandt, E. Cohen, C. Blanchard, R. Ahrens, L. Seidu, A. McKenzie, R. Strait, F. D. Finkelman, P. S. Foster, K. I. Matthaei, M. E. Rothenberg, and S. P. Hogan. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J.Exp.Med. 205 (4):897-913, 2008.

Tuesday, April 20, 2010

IMPRS-MCB PhD program: 2010

International Max Planck Research School for Molecular and Cellular biology (IMPRS-MCB) - a joint international PhD program of the Max Planck Institute of Immunobiology (MPI-IB) and the University of Freiburg.
You have a passion for Molecular and Cellular Biology and want to do cutting edge research in

EPIGENETICS, IMMUNOBIOLOGY, CELL BIOLOGY or BIOINFORMATICS?


We bring together scientists from the Max Planck Institute of Immunobiology and from the University of Freiburg - two leading scientific institutions in Europe.
With us you will
  • work on challenging cutting edge scientific projects
  • get full funding for the time of the PhD
  • go through intensive scientific education- theoretical and practical
  • get in contact with world leading scientist
  • enjoy the privilege of intense mentoring
  • have a chance to test 3 labs of your choice before starting a PhD (rotation)
  • earn your PhD in 3-4 years
At IMPRS-MCB you can become first class scientist and make a fantastic step to very fruitful scientific career.
Please read more about Our Research, Funding, Application and Your PhD in corresponding sections.
We are looking forward to your application.


How should you apply?
You can apply for the program two times a year- in spring and in autumn.
You need to be an MSc or Excellent BSc student/holder. You can apply for Autumn Semester by 31st May. For the details on the application flow visit the "How to apply" section.

Thursday, April 8, 2010

Altered regulatory T cells: A consequence of mast cells in colorectal cancer

I justed came across this paper by Blatner et al. Colorectal cancer is characterised by abundant Tregs and mast cells. However, mechanisms on how the tumor is able to survive in spite of such atmosphere is unclear. Here the authors study human CRC and murine polyposis tumors. The authors report systemic skewing of Treg from anti- to proinflammatory functions in both human CRC and murine polyposis; which they call "altered Tregs". MC are target of suppression by Treg but at the same time play a critical role to reverse the anti-inflammatory function of the Treg. They predict that targeting the pathogenic cross-talk between Treg and MC to allow recovery of Treg antiinflammatory functions will help to control CRC.
First, the  authors show that cytokine milieu in the tumors show increased IL17, TGFβ, IL6, and IL1β with corresponding reductions in IL10 and INFγ; these favor Th17 polarization.They then show that there is increased FoxP3 Tregs and mast cells in the colorectal cancer tumors. These tregs from patient tumors are unable to suppress mast cell degranulation, lack IL10 but show increased IL17 when compared to healthy donors. Then, the authors show that IL6 enables the diversion of healthy human Tregs to a pro-inflammatory phenotype with ability to inhibit CD4 T cells. The authors even generate pSTAT3+ rpo-inflammatory Tregs by co-culturing of naive Treg with primary MC. However, by performing bone marrow transplantation experiments, the authors show that IL6 is sufficient but not absolutely necessary for Treg conversion.Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell–suppressive properties without the need of  IL6 and IL17 in this process.


Suggested Reading:
1. Blatner et al, In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction, PNAS 2010,  107 (14), 6430-6435 
2. Gri G, et al. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 2008, 29:771781. 
3. Piconese S, et al. Mast cells counteract regulatory T cell suppression through interleukin-6 and OX40/OX40L axis toward Th17 cell differentiation. Blood 2009, 114:26392648.

16 PhD Fellowships in Life Sciences: Muenster, Germany

The International Max Planck Research School – Molecular Biomedicine (IMPRS-MBM) and the Graduate Program Cell Dynamics and Disease (CEDAD) offer 16 PhD Fellowships in Life Sciences. CEDAD and IMPRS-MBM - jointly run by the University of Münster and the Max Planck Institute for Molecular Biomedicine - offer integrative approaches to biomedical research with a strong emphasis on imaging.
Research areas: Cell and Molecular Biology Stem Cell Biology Developmental Biology Neurobiology Vascular Biology Immunology Microbiology and more.

The application period for the 3-year PhD program is 7 March 2010 - 20 May 2010.
Projects start in October 2010.
For online application and further information go to
WWW.CEDAD.UNI-MUENSTER.DE.

The program offers excellent scientific and transferable skills training. The program language is English. There are no tuition fees. Successful candidates will receive a competitive tax-free fellowship as well as support with administrative matters, accomodation, visas etc. We invite applications from highly qualified and motivated students of any nationality. We are looking forward to your application for a PhD fellowship in Münster, "the world’s most liveable city" (LivCom Award 2004). 
Date of fist online : 2010/02/12
Fist online date : 2010/02/12
Expected end of parution : 2010/05/14
Type of funding: Public sector funding (Grant)
Precision on the financing: Fellowship of 1365-1400 Euro per month
Wage: Fellowship of 1365-1400 Euro per month, tax-free
 

Catalytic antibodies in hemophilia patients

This is the PhD project of my friend Bharath Wootla. It's interesting how his mentor Sébastien Lacroix-Desmazes guided by Srinivas Kaveri got this idea, and published in Nature Medicine, and a much bigger study later on in the New England Journal of Medicine. The idea is simple: congenital hemophilia patients lack the gene for factor VIII, a protein that is pivotal in blood coagulation pathway. When patients suffering from hemophilia undergo an injury, their blood does not clot and can lead to death due to bleeding. One way of treating these people is to administer exogenous FVIII. However, the immune system of some patients consider the exogenous FVIII as foreign and develop anti-FVIII antibodies. These antibodies inhibit the procoagulant activity of FVIII and hence are also known as FVIII inhibitors. Sébastien in 1999 showed that these antibodies possess catalytic activity and Bharath later on from 2004-2009 studied the mechanisms by which these antibodies inactivate FVIII. The enzymatic activities were studied by incubating the patient's IgG with FVIII. The resultant mixture was analyzed using SDS-PAGE gels for the hydrolysis of FVIII. They have used intravenous immunoglobulin, a pool of IgG from 1000's of healthy blood donors as a control along with the molecules incubated alone in the buffer to check for auto-degradation of proteins. Due to my limited knowledge of enzyme kinetics, I would suggest the readers to refer the publications listed below for more information.

Suggested Reading:
1. Lacroix-Desmazes S, Moreau A, Sooryanarayana, Bonnemain C, Stieltjes N, Pashov A, Sultan Y, Hoebeke J, Kazatchkine MD, Kaveri SV. Catalytic activity of antibodies against factor VIII in patients with hemophilia A. Nat Med. 1999 Sep;5(9):1044-7.
2. Lacroix-Desmazes S, Wootla B, Dasgupta S, Delignat S, Bayry J, Reinbolt J, Hoebeke J, Saenko E, Kazatchkine MD, Friboulet A, Christophe O, Nagaraja V, Kaveri SV. Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII. J Immunol. 2006 Jul 15;177(2):1355-63.
3. Wootla B, Mahendra A, Dimitrov JD, Friboulet A, Borel-Derlon A, Rao DN, Uda T, Borg JY, Bayry J, Kaveri SV, Lacroix-Desmazes S. Factor VIII-hydrolyzing IgG in acquired and congenital hemophilia. FEBS Lett. 2009 Aug 6;583(15):2565-72.

Wednesday, April 7, 2010

The orign of IKDC (Interferon producing killer dendritic cells)

The discovery of IKDC or Interferon producing Dendritic Cells in 2006 created enthusiasm in the immunology research (refrences 1 and 2). The DCs that can kill! what a link between innate and adaptive immunity. Interferons are involved in elimination of  viruses etc that are engulfed in the phagocytes. These interferons are secreted by NK or natural killer cells. The IKDCs were put along with other "hybrid cells" such as NKT cells, which share features with natural killer (NK) cells and T lymphocytes, and plasmacytoid dendritic cells (DCs), which combine the qualities of B cells and conventional DCs. IKDCs can function as NK cells by killing the cells lacking MHC molecules, like plasmacytoid DCs that produce interferon and like DCs that present antigen to conventional T cells. IKDCs not only secret type I and type II interferons to recognize and kill tumor cells effectively, but also express MHC-II molecules to present antigens. Thus, IKDCs are considered as important immunosurveilance cells for tumors, providing a link between innate and adaptive immunity. However, the developmental pathways of these cells were not fully understood.
However, Di Santos group from Pasteur Institute, Paris and Caminschi group from Australia studied the development of IKDCs and proved that these are not DCs but actually a subset of NK cells (Refrence 3 and 4). Generally mature NK cells in humans or mice express NK group 2, member D (NKG2D), CD161, NK-cell protein 46 (NKp46) and CD122. However, the expression of Ly49 family members, CD127, CD27 and KLRG1 (killer-cell lectin-like receptor subfamily G, member 1) in mice, and of KIRs (killer-cell immunoglobulin-like receptors), CD56 and CD16 in humans suggests heterogeneity within the mature NK-cell pool.


Suggested reading:
1. Chan et al, Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity, Nature Medicine - 12, 207 - 213 (2006)
2. Taieb et al, A novel dendritic cell subset involved in tumor immunosurveillance, Nature Medicine - 12, 214 - 219 (2006)
3. Vosshenrich et al, CD11cloB220+ interferon-producing killer dendritic cells are activated natural killer cells.J Exp Med. Oct 29;204(11):2569-78 (2007)
4. Caminschi et al, Putative IKDCs are functionally and developmentally similar to natural killer cells, but not to dendritic cells.J Exp Med. Oct 29;204(11):2579-90 (2007)
5. Huntington et al, Developmental pathways that generate natural-killer-cell diversity in mice and humans, Nature Reviews Immunology 7, 703-714 (2007)

Tuesday, April 6, 2010

Antibiotic resistence in the natural environment

The discovery of penicillin in the petri dished that could not be washed in time revolutionized the health care during the 20th century. Unfortunately, it created a new problem:  the resistance of bacteria towards antibiotics.One of the reasons for this is the indiscriminate use of antibiotics for diseases where it is not "essential". In addition, the reference I suggested below elucidates the role of natural environment in spreading the antibiotic resistant bacteria. the micro-organisms themselves have antibiotic resistant genes under natural circumstances. These could be spread by wild animals and migratory birds compounding the effect.
The indiscriminate use of antibiotics for clinical and agricultural purposes will have a drastic impact of future human health. Sweden should be applauded for banning the use of antibiotics in cattle health. As a result, the chances of antibiotics resistant strains passing over to humans are minimized. However, there is a need for judicious use or alternative strategies for controlling infections.


Suggested reading:
Heather K. Allen, Justin Donato, Helena Huimi Wang, Karen A. Cloud-Hansen, Julian Davies & Jo Handelsman, Call of the wild: antibiotic resistance genes in natural environments, Nature Reviews Microbiology, 8, 251-259 (April 2010).

The lakshman rekha between science and business

Is science for betterment of humanity or for profits? No one has a better answer. When we see the breakthroughs in science over the past century, one feels that science has revolutionised the health and reduced mortality rate. Probably, 33% of present population are living due to timely intervention of science and health (for eg, vaccination, first aid etc). but, if we see the profits of the multinational pharmaceutical companies such as Pfizer, GSK, Astrazeneca, Monsanto etc, we feel that science is just a business.
The controversy over Bt brinjal is a good example where the MNCs are pushing their products over poor farmers. No one thinks whether the toxin towards pests is safe for humans or not. moreover, Bt cotton has increased burden on farmers rather than reducing them. the prices of seeds have increased enormously over the period when Bt cotton was introduced. Now, Monsanto claims that the old Bt cotton variety is vulnerable to pests and is planning to introduce new one. Imagine long terms effects if these are short term effects?
Latest article in science tells that a US judge rejects patent on breast cancer genes BRCA1 and BRCA2 by Myriad Genetics of Salt Lake City. The opposition groups claim that these genes are product of nature and thus can not be patented. Myriad, licensed the BRCA genes from the University of Utah and others who discovered them. In addition, it runs a testing service to check for mutations that convey a risk for breast cancer. Hope sense prevails on the scientists who discovered them and not become too capitalist.

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