In the News:- TOLL like receptors and Nobel Prize in Medicine 2011

The nobel prize this year in 2011 for Medicine is going to the discovery of the Toll like receptors and dendritic cells. Check out the website of Nobel Prize at : http://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/#
Some minor information.


Dendritic cell:- An antigen presenting cell is a very prominent cell now in our textbooks and especially when we deal with transplantation immunology. This was discovered by Ralph Steinman in 1973. He speculated that it could be important in the immune system and went on to test whether dendritic cells could activate T cells, a cell type that has a key role in adaptive immunity and develops an immunologic memory against many different substances. 
Toll like receptors: Bruce Beutler was searching for a receptor that could bind the bacterial product, lipopolysaccharide (LPS), which can cause septic shock, a life threatening condition that involves overstimulation of the immune system.  TLR were hence discovered. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes. They are more like pattern recognizing receptors. Three subgroups of TIR domains exist. Sub group 1 are receptors for interleukins, subgroup 2 directly to microbes, subgroup 3 to get signals from subgroup 1 and 2. 

image Source: Wikipedia.com

TOPIC DISCUSSION: Dendritic Cells and Renal disease

Dendritic cells(DC) are traditional thought to be anti infectious and a link between the innate and the adaptive immune system.  A nice breakdown of DC role in kidney disease recently discusses its role in homeostatic, anti inflammatory and pro inflammatory roles in kidney diseases.
In terms of homeostatic roles: there is evidence that DCs can do some immune tolerance in renal allografts, and small molecular weight antigens.  The anti inflammatory roles have been in mostly nephrotoxic nephritis(drug induced) especially cisplatin nephrotoxicity. Some data is also present in suppressing pro inflammatory cytokines in ischemic reperfusion injury. Most of the data is in being pro inflammatory in nature and that is in causing proteinuria, promoting ANCA through Th cells, IL-12 secretion in lupus and Th1 response in tubular insterstitial disease.
This leads us to believe that there might be many types of DC and there are.  CD11B like DC due immune surveillance and activate Th cells and are present in kidney in certain glomerular diseases.  CD8 like DC are found in renal lymph nodes and have some T cell activation role.  Inflammatory DC regulate Th cells and Plasmacytoid DC may have some role in lupus nephritis.

Check out these recent references.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21613986
http://www.ncbi.nlm.nih.gov/pubmed/19276627
http://www.ncbi.nlm.nih.gov/pubmed/19381017

CLINICAL CASE 37, ANSWERS AND SUMMARY

Dendritic Cells(DC) are important players in transplant immunology. Which one of these syndromes is associated with loss of IL-12 producing myeloid dendritic cells?
IPEX syndrome 16%IRF8 syndrome 41%BCG syndrome 33%OPES syndrome 8%

Nice work but slightly tough question. Not many responders. No such syndromes as BCG and OPES( made it up).  IPEX syndrome is a T reg FOXP3 deficiency syndrome. Hence, the right answer is IRF8 syndrome.  A recent article in NEJM May 2011 talks about description of this syndrome in few cases.  Infants were evaluated and looked at genetic analysis.  Disseminated infection caused by BCG vaccines is the early manifestation of primary immunodeficiencies - such as SCID.  Two distinct disease causing mutations were noted.  Both effecting Interferon regulatory factor 8 or IRF8 and leading to the disorder.  IRF8 is critical for development of monocytes and dendritic cells and anti mycobacterial immunity.  This is an interesting finding.

As we discover more and more of such associations ( FOXP3 deficiency and T regs) and this one now- we can use this information for better understanding immunology and hence transplant medicine benefits. Dendritic cells are antigen presenting cells and knowing that IRF8 is crucial in their functioning, perhaps an inhibitory molecule to IRF8 might be a target for future drug development in transplantation.  Lets see where this new disease entity takes us: as everyone knows- its not that simple.

take a look:

http://www.ncbi.nlm.nih.gov/pubmed/21524210

http://www.ncbi.nlm.nih.gov/pubmed/21178004

http://www.ncbi.nlm.nih.gov/pubmed/21216962