Infection-Fighting Protein Could be Key to Autoimmune Disease

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Infection-Fighting Protein Could be Key to Autoimmune Disease

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AUTOIMMUNE INFLAMMATORY CRYOPYRIN ARTHRITIS BACTERIA NOD CASPASE-1

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Scientists have discovered that a protein called cryopyrin responds

to invading bacteria by triggering the activation of a powerful

inflammatory molecule called IL-1beta, which signals the immune

system to attack pathogens and induces fever to protect the body

against infection.

Newswise — Scientists at the University of Michigan Medical School

have discovered that a protein called cryopyrin responds to invading

bacteria by triggering the activation of a powerful inflammatory

molecule called IL-1beta, which signals the immune system to attack

pathogens and induces fever to protect the body against infection.

The discovery could help scientists understand what causes autoimmune

diseases like rheumatoid arthritis where the immune system attacks

and destroys tissue in the patient’s body.

“IL-1beta is a master regulator of infection, and it’s known to be

involved in the development of rheumatoid arthritis,” says

Nunez, M.D., a professor of pathology in the U-M Medical School, who

directed the research study. “So it’s likely that these findings will

apply to other autoimmune diseases, as well.”

In a study being published Jan. 11 as an Advance Online Publication

in Nature, U-M scientists show, for the first time, that cryopyrin is

activated by bacterial RNA and that it is essential to the cell’s

ability to mount an effective defense against bacteria.

Found in the cytosol, or fluid inside cells, cryopyrin is a member of

the NOD-LRR family of proteins, which protect cells against microbial

infection. Defective cryopyrin is predicted to be associated with

increased susceptibility to infection.

Small mutations in CIAS1 – the human gene for cryopyrin – are known

to cause three rare autoinflammatory diseases: familial cold

autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset

multiple-system inflammatory disease. People with these diseases

produce uncontrolled amounts of IL-1beta and other inflammatory

molecules. This causes them to have recurrent episodes of fever and

to develop rashes – often when they are exposed to cold temperatures.

Based on previous research with cell lines, scientists suspected that

cryopyrin was an important link between the immune system’s normal

job of killing bacteria and the abnormal development of autoimmune

diseases. But no one was sure exactly how cryopyrin was “turned on”

in living animals or how it stimulated the immune response.

In previous research, the U-M team found that the single-point

mutation in CIAS1 – which causes autoinflammatory syndromes in people

– activates cryopyrin, even when there is no bacterial RNA present in

the cell. “The mutation fools the cell into producing the activated

form of cryopyrin, even when bacteria aren’t there,” Nunez says.

To decipher cryopyrin’s signal, Thirumala-Devi Kanneganti, Ph.D., a U-

M post-doctoral research fellow in pathology, studied immune cells

called macrophages and several strains of laboratory mice. One of

these strains was unable to produce cryopyrin, because the CIAS1 gene

had been removed.

Kanneganti exposed the macrophages and mice to bacterial RNA and to

small synthetic molecules called R837 (Imiquimod) and R848

(Resiquimod). These adjuvant molecules activate the pro-inflammatory

response in mice and are used as anti-tumor agents and to treat

genital warts caused by a virus in human patients.

“We found that cryopyrin was activated and the macrophages began

secreting IL-1beta following stimulation with R837 or R848,”

Kanneganti says. “Since the structure of these molecules is very

similar to DNA or RNA, we believe the natural ligand, or activating

molecule, for cryopyrin could be DNA or RNA.”

In previous research, other scientists discovered a signaling pathway

in which molecules called toll-like receptors on the cell’s surface

recognize invading bacteria and activate the immune response. But U-M

scientists found that cryopyrin uses a different signaling pathway.

Activated cryopyrin triggers an enzyme called caspase-1, which splits

the immature form of IL-1beta to produce the active form of the

molecule. Once IL-1beta is activated, it can be secreted out of the

cell where it binds to the IL-1beta receptor on other cells to

trigger an immune response.

“These two signaling pathways cooperate,” Nunez explains. “The toll-

like receptor pathway recognizes bacteria outside the cell, while

cryopyrin recognizes bacteria that’s already in the cell. When a toll

receptor on the membrane senses bacterial RNA, it activates a

signaling pathway called NF-kappaB, which induces the production of

IL-1beta. Cryopyrin does the same thing, but it works through

caspase-1 to produce the active form of IL-1beta.”

In her experiments, Kanneganti confirmed that the signaling pathway

requires the presence of cryopyrin. Macrophages and mice that lacked

the CIAS1 gene for cryopyrin were unable to generate an immune

response when exposed to bacterial products.

The research was funded by the National Institute of Allergy and

Infectious Diseases (NIAID). The University of Michigan has filed a

patent application on this research technology.

Additional U-M collaborators on the study included Nesrin Ozoren,

Mathilde Body-Malapel, Amal Amer, Jong-Hwan Park, Luigi Franchi and

Whitfield. Other collaborators were Winfried Barchet and Marco

Colonna from the Washington University School of Medicine,

Vandenabeele from Belgium’s Ghent University, Bertin,

Coyle and Ethan P. Grant from Millennium Pharmaceuticals and Shizuo

Akira from Japan’s Osaka University.

Citation: Nature DOI: 10.1038/nature04517

http://www.newswise.com/p/articles/view/517220/