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Mouse model underestimates the critical role of Tyk2 in human immune system

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10.11.2006

A new study identifies a human Tyk2 deficiency and definitively links this molecule with multiple cytokine signals that are critical for the human immune responses. The research, published online in October 2006 by the journal Immunity, highlights the importance of Tyk2 function in humans and its differences in mice.

Dr. Yoshiyuki Minegishi from Tokyo Medical and Dental University and colleagues investigated immunological abnormalities in a patient diagnosed with a unique primary immunodeficiency called hyper IgE syndrome (HIES). The researchers observed that the patient showed some symptoms not frequently associated with HIES and found that the signaling pathways of two different soluble proteins (cytokines), IL-12 and IFN-á, were defective in the patient.

The researchers subsequently discovered that the patient carried a mutation in both copies of the gene for Tyk2. Tyk2, a non-receptor tyrosine kinase that belongs to the Janus kinase (Jak) family, is an enzyme shared by both IL-12 and IFN-á signaling pathways.

Surprisingly, the patient's cells displayed severe defects in signaling pathways not only for IL-12 and IFN-á but also for other cytokines including IL-6, IL-10 and IL-23, an observation that is in stark contrast to earlier studies with Tyk2-deficient mice that exhibited partially impaired IFN signaling and normal IL-6 and IL-10 signaling. This discrepancy is most likely due to a species difference between humans and mice. When normal Tyk2 was given to the patient's cells, it restored IL-12 and type I IFN signaling. In contrast, inhibition of Tyk2 expression in a normal human cell line disrupted IFN-á signaling. Therefore, unlike what has been observed in mice, Tyk2 appears to be critical for the multiple cytokine signals involved in the immune system in humans.

The researchers conclude that the absence of functional Tyk2 caused the defects in the multiple cytokine signals that were observed in the patient and identify human Tyk2 mutation as a unique type of primary immunodeficiency with characteristics similar to autosomal recessive HIES. "This study is the first to identify human Tyk2 deficiency and demonstrates the unique and indispensable role played by Tyk2 in the innate and acquired immune response in human," says Dr. Minegishi.

Heidi Hardman | Source: EurekAlert!
Further information: www.immunity.com/
www.cell.com

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