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JCI online early table of contents: Dec. 15, 2008

JCI Journals

EDITOR'S PICK: New genetic cause of Boy in the bubble syndrome

Severe combined immunodeficiency (SCID) is an inherited disease sometimes known as 'Boy in the bubble syndrome', baecause the patient lacks one or more type of immune cell, making them very susceptible to infections. Dik van Gent and colleagues, at Erasmus Medical Center, The Netherlands, have now identified a new genetic cause of SCID characterized by a lack of T cells and B cells (T-B- SCID). Specifically, they identified a patient with T-B- SCID who has a mutation in the gene DNA-PKcs.

Further analysis revealed the reason that the mutant DNA-PKcs protein generated as a result of the DNA-PKcs genetic mutation caused SCID: it was unable to activate another protein (known as Artemis) that is essential for the development of T cells and B cells. Importantly, the mutant DNA-PKcs protein retained the ability to perform one of the main functions of normal DNA-PKcs protein (a process known as kinase activity). The authors therefore conclude that clinicians with patients who have T-B- SCID should consider the possibility that mutations in the gene DNA-PKcs might be the cause of disease, even in those individuals who have normal DNA-PKcs kinase activity.

TITLE: A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining

Dik C. van Gent
Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Phone: 31-10-7043932; Fax: 31-10-7044743; E-mail:

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EDITOR'S PICK: New insight into birth defect characterized by digit duplication and fusion

Birth defects characterized by malformation of the limbs are relatively common. New insight into one form of the birth defect synpolydactyly, where individuals have 1 or more digit (finger or toe) duplicated and 2 or more digits fused together, has now been provided by Stefan Mundlos and colleagues, at Universitätsmedizin Berlin, Germany, who studied a mouse model of the condition.

One form of synpolydactyly is caused by mutations in the HOXD13 gene. To understand how these mutations cause disease the authors analyzed mice carrying one of these mutations, Spdh/Spdh mice. Surprisingly, the protein generated by the mutated gene was found to have lost a function of the normal Hoxd13 protein and to have gained a new function. Specifically, the mutant protein was unable to facilitate normal levels of production of the soluble factor RA, and intrauterine treatment with RA restored normal digit formation in Spdh/Spdh mice. As RA was shown to normally suppress the generation of cells that produce and maintain cartilage, the loss-of-function mutated Hoxd13 therefore indirectly promotes the formation of cartilage. Importantly, further analysis indicated the mutated protein also directly induced the generation of cells that produce and maintain cartilage, whereas normal Hoxd13 did not. Thus, mutated Hoxd13 causes syndpolydactyly by inducing the generation of cells that produce and maintain cartilage, both directly and indirectly.

TITLE: Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retinoic acid synthesis

Stefan Mundlos
Universitätsmedizin Berlin, Berlin, Germany.
Phone: 49-30-450-569-121; Fax: 49-30-450-569-915; E-mail:

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METABOLISM: Your genetic make-up influences the levels of fats in your blood

A team of researchers, led by Helen Hobbs and Jonathan Cohen, at the University of Texas Southwestern Medical Center, Dallas, has provided new insight into how genetic variation can cause different individuals to have distinct levels of a fat known as triglyceride in their blood.

The team focused on a family of genes known as ANGPTL genes and analyzed three family members (ANGPTL3, ANGPTL5, and ANGPT6L) in over 3,000 individuals. Several rare variations in the ANGPTL3 and ANGPTL5 genes were identified in individuals with low triglyceride levels in their blood and no other detectable defects in handling fats. Previous studies have indicated a similar finding for ANGPTL4. Further analysis revealed that the ANGPTL3, ANGPTL4, and ANGPTL5 variants associated with low triglyceride levels in the blood generated proteins that had lost their normal function. The team therefore conclude that variation in the ANGPTL3, ANGPTL4, and ANGPT6L genes contributes to the diversity of triglyceride levels in the blood of different individuals.

TITLE: Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans

Helen H. Hobbs
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-6724; Fax: (214) 648-7539; E-mail:

Jonathan C. Cohen
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-6724; Fax: (214) 648-7539; E-mail:

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IMMUNOLOGY: Don't scratch that itch: blocking the protein IL-21R helps prevent a form of eczema

Raif Geha and colleagues, at Children's Hospital, Boston, have identified a role for the protein IL-21R in a mouse model of atopic dermatitis, a common allergic inflammatory skin disease often known as eczema. As analysis of affected skin from patients with atopic dermatitis showed increased expression of IL-21R and the soluble factor that binds to it (IL-21), the authors suggest that targeting the IL-21/IL-21R interaction in the skin might help prevent skin sensitization, and therefore atopic dermatitis.

In the study, expression of IL-21R and IL-21 was increased in affected skin from patients with atopic dermatitis and in mouse skin subjected to irritation. The importance of this was highlighted by the observation that mice lacking IL-21R and normal mice treated with a molecule that blocks the IL-21/IL-21R interaction did not develop inflammation resembling atopic dermatitis after skin irritation and exposure to an allergen. Further analysis determined one mechanism underlying the central role of IL-21R in the mouse model of atopic dermatitis. Briefly, immune cells known as DCs in the skin did not migrate to local lymph nodes and activate other immune cells important for causing the allergic inflammatory response in the skin.

TITLE: IL-21R is essential for epicutaneous sensitization and allergic skin inflammation in humans and mice

Raif S. Geha
Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 919-2482; Fax: (617) 730-0528; E-mail:

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AUTOIMMUNITY: The signature soluble factor of Th17 cells does not cause autoimmunity

Recent mouse studies have led to the idea that a subset of immune cells known as Th17 cells have a central role in autoimmune diseases such as multiple sclerosis. However, whether the soluble factors that Th17 cells produce contribute to disease has not been determined. Now, a team of researchers, at the University of Zurich, Switzerland, and the University of Mainz, Germany, has found that neither IL-17A nor IL-17F (two of the soluble factors produced by Th17 cells) are crucially important for the development of disease in a mouse model of multiple sclerosis.

The team, led by Burkhard Becher and Ari Waisman, showed that mice with T cells that produce very high levels of IL-17A have no health problems. In the mouse model of multiple sclerosis, neither mice with T cells producing high levels of IL-17A nor mice lacking IL-17A were distinguishable from normal mice. Similarly, mice lacking IL-17F also developed disease to the same extent as normal mice. Furthermore, only a small improvement in the course of disease was observed when mice lacking IL-17F were treated with molecules that block IL-17A. The authors therefore conclude that although IL-17A and IL-17F are produced by cells linked to the development of autoimmune disease, they do not have a central role in the development of disease in a mouse model of multiple sclerosis.

TITLE: IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice

Burkhard Becher
University of Zurich, Zürich, Switzerland.
Phone: 41-44-635-3703; Fax: 41-44-635-6883; E-mail:

Ari Waisman
University of Mainz, Mainz, Germany.
Phone: 49-6131-3933357; Fax: 49-6131-3932104; E-mail:

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INFECTIOUS DISEASE: How the protein TLR9 helps wall of the bacterium that causes tuberculosis

Many of the millions of individuals infected with the bacterium that causes tuberculosis (Mycobacterium tuberculosis) do not develop full-blown disease. This is because the bacteria are 'walled off' by the immune system inside a nodule, known as a granuloma, in the lung tissue. Activation of the protein TLR9 is important for maintaining the granulomatous response to mycobacterial proteins in mice, but the mechanism(s) behind this has not been determined. Now however, Steven Kunkel and colleagues, at the University of Michigan Medical School, Ann Arbor, have identified a molecular mechanism by which TLR9 regulates mycobacteria-elicited granulomatous immune responses in mice. Specifically, activation of TLR9 on immune cells known as DCs by BCG (a vaccine for tuberculosis consisting of a weakened mycobacterium) induced the DCs to upregulate expression of the protein dll4, and this, in turn, induced the activation of immune effector cells known as Th17 cells. The authors therefore suggest that further studies to determine how dll4 regulates the activity of Th17 cells might identify clinically beneficial approaches to modulating the immune response following infection with Mycobacterium tuberculosis.

TITLE: TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4

Steven L. Kunkel
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: (734) 936-1020; Fax: (734) 764-2397; Email:

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