[PAGID] [SPAM?] Re: VOD/CID - Sp110

[John B. Ziegler]

What you say is absolutely right. However, we looked at that and 
didn't find any evidence. You'll find brief reference to that in the 
Nature Genetics paper.  But there's a lot to learn about sp110.

At 10:24 PM 27/09/2008, you wrote:

>Thanks John:

>

>I had been hoping for your input. Finishing the Sp110 inquiry, any 

>reason to think that this gene is a susceptibility gene for VOD post HSCT?

>

>Have you considered other Sp family members. For example, Sp100 is a 

>target autoantigen in autoimmunity affecting bile ducts (including 

>primary biliary cirrhosis) and it's expression is affected by 

>[viral] infections and other stimuli.

>

>Regards,

>

>Jack

>

>---------------------------------------------------------------------------

>Jack J.H. Bleesing, M.D., Ph.D.

>Associate Professor of Pediatrics

>Cincinnati Children's Hospital Medical Center

>Division of Hematology/Oncology

>3333 Burnet Avenue, MLC 7015

>Cincinnati, OH 45229

>513-636-4266 (phone)

>513-636-3549 (fax)

>Jack.Bleesing at CCHMC.org

>http://www.cincinnatichildrens.org/immunodeficiencies/

>

>

> >>> "John B. Ziegler" <j.ziegler at unsw.edu.au> 9/27/2008 3:14 AM >>>

>Jack

>

>In Sydney we have seen about 20 children with VODI often with large

>sibships. Although only a minority of the siblings has been genotyped

>we can speculate that there have been about 20 heterozygous siblings

>as well as a similar number of carrier parents, about 40 people.

>Among them there has been no phenotype. In addition there has been

>genotyping carried out on some candidate phenotype cohorts, with no

>heterozygotes identified.

>

>That said, it seems pretty clear to us that VODI cases in Lebanese

>communities are probably going undetected.  In the Sydney Lebanese

>communities the carrier frequency appears to be about

>1:50.  Extrapolating that to the population of Lebanon we would

>expect 8 new cases a year in that country. And it could be expected

>to be seen in other expatriate Lebanese communities. It has been seen

>in both Muslim and Christian families and they don't appear to

>originate in any particular part of Lebanon. Two sp110 mutations have

>been detected in the Sydney cohort. (Other mutations have been seen

>in non-Lebanese babies in the US and Italy.)  HLH has not been seen

>to date. The immunological phenotype does resemble CVID in that there

>is usually marked hypogamma but no lymphopenia and standard T cell

>function testing is usually normal. There has occasionally been a

>SCID phenotype.

>

>That said, it is clearly early days and I'm sure we don't know the

>full story about the clinical phenotype(s). Indeed the phenotype

>paper lamentably langusihes as a manuscript.  You can get more

>information at

>http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=vodi.

>

>Your patients sound like an interesting group, rare presentation of

>heterozygotes would have to be a possibility, or a milder phenotype

>associated with mutations with less impact on the function of sp110

>than has been seen in VODI.

>

>Best wishes

>

>John

>

>.   10:40 PM 26/09/2008, you wrote:

> >Good morning Folks:

> >

> >I was wondering if there is anybody, who would like speculate

> >whether [mono-allelic] Sp110 mutations have a clinical phenotype.

> >

> >The reason I am asking is that every couple of months or so, we see

> >a child (male and  - seemingly healthy - present with severe

> >hepatitis/cholangitis that is cellular based (no autoantibodies and

> >no response to "low" dose steroids). When we get involved and look

> >at the immune system (sometimes before steroids are started, as the

> >Liver Team is starting to see a pattern as well), it looks like a

> >SCID/CID immune system. Multi-gene workup of everything under the

> >CID/HLH/XLP Sun, has not shown any defect.

> >

> >The cellular mechanism in the liver appears to suggest a HLH-like

> >process (with increased sIL-2Ra and ferritin) with cytotoxic

> >T-cells, akin EBV-driven HLH. In the liver, we sometimes, not

> >always, find some virus (HHV-6, entervirus, adenovirus found so

> >far), suggesting that a viral infection provided the trigger. When

> >we initiate HLH therapy, things improve relatively quickly.

> >Cytopenias, especially involving platelets and neutrophils are

> >invariably present, sometimes with hemophagocytosis in the bone

> >marrow. Coagulapathy (not due to synthetic dysfunction) also.

> >

> >Sp110 hasn't been looked at.

> >

> >Regards,

> >

> >Jack

> >

> >---------------------------------------------------------------------------

> >Jack J.H. Bleesing, M.D., Ph.D.

> >Associate Professor of Pediatrics

> >Cincinnati Children's Hospital Medical Center

> >Division of Hematology/Oncology

> >3333 Burnet Avenue, MLC 7015

> >Cincinnati, OH 45229

> >513-636-4266 (phone)

> >513-636-3549 (fax)

> >Jack.Bleesing at CCHMC.org

> >http://www.cincinnatichildrens.org/immunodeficiencies/

>

>A/Prof John B. Ziegler

>Department of Immunology and Infectious Diseases

>Sydney Children's Hospital

>High Street, RANDWICK NSW 2031

>Australia

>Tel: (02) 93821515

>Fax: + 61 + 2 + 93821580

>Email: j.ziegler at unsw.edu.au


A/Prof John B. Ziegler
Department of Immunology and Infectious Diseases
Sydney Children's Hospital
High Street, RANDWICK NSW 2031
Australia
Tel: (02) 93821515
Fax: + 61 + 2 + 93821580
Email: j.ziegler at unsw.edu.au