Dave Re: scelorsing colangitis/primary versus secondary

[Guest guest]

Hi Dave,

Thanks so much for putting that earlier "interesting article" in lamens terms. Will you please share your theory you mention below. I think I might be in agreement. Not sure if you are referring to leaky gut syndrome or something related to it. I just bought a book called the "The leaky Gut Syndrome". I think digestion plays a huge role. Please share your thoughts on the non-genentic factors of IBD and PSC! Thanks in advance.

I have some other thoughts on selective IgA deficiency in the gut that may be caused by non-genetic factors and which may play a role in IBD and PSC, but I will not write about these here because it sounds like you are more interested in the genetic aspects? I can very much understand your concern for your daughter's health, but I hope that she does not develop PSC

Lori A.

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To: Sent: Saturday, January 31, 2009 11:14:33 PMSubject: Re: scelorsing colangitis/primary versus secondary

Dear Dawn;

Here are my thoughts on genetic associations between IgA deficiency and PSC. Sorry if this is a bit repetitive of material I may have posted earlier.

Early reports on PSC and PBC in the 1980's have noted an association between both PSC and PBC in isolated or selective IgA deficiency patients:

Wagner A, Eichmann D 1989 Primary sclerosing cholangitis in isolated IgA deficiency. Schweiz. Med. Wochenschr. 119: 835-838.

Curzio M, Bernasconi G, Gullotta R, Ceriani A, Sala G 1985 Association of ulcerative colitis, sclerosing cholangitis and cholangiocarcinoma in a patient with IgA deficiency. Endoscopy 17: 123-125.

SP, EA, Schafer DF, Hoofnagle JH, Varma RR, Strober W 1986 Selective immunoglobulin A deficiency associated with primary biliary cirrhosis in a family with liver disease. Gastroenterology 90: 283-288.

More recently, IgA deficiency has been associated with type 2 autoimmune hepatitis in children:

Mieli-Vergani G, Vergani D 2008 Autoimmune paediatric liver disease. World J. Gastroenterol. 14: 3360-3367.

Genetic studies indicate that the major genetic risk factor for IgA deficiency resides in the major histocompatibility complex, as does the major genetic risk factor for PSC. In fact, the same haplotype may be involved:

http://www.ncbi. nlm.nih.gov/ entrez/dispomim. cgi?id=137100

" HLA-A1, B8, DR3, a haplotype associated with selective IgA deficiency"

s EB, Chapman RW 1999 Sclerosing cholangitis. Curr. Opin. Gastroenterol. 15: 436.

"Susceptibility to PSC is associated with the HLA A1-B8-DR3 haplotype"

The involvement of the HLA-DQB1 gene cannot be ruled out in both IgA deficiency and PSC:

Olerup O, CI, Bjorkander J, Hammarstrom L 1992 Shared HLA class II-associated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency. Proc. Natl. Acad. Sci. U.S.A. 89: 10653-10657.

son PT, Norris S 2002 Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis. Autoimmunity 35: 555-564.

and the HLA-DQB1 gene is a very important determinant of celiac disease:

Jores RD, Frau F, Cucca F, Clemente MG, Orru S, Rais M, De Virgiliis S, Congia M 2007 HLA-DQB1*0201 homozygosis predisposes to severe intestinal damage in celiac disease. Scand. J. Gastroenterol. 42: 48-53.

More recently, the CTLA-4/ICOS gene region has been associated with both celiac disease and IgA deficiency:

Haimila K, Einarsdottir E, Kauwe AD, Koskinen LL, Pan-Hammarstrom Q, Kaartinen T, Kurppa K, Ziberna F, Not T, Vatta S, Ventura A, Korponay-Szabo IR, Adany R, Pocsai Z, Szeles G, Dukes E, Kaukinen K, Maki M, Koskinen S, Partanen J, Hammarstrom L, et al 2008 The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency. Genes Immun. Nov 20 [Epub ahead of print].

and it's known that the CTLA-4 gene is also a susceptibility gene for autoimmune hepatitis and primary biliary cirrhosis:

Agarwal K, Czaja AJ, DE, son PT 2000 Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology 31: 49-53.

Juran BD, Atkinson EJ, Schlicht EM, Fridley BL, Lazaridis KN 2008 Primary biliary cirrhosis is associated with a genetic variant in the 3' flanking region of the CTLA4 gene. Gastroenterology 135: 1200-1206.

It is noteworthy that IgA deficiency is commonly associated with celiac disease:

Heneghan MA, s FM, Cryan EM, Warner RH, McCarthy CF 1997 Celiac sprue and immunodeficiency states: a 25-year review. J. Clin. Gastroenterol. 25: 421-425.

and that celiac disease is in turn commonly associated with PSC, PBC and autoimmune hepatitis:

Volta U 2008 Liver dysfunction in celiac disease. Minerva Med. 99: 619-629.

So, it appears that celiac disease, PSC, AIH, PBC and IgA deficiency may share some common genetic risk factors.

I have some other thoughts on selective IgA deficiency in the gut that may be caused by non-genetic factors and which may play a role in IBD and PSC, but I will not write about these here because it sounds like you are more interested in the genetic aspects? I can very much understand your concern for your daughter's health, but I hope that she does not develop PSC.

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)