Guest guest Posted September 21, 2008 Report Share Posted September 21, 2008 Dave, Are you aware of any studies going on regarding IgA as both myself and my daughter are Dx with it. I have PSC and worry about my daughter, who at times has URQ pain and had to have her gallbladder removed at 14 due to sludge, which is also how mine went. So far her LFT's have been normal except when they removed her gallbladder, and there have been no other symptoms of PSC other then the URQ pain. If there is a study out there that you are aware of would you please send me the information. Dawn In , " " wrote: > > Hi Lori; > > I've been meaning to answer your questions for a few days now, but I > don't think I can answer all of them just yet. I've mostly read about > IgM and IgA, and know too little to comment much on IgG and IgE at > the moment; sorry! > > As I inderstand it, IgM is the first immunoglobulin type to be > produced by B cells. The B cells then normally undergo immunoglobulin > isotype class switching, and in the mucosal tissue (e.g. tissue > lining the gut) the main isotype that they start producing is IgA. > This class switching from IgM to IgA requires interactions between > the T cells and B cells, and is probably also dependent upon > dendritic cells. The dendritic cells in the gut associated lymphoid > tissue produce retinoic acid which triggers the switch from IgM to > IgA production in B cells. Several cytokines may also be involved, > such as interleukin 10 and transforming growth factor beta. The > interaction between the T cells and B cells also involves proteins on > the T cell and B cell surfaces, such as CD40 and its ligand CD40L. > In any event, in normal gut tissue, IgA is produced by the B cells > (now differentiated into plasma cells) and then secreted into the gut > lumen. The secreted IgA then binds to bacterial toxins and bacterial > cell walls, keeping bacterial populations in check. > > The most common type of hyper-IgM syndrome is due to a genetic defect > in the CD40L molecule, so the B cells can't interact with T cells, > and so don't make very much IgA (or IgG or IgE for that matter). They > continue to make only IgM. So these patients have high IgM, low IgA, > low IgG and low IgE. The CD40L gene is localized on the X chromosome, > and so this disease is more common in males, who have only one copy > of the X chromosome. Their deficiency in IgA makes these patients > very susceptible to gastrointestinal infections (also infections at > other mucosal surfaces where secreted IgA is important in keeping > bacteria in check). Hyper-IgM patients seem to be particularly > susceptible to sclerosing cholangitis caused by various > pathogens .... Cryptosporidium parvum seems to be the most common. > This type of sclerosing cholangitis is not usually referred to as > primary sclerosing cholangitis because it is secondary to a known > cause ... hyper-IgM syndrome and biliary tree infection. > > I would not say that hyper-IgM is an " autoimmune indicator " . Rather, > I would say it is an " immune deficiency " , resulting in increased risk > of various types of infections because of a lack of IgA, IgG and IgE. > > There is also a type of IgA deficiency that does not seem to involve > CD40 or CD40L. This is referred to as " isolated " or " selective " IgA > deficiency. The exact molecuar mechanisms responsible for this type > of IgA deficiency are not known, but some studies have tracked the > genetic susceptibility to isolated IgA deficiency to the major > histocompatibility complex, and some workers suggest that the > susceptibility gene (or genes) may be specific to the HLA-A1-B8-DR3 > haplotype: > > IMMUNOGLOBULIN A DEFICIENCY 1; IGAD1 > http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=137100 > > Most interesting the HLA-A1-B8-DR3 haplotype has also been linked to > PSC susceptibility (see for example): > > s EB, Chapman RW 1999 Sclerosing cholangitis. Curr Opin > Gastroenterol. 15: 436-441. PMID: 17023986. > > " Susceptibility to PSC is associated with the HLA A1-B8-DR3 > haplotype " > > http://www.ncbi.nlm.nih.gov/pubmed/17023986 > > I've mentioned before that " isolated " IgA deficiency is associated > with PSC: > > Wagner A, Eichmann D 1989 Primary sclerosing cholangitis in isolated > IgA deficiency. Schweiz Med Wochenschr. 119: 835-838. PMID: 2672299. > > " Primary sclerosing cholangitis was diagnosed in a patient with > isolated IgA deficiency. Similar reports in the literature suggest > that the two conditions are related. Patients with primary sclerosing > cholangitis associated with isolated IgA deficiency are distinguished > by the fact that it is mainly the intrahepatic bile ducts that are > narrowed by the fibrosing process. The disease manifests itself > comparatively early. Recurrent bouts of fever, in combination with > elevated AP, can become the leading symptom even before the onset of > jaundice. The prognosis seems somewhat more favourable than in other > patients with primary sclerosing cholangitis. " > > http://www.ncbi.nlm.nih.gov/pubmed/2672299 > > One might expect then that if these two conditions are linked (PSC > and IgA deficiency), PSCers might have a somewhat elevated IgM? In a > recent review article by Chapman, this is in fact noted: > > " Particularly common serological abnormalities are raised IgM levels > in up to 50% " > > Saich R, Chapman R 2008 Primary sclerosing cholangitis, autoimmune > hepatitis and overlap syndromes in inflammatory bowel disease. > World J Gastroenterol. 14: 331-337. PMID: 18200656 > > http://www.wjgnet.com/1007-9327/14/331.asp > > I've also mentioned that in principle, retinoic acid (vitamin A) > deficiency in the gut associated lymphoid tissue could be major > dietary factor result in markedly reduced secretion of IgA. This is > because retinoic acid produced from vitamin A by the dendritic cells > in the gut associated lymphoid tissue is required for B cells to > switch from IgM to IgA production. > > Certainly PSCers seem to be commonly deficient in vitamin A (and > therefore probably retinoic acid). > > So, overall, I think there are very strong ties between IgA > deficiency, and/or vitamin A deficiency and PSC. > > Sorry, but I am currently at a loss as to how to explain you son's > normal IgA and IgE but low IgG and IgM. > > Best regards, > > Dave > (father of (23); PSC 07/03; UC 08/03) > > > > > > > Hi Dave > > You have been such a great resource to everyone here, myself > included > > and I really appreciate your input on this. The recent question @ > IgA > > deficiency has me wondering if there is much research out there > about > > immunodeficencies and PSC. My son Braden has low IgG and IgM and has > > not retained immunity to all but one (and minimal on the one- barely > in > > normal range) of the immunizations they have tested in his immune > > function tests. His IgA and IgE are ok. > > He was getting monthly IVIG infusions, until our insurance randomly > > decided not to pay some of the cost- but did for most months ?!?! so > > we finally (crossed fingers) have that straightened out and will > start > > again soon hopefully... > > Hyper IgM is an autoimmune indicator right ? Because IgM fights > > bacterial infections ? > > I think in my son's case the low IgG is caused by his very poor gut > > functioning- most his small bowel has been removed and he has had > > chronic and severe small bowel bacterial overgrowth problems that I > > feel were there the triggers for his PSC. He does not have > autoimmune > > problems so maybe his PSC is 'just' SC ?? I am still not clear on > why > > the 'P' is added to make it a primary and why it is considered > > secondary if there is a known source isn't the autoimmune disease > the > > known source so shouldn't it be called auto-immune sclerosing > > cholangitis then ? This is just my take on things that it is called > > secondary when there is a known source and that assumes you can > > control the known source- not the case with my son though that we > can > > control the source... > > > > I guess I am just confused on what the immune connection is and how > it > > relates to my son and if it is different for him than others with > > auto- immune disease. Any thought appreciated -even if you just want > > to tell me I am rambling and not making sense :-) > > > > Lori > > lucky mom blessed with triplets > > > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 21, 2008 Report Share Posted September 21, 2008 Dear Dawn; I've not come across any recent research on IgA deficiency and primary scleroing cholangitis. The papers I have read on this are from over 20 years ago, and there are very few of them! This is one from 23 years ago (the same year and month of my son's birth!): ___________________________________________ Endoscopy. 1985 May;17(3):123-5. Association of ulcerative colitis, sclerosing cholangitis and cholangiocarcinoma in a patient with IgA deficiency. Curzio M, Bernasconi G, Gullotta R, Ceriani A, Sala G A case of an unusual association of ulcerative colitis, sclerosing cholangitis, cholangiocarcinoma and IgA deficiency in a 22-year-old man is reported. The patient was admitted to the hospital with jaundice. Ulcerative colitis had been diagnosed 4 years before. The association of sclerosing cholangitis and cholangiocarcinoma was demonstrated. In addition IgA deficiency was discovered. Possible pathogenetic implications are discussed. PMID: 2988928. http://www.ncbi.nlm.nih.gov/pubmed/2988928 ___________________________________________ There has been some work on impaired IgA production and secretion in ulcerative colitis that might be relevant, since UC and PSC seem to be closely tied: ___________________________________________ Dig Dis Sci. 1995 Apr;40(4):805-11. Decreased mucosal IgA levels in ileum of patients with chronic ulcerative colitis. Cicalese L, Duerr RH, Nalesnik MA, Heeckt PF, Lee KK, Schraut WH Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania, USA. Patients with chronic ulcerative colitis (CUC) are known to have decreased spontaneous IgA secretion by colonic mononuclear cells. The aim of this study was to determine whether a similar alteration exists in the apparently healthy ileum of patients with CUC. The concentration of IgA was measured in the supernatant from homogenized mucosal ileal biopsies using a sandwich-type ELISA. The concentration of IgA was significantly (P = 0.025) decreased in the ileum of patients with CUC (N = 24) in comparison to normal ileum (N = 10). The number of mucosal IgA-containing mononuclear cells (MNC) was also determined using an avidin-biotin-immunoperoxidase technique on paraffin-embedded ileal sections. Although reduced, the number of positive cells and their distribution was not significantly different in the ileum of patients with CUC (N = 20) when compared to normal ileum (N = 10). We suggest that decreased mucosal IgA levels are a panintestinal condition in CUC and that this is a primary alteration rather than a secondary response to the inflammatory process. Considering the role of IgA, we propose that decreased mucosal IgA levels in CUC may predispose to the disease by a reduction of the immune-mediated exclusion mechanism and/or by an impairment of the down-regulation of the inflammatory response. PMID: 7720473. http://www.ncbi.nlm.nih.gov/pubmed/7720473 _________________________________ Gut. 1988 Aug;29(8):1070-5. Local immunity in ulcerative colitis: evidence for defective secretory IgA production. Badr-el-Din S, Trejdosiewicz LK, Heatley RV, Losowsky MS Department of Medicine, University of Leeds, St 's Hospital. To investigate local humoral immunity in ulcerative colitis (UC), immunoglobulin (Ig) contents and net Ig production in vitro was assessed using organ cultures of colonic biopsies from 21 patients with quiescent disease and 11 controls. Ig was estimated by enzyme linked immunoassay (ELISA) for IgA, secretory IgA (sIgA), IgM, and IgG. In parallel, numbers of IgA plasma cells were estimated by indirect immunoperoxidase staining of tissue sections for IgA. IgA was the dominant Ig isotype found pre-existing in colonic mucosae, and secreted in vitro. In UC patients, preformed tissue IgA and IgA produced in vitro were significantly increased compared with controls. There was no concomitant increase in amounts of sIgA synthesised in culture, however, although numbers of IgA plasma cells were increased in UC patients by an amount comparable with the increased in vitro IgA production. These results directly show a dysfunction of transepithelial IgA secretion in quiescent ulcerative colitis. Despite a significantly raised concentration of tissue IgG in UC patients, little was produced in vitro in patient and control groups alike, suggesting that mucosal IgG was serum derived, and not linked to local IgA production. PMID: 3410333. http://www.ncbi.nlm.nih.gov/pubmed/3410333 (follow the link to the full test article) _________________________________ IgA deficiency seems to have been given more attention in diagnostic work-ups for celiac disease (which can often come with liver disease, including PSC!). The problem is that detection of celiac disease often relies on antibody tests, but they mostly look for diagnostic IgA antibodies. In patients with IgA deficiency these antibodies will not be present, and so you can get a false negative. This problem is described quite well in this article: A 10-Year-Old Girl With Mild Elevation of Liver Transaminases http://bcbsma.medscape.com/viewarticle/566586_print " The combination of serologic markers that seems to provide the most sensitivity and specificity for the diagnosis of celiac disease is the anti-endomysial IgA and tTG IgA antibodies. IgA deficiency is one of several conditions that may yield a false-negative result, and because IgA deficiency is often seen in patients with celiac disease, patients should have a total IgA level drawn at the same time that the antibody testing is done. Both serologic markers may be falsely negative in children younger than 2 years of age (because it takes a somewhat mature immune system to make some anti-self antibodies) or in IgA-deficient patients. These patients may be screened for celiac disease using an IgG-based antigliadin or tTG antibody. " Let me know if you can't access this medscape article and I'll send it to you privately. The most recent relevant article that I have been able to find mentions IgA deficiency in relation to autoimmune hepatitis and autoimmune sclerosing cholangitis in children: _________________________________ World J Gastroenterol. 2008 Jun 7;14(21):3360-3367 Autoimmune paediatric liver disease. Mieli-Vergani G, Vergani D Paediatric Liver Centre, Variety Club Children‚s Hospital, King‚s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. giorgina.vergani@.... Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, type 1) or liver kidney microsomal antibody (LKM1, type 2). There is a female predominance in both. LKM1 positive patients tend to present more acutely, at a younger age, and commonly have partial IgA deficiency, while duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment, and long-term prognosis are similar in both groups. The most common type of paediatric sclerosing cholangitis is ASC. The clinical, biochemical, immunological, and histological presentation of ASC is often indistinguishable from that of AIH type 1. In both, there are high IgG, non-organ specific autoantibodies, and interface hepatitis. Diagnosis is made by cholangiography. Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates, times to normalization of biochemical parameters, and decreased inflammatory activity on follow up liver biopsies. However, the cholangiopathy can progress. There may be evolution from AIH to ASC over the years, despite treatment. De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH, including elevated titres of serum antibodies, hypergammaglobulinaemia, and histological findings of interface hepatitis, bridging fibrosis, and collapse. Like classical AIH, it responds to treatment with prednisolone and azathioprine. De novo AIH post liver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection. Whether this condition is a distinct entity or a form of atypical rejection in individuals susceptible to the development of autoimmune phenomena is unclear. Whatever its etiology, the recognition of this potentially life- threatening syndrome is important since its management differs from that of standard anti-rejection therapy. PMID: 18528933. http://www.ncbi.nlm.nih.gov/pubmed/18528933 (follow the link to the full text article) _________________________________ I hope this helps you in your quest for information. Best regards, Dave (father of (23); PSC 07/03; UC 08/03) > > Dave, > > Are you aware of any studies going on regarding IgA as both myself > and my daughter are Dx with it. I have PSC and worry about my > daughter, who at times has URQ pain and had to have her gallbladder > removed at 14 due to sludge, which is also how mine went. So far her > LFT's have been normal except when they removed her gallbladder, and > there have been no other symptoms of PSC other then the URQ pain. If > there is a study out there that you are aware of would you please > send me the information. > > Dawn Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 21, 2008 Report Share Posted September 21, 2008 Thank you very much Dave Dawn In , " " wrote: > > Dear Dawn; > > I've not come across any recent research on IgA deficiency and > primary scleroing cholangitis. The papers I have read on this are > from over 20 years ago, and there are very few of them! This is one > from 23 years ago (the same year and month of my son's birth!): > ___________________________________________ > > Endoscopy. 1985 May;17(3):123-5. > > Association of ulcerative colitis, sclerosing cholangitis and > cholangiocarcinoma in a patient with IgA deficiency. > > Curzio M, Bernasconi G, Gullotta R, Ceriani A, Sala G > > A case of an unusual association of ulcerative colitis, sclerosing > cholangitis, cholangiocarcinoma and IgA deficiency in a 22-year-old > man is reported. The patient was admitted to the hospital with > jaundice. Ulcerative colitis had been diagnosed 4 years before. The > association of sclerosing cholangitis and cholangiocarcinoma was > demonstrated. In addition IgA deficiency was discovered. Possible > pathogenetic implications are discussed. PMID: 2988928. > > http://www.ncbi.nlm.nih.gov/pubmed/2988928 > ___________________________________________ > > There has been some work on impaired IgA production and secretion in > ulcerative colitis that might be relevant, since UC and PSC seem to > be closely tied: > ___________________________________________ > > Dig Dis Sci. 1995 Apr;40(4):805-11. > > Decreased mucosal IgA levels in ileum of patients with chronic > ulcerative colitis. > > Cicalese L, Duerr RH, Nalesnik MA, Heeckt PF, Lee KK, Schraut WH > > Department of Surgery, University of Pittsburgh School of Medicine, > Pennsylvania, USA. > > Patients with chronic ulcerative colitis (CUC) are known to have > decreased spontaneous IgA secretion by colonic mononuclear cells. The > aim of this study was to determine whether a similar alteration > exists in the apparently healthy ileum of patients with CUC. The > concentration of IgA was measured in the supernatant from homogenized > mucosal ileal biopsies using a sandwich-type ELISA. The concentration > of IgA was significantly (P = 0.025) decreased in the ileum of > patients with CUC (N = 24) in comparison to normal ileum (N = 10). > The number of mucosal IgA-containing mononuclear cells (MNC) was also > determined using an avidin-biotin-immunoperoxidase technique on > paraffin-embedded ileal sections. Although reduced, the number of > positive cells and their distribution was not significantly different > in the ileum of patients with CUC (N = 20) when compared to normal > ileum (N = 10). We suggest that decreased mucosal IgA levels are a > panintestinal condition in CUC and that this is a primary alteration > rather than a secondary response to the inflammatory process. > Considering the role of IgA, we propose that decreased mucosal IgA > levels in CUC may predispose to the disease by a reduction of the > immune-mediated exclusion mechanism and/or by an impairment of the > down-regulation of the inflammatory response. PMID: 7720473. > > http://www.ncbi.nlm.nih.gov/pubmed/7720473 > _________________________________ > > Gut. 1988 Aug;29(8):1070-5. > > Local immunity in ulcerative colitis: evidence for defective > secretory IgA production. > > Badr-el-Din S, Trejdosiewicz LK, Heatley RV, Losowsky MS > > Department of Medicine, University of Leeds, St 's Hospital. > > To investigate local humoral immunity in ulcerative colitis (UC), > immunoglobulin (Ig) contents and net Ig production in vitro was > assessed using organ cultures of colonic biopsies from 21 patients > with quiescent disease and 11 controls. Ig was estimated by enzyme > linked immunoassay (ELISA) for IgA, secretory IgA (sIgA), IgM, and > IgG. In parallel, numbers of IgA plasma cells were estimated by > indirect immunoperoxidase staining of tissue sections for IgA. IgA > was the dominant Ig isotype found pre-existing in colonic mucosae, > and secreted in vitro. In UC patients, preformed tissue IgA and IgA > produced in vitro were significantly increased compared with > controls. There was no concomitant increase in amounts of sIgA > synthesised in culture, however, although numbers of IgA plasma cells > were increased in UC patients by an amount comparable with the > increased in vitro IgA production. These results directly show a > dysfunction of transepithelial IgA secretion in quiescent ulcerative > colitis. Despite a significantly raised concentration of tissue IgG > in UC patients, little was produced in vitro in patient and control > groups alike, suggesting that mucosal IgG was serum derived, and not > linked to local IgA production. PMID: 3410333. > > http://www.ncbi.nlm.nih.gov/pubmed/3410333 > (follow the link to the full test article) > _________________________________ > > IgA deficiency seems to have been given more attention in diagnostic > work-ups for celiac disease (which can often come with liver disease, > including PSC!). The problem is that detection of celiac disease > often relies on antibody tests, but they mostly look for diagnostic > IgA antibodies. In patients with IgA deficiency these antibodies will > not be present, and so you can get a false negative. This problem is > described quite well in this article: > > A 10-Year-Old Girl With Mild Elevation of Liver Transaminases > http://bcbsma.medscape.com/viewarticle/566586_print > > " The combination of serologic markers that seems to provide the most > sensitivity and specificity for the diagnosis of celiac disease is > the anti-endomysial IgA and tTG IgA antibodies. IgA deficiency is one > of several conditions that may yield a false-negative result, and > because IgA deficiency is often seen in patients with celiac disease, > patients should have a total IgA level drawn at the same time that > the antibody testing is done. Both serologic markers may be falsely > negative in children younger than 2 years of age (because it takes a > somewhat mature immune system to make some anti-self antibodies) or > in IgA-deficient patients. These patients may be screened for celiac > disease using an IgG-based antigliadin or tTG antibody. " > > Let me know if you can't access this medscape article and I'll send > it to you privately. > > The most recent relevant article that I have been able to find > mentions IgA deficiency in relation to autoimmune hepatitis and > autoimmune sclerosing cholangitis in children: > _________________________________ > > World J Gastroenterol. 2008 Jun 7;14(21):3360-3367 > > Autoimmune paediatric liver disease. > > Mieli-Vergani G, Vergani D > > Paediatric Liver Centre, Variety Club Children‚s Hospital, King‚s > College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. > giorgina.vergani@... > > Liver disorders with a likely autoimmune pathogenesis in childhood > include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis > (ASC), and de novo AIH after liver transplantation. AIH is divided > into two subtypes according to seropositivity for smooth muscle > and/or antinuclear antibody (SMA/ANA, type 1) or liver kidney > microsomal antibody (LKM1, type 2). There is a female predominance in > both. LKM1 positive patients tend to present more acutely, at a > younger age, and commonly have partial IgA deficiency, while duration > of symptoms before diagnosis, clinical signs, family history of > autoimmunity, presence of associated autoimmune disorders, response > to treatment, and long-term prognosis are similar in both groups. The > most common type of paediatric sclerosing cholangitis is ASC. The > clinical, biochemical, immunological, and histological presentation > of ASC is often indistinguishable from that of AIH type 1. In both, > there are high IgG, non-organ specific autoantibodies, and interface > hepatitis. Diagnosis is made by cholangiography. Children with ASC > respond to immunosuppression satisfactorily and similarly to AIH in > respect to remission and relapse rates, times to normalization of > biochemical parameters, and decreased inflammatory activity on follow > up liver biopsies. However, the cholangiopathy can progress. There > may be evolution from AIH to ASC over the years, despite treatment. > De novo AIH after liver transplantation affects patients not > transplanted for autoimmune disorders and is strikingly reminiscent > of classical AIH, including elevated titres of serum antibodies, > hypergammaglobulinaemia, and histological findings of interface > hepatitis, bridging fibrosis, and collapse. Like classical AIH, it > responds to treatment with prednisolone and azathioprine. De novo AIH > post liver transplantation may derive from interference by > calcineurin inhibitors with the intrathymic physiological mechanisms > of T-cell maturation and selection. Whether this condition is a > distinct entity or a form of atypical rejection in individuals > susceptible to the development of autoimmune phenomena is unclear. > Whatever its etiology, the recognition of this potentially life- > threatening syndrome is important since its management differs from > that of standard anti-rejection therapy. PMID: 18528933. > > http://www.ncbi.nlm.nih.gov/pubmed/18528933 > (follow the link to the full text article) > _________________________________ > > I hope this helps you in your quest for information. > > Best regards, > > Dave > (father of (23); PSC 07/03; UC 08/03) > > > > > > > Dave, > > > > Are you aware of any studies going on regarding IgA as both myself > > and my daughter are Dx with it. I have PSC and worry about my > > daughter, who at times has URQ pain and had to have her gallbladder > > removed at 14 due to sludge, which is also how mine went. So far > her > > LFT's have been normal except when they removed her gallbladder, > and > > there have been no other symptoms of PSC other then the URQ pain. > If > > there is a study out there that you are aware of would you please > > send me the information. > > > > Dawn > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 21, 2008 Report Share Posted September 21, 2008 Thank you very much Dave Dawn In , " " wrote: > > Dear Dawn; > > I've not come across any recent research on IgA deficiency and > primary scleroing cholangitis. The papers I have read on this are > from over 20 years ago, and there are very few of them! This is one > from 23 years ago (the same year and month of my son's birth!): > ___________________________________________ > > Endoscopy. 1985 May;17(3):123-5. > > Association of ulcerative colitis, sclerosing cholangitis and > cholangiocarcinoma in a patient with IgA deficiency. > > Curzio M, Bernasconi G, Gullotta R, Ceriani A, Sala G > > A case of an unusual association of ulcerative colitis, sclerosing > cholangitis, cholangiocarcinoma and IgA deficiency in a 22-year-old > man is reported. The patient was admitted to the hospital with > jaundice. Ulcerative colitis had been diagnosed 4 years before. The > association of sclerosing cholangitis and cholangiocarcinoma was > demonstrated. In addition IgA deficiency was discovered. Possible > pathogenetic implications are discussed. PMID: 2988928. > > http://www.ncbi.nlm.nih.gov/pubmed/2988928 > ___________________________________________ > > There has been some work on impaired IgA production and secretion in > ulcerative colitis that might be relevant, since UC and PSC seem to > be closely tied: > ___________________________________________ > > Dig Dis Sci. 1995 Apr;40(4):805-11. > > Decreased mucosal IgA levels in ileum of patients with chronic > ulcerative colitis. > > Cicalese L, Duerr RH, Nalesnik MA, Heeckt PF, Lee KK, Schraut WH > > Department of Surgery, University of Pittsburgh School of Medicine, > Pennsylvania, USA. > > Patients with chronic ulcerative colitis (CUC) are known to have > decreased spontaneous IgA secretion by colonic mononuclear cells. The > aim of this study was to determine whether a similar alteration > exists in the apparently healthy ileum of patients with CUC. The > concentration of IgA was measured in the supernatant from homogenized > mucosal ileal biopsies using a sandwich-type ELISA. The concentration > of IgA was significantly (P = 0.025) decreased in the ileum of > patients with CUC (N = 24) in comparison to normal ileum (N = 10). > The number of mucosal IgA-containing mononuclear cells (MNC) was also > determined using an avidin-biotin-immunoperoxidase technique on > paraffin-embedded ileal sections. Although reduced, the number of > positive cells and their distribution was not significantly different > in the ileum of patients with CUC (N = 20) when compared to normal > ileum (N = 10). We suggest that decreased mucosal IgA levels are a > panintestinal condition in CUC and that this is a primary alteration > rather than a secondary response to the inflammatory process. > Considering the role of IgA, we propose that decreased mucosal IgA > levels in CUC may predispose to the disease by a reduction of the > immune-mediated exclusion mechanism and/or by an impairment of the > down-regulation of the inflammatory response. PMID: 7720473. > > http://www.ncbi.nlm.nih.gov/pubmed/7720473 > _________________________________ > > Gut. 1988 Aug;29(8):1070-5. > > Local immunity in ulcerative colitis: evidence for defective > secretory IgA production. > > Badr-el-Din S, Trejdosiewicz LK, Heatley RV, Losowsky MS > > Department of Medicine, University of Leeds, St 's Hospital. > > To investigate local humoral immunity in ulcerative colitis (UC), > immunoglobulin (Ig) contents and net Ig production in vitro was > assessed using organ cultures of colonic biopsies from 21 patients > with quiescent disease and 11 controls. Ig was estimated by enzyme > linked immunoassay (ELISA) for IgA, secretory IgA (sIgA), IgM, and > IgG. In parallel, numbers of IgA plasma cells were estimated by > indirect immunoperoxidase staining of tissue sections for IgA. IgA > was the dominant Ig isotype found pre-existing in colonic mucosae, > and secreted in vitro. In UC patients, preformed tissue IgA and IgA > produced in vitro were significantly increased compared with > controls. There was no concomitant increase in amounts of sIgA > synthesised in culture, however, although numbers of IgA plasma cells > were increased in UC patients by an amount comparable with the > increased in vitro IgA production. These results directly show a > dysfunction of transepithelial IgA secretion in quiescent ulcerative > colitis. Despite a significantly raised concentration of tissue IgG > in UC patients, little was produced in vitro in patient and control > groups alike, suggesting that mucosal IgG was serum derived, and not > linked to local IgA production. PMID: 3410333. > > http://www.ncbi.nlm.nih.gov/pubmed/3410333 > (follow the link to the full test article) > _________________________________ > > IgA deficiency seems to have been given more attention in diagnostic > work-ups for celiac disease (which can often come with liver disease, > including PSC!). The problem is that detection of celiac disease > often relies on antibody tests, but they mostly look for diagnostic > IgA antibodies. In patients with IgA deficiency these antibodies will > not be present, and so you can get a false negative. This problem is > described quite well in this article: > > A 10-Year-Old Girl With Mild Elevation of Liver Transaminases > http://bcbsma.medscape.com/viewarticle/566586_print > > " The combination of serologic markers that seems to provide the most > sensitivity and specificity for the diagnosis of celiac disease is > the anti-endomysial IgA and tTG IgA antibodies. IgA deficiency is one > of several conditions that may yield a false-negative result, and > because IgA deficiency is often seen in patients with celiac disease, > patients should have a total IgA level drawn at the same time that > the antibody testing is done. Both serologic markers may be falsely > negative in children younger than 2 years of age (because it takes a > somewhat mature immune system to make some anti-self antibodies) or > in IgA-deficient patients. These patients may be screened for celiac > disease using an IgG-based antigliadin or tTG antibody. " > > Let me know if you can't access this medscape article and I'll send > it to you privately. > > The most recent relevant article that I have been able to find > mentions IgA deficiency in relation to autoimmune hepatitis and > autoimmune sclerosing cholangitis in children: > _________________________________ > > World J Gastroenterol. 2008 Jun 7;14(21):3360-3367 > > Autoimmune paediatric liver disease. > > Mieli-Vergani G, Vergani D > > Paediatric Liver Centre, Variety Club Children‚s Hospital, King‚s > College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. > giorgina.vergani@... > > Liver disorders with a likely autoimmune pathogenesis in childhood > include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis > (ASC), and de novo AIH after liver transplantation. AIH is divided > into two subtypes according to seropositivity for smooth muscle > and/or antinuclear antibody (SMA/ANA, type 1) or liver kidney > microsomal antibody (LKM1, type 2). There is a female predominance in > both. LKM1 positive patients tend to present more acutely, at a > younger age, and commonly have partial IgA deficiency, while duration > of symptoms before diagnosis, clinical signs, family history of > autoimmunity, presence of associated autoimmune disorders, response > to treatment, and long-term prognosis are similar in both groups. The > most common type of paediatric sclerosing cholangitis is ASC. The > clinical, biochemical, immunological, and histological presentation > of ASC is often indistinguishable from that of AIH type 1. In both, > there are high IgG, non-organ specific autoantibodies, and interface > hepatitis. Diagnosis is made by cholangiography. Children with ASC > respond to immunosuppression satisfactorily and similarly to AIH in > respect to remission and relapse rates, times to normalization of > biochemical parameters, and decreased inflammatory activity on follow > up liver biopsies. However, the cholangiopathy can progress. There > may be evolution from AIH to ASC over the years, despite treatment. > De novo AIH after liver transplantation affects patients not > transplanted for autoimmune disorders and is strikingly reminiscent > of classical AIH, including elevated titres of serum antibodies, > hypergammaglobulinaemia, and histological findings of interface > hepatitis, bridging fibrosis, and collapse. Like classical AIH, it > responds to treatment with prednisolone and azathioprine. De novo AIH > post liver transplantation may derive from interference by > calcineurin inhibitors with the intrathymic physiological mechanisms > of T-cell maturation and selection. Whether this condition is a > distinct entity or a form of atypical rejection in individuals > susceptible to the development of autoimmune phenomena is unclear. > Whatever its etiology, the recognition of this potentially life- > threatening syndrome is important since its management differs from > that of standard anti-rejection therapy. PMID: 18528933. > > http://www.ncbi.nlm.nih.gov/pubmed/18528933 > (follow the link to the full text article) > _________________________________ > > I hope this helps you in your quest for information. > > Best regards, > > Dave > (father of (23); PSC 07/03; UC 08/03) > > > > > > > Dave, > > > > Are you aware of any studies going on regarding IgA as both myself > > and my daughter are Dx with it. I have PSC and worry about my > > daughter, who at times has URQ pain and had to have her gallbladder > > removed at 14 due to sludge, which is also how mine went. So far > her > > LFT's have been normal except when they removed her gallbladder, > and > > there have been no other symptoms of PSC other then the URQ pain. > If > > there is a study out there that you are aware of would you please > > send me the information. > > > > Dawn > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 21, 2008 Report Share Posted September 21, 2008 Thank you very much Dave Dawn In , " " wrote: > > Dear Dawn; > > I've not come across any recent research on IgA deficiency and > primary scleroing cholangitis. The papers I have read on this are > from over 20 years ago, and there are very few of them! This is one > from 23 years ago (the same year and month of my son's birth!): > ___________________________________________ > > Endoscopy. 1985 May;17(3):123-5. > > Association of ulcerative colitis, sclerosing cholangitis and > cholangiocarcinoma in a patient with IgA deficiency. > > Curzio M, Bernasconi G, Gullotta R, Ceriani A, Sala G > > A case of an unusual association of ulcerative colitis, sclerosing > cholangitis, cholangiocarcinoma and IgA deficiency in a 22-year-old > man is reported. The patient was admitted to the hospital with > jaundice. Ulcerative colitis had been diagnosed 4 years before. The > association of sclerosing cholangitis and cholangiocarcinoma was > demonstrated. In addition IgA deficiency was discovered. Possible > pathogenetic implications are discussed. PMID: 2988928. > > http://www.ncbi.nlm.nih.gov/pubmed/2988928 > ___________________________________________ > > There has been some work on impaired IgA production and secretion in > ulcerative colitis that might be relevant, since UC and PSC seem to > be closely tied: > ___________________________________________ > > Dig Dis Sci. 1995 Apr;40(4):805-11. > > Decreased mucosal IgA levels in ileum of patients with chronic > ulcerative colitis. > > Cicalese L, Duerr RH, Nalesnik MA, Heeckt PF, Lee KK, Schraut WH > > Department of Surgery, University of Pittsburgh School of Medicine, > Pennsylvania, USA. > > Patients with chronic ulcerative colitis (CUC) are known to have > decreased spontaneous IgA secretion by colonic mononuclear cells. The > aim of this study was to determine whether a similar alteration > exists in the apparently healthy ileum of patients with CUC. The > concentration of IgA was measured in the supernatant from homogenized > mucosal ileal biopsies using a sandwich-type ELISA. The concentration > of IgA was significantly (P = 0.025) decreased in the ileum of > patients with CUC (N = 24) in comparison to normal ileum (N = 10). > The number of mucosal IgA-containing mononuclear cells (MNC) was also > determined using an avidin-biotin-immunoperoxidase technique on > paraffin-embedded ileal sections. Although reduced, the number of > positive cells and their distribution was not significantly different > in the ileum of patients with CUC (N = 20) when compared to normal > ileum (N = 10). We suggest that decreased mucosal IgA levels are a > panintestinal condition in CUC and that this is a primary alteration > rather than a secondary response to the inflammatory process. > Considering the role of IgA, we propose that decreased mucosal IgA > levels in CUC may predispose to the disease by a reduction of the > immune-mediated exclusion mechanism and/or by an impairment of the > down-regulation of the inflammatory response. PMID: 7720473. > > http://www.ncbi.nlm.nih.gov/pubmed/7720473 > _________________________________ > > Gut. 1988 Aug;29(8):1070-5. > > Local immunity in ulcerative colitis: evidence for defective > secretory IgA production. > > Badr-el-Din S, Trejdosiewicz LK, Heatley RV, Losowsky MS > > Department of Medicine, University of Leeds, St 's Hospital. > > To investigate local humoral immunity in ulcerative colitis (UC), > immunoglobulin (Ig) contents and net Ig production in vitro was > assessed using organ cultures of colonic biopsies from 21 patients > with quiescent disease and 11 controls. Ig was estimated by enzyme > linked immunoassay (ELISA) for IgA, secretory IgA (sIgA), IgM, and > IgG. In parallel, numbers of IgA plasma cells were estimated by > indirect immunoperoxidase staining of tissue sections for IgA. IgA > was the dominant Ig isotype found pre-existing in colonic mucosae, > and secreted in vitro. In UC patients, preformed tissue IgA and IgA > produced in vitro were significantly increased compared with > controls. There was no concomitant increase in amounts of sIgA > synthesised in culture, however, although numbers of IgA plasma cells > were increased in UC patients by an amount comparable with the > increased in vitro IgA production. These results directly show a > dysfunction of transepithelial IgA secretion in quiescent ulcerative > colitis. Despite a significantly raised concentration of tissue IgG > in UC patients, little was produced in vitro in patient and control > groups alike, suggesting that mucosal IgG was serum derived, and not > linked to local IgA production. PMID: 3410333. > > http://www.ncbi.nlm.nih.gov/pubmed/3410333 > (follow the link to the full test article) > _________________________________ > > IgA deficiency seems to have been given more attention in diagnostic > work-ups for celiac disease (which can often come with liver disease, > including PSC!). The problem is that detection of celiac disease > often relies on antibody tests, but they mostly look for diagnostic > IgA antibodies. In patients with IgA deficiency these antibodies will > not be present, and so you can get a false negative. This problem is > described quite well in this article: > > A 10-Year-Old Girl With Mild Elevation of Liver Transaminases > http://bcbsma.medscape.com/viewarticle/566586_print > > " The combination of serologic markers that seems to provide the most > sensitivity and specificity for the diagnosis of celiac disease is > the anti-endomysial IgA and tTG IgA antibodies. IgA deficiency is one > of several conditions that may yield a false-negative result, and > because IgA deficiency is often seen in patients with celiac disease, > patients should have a total IgA level drawn at the same time that > the antibody testing is done. Both serologic markers may be falsely > negative in children younger than 2 years of age (because it takes a > somewhat mature immune system to make some anti-self antibodies) or > in IgA-deficient patients. These patients may be screened for celiac > disease using an IgG-based antigliadin or tTG antibody. " > > Let me know if you can't access this medscape article and I'll send > it to you privately. > > The most recent relevant article that I have been able to find > mentions IgA deficiency in relation to autoimmune hepatitis and > autoimmune sclerosing cholangitis in children: > _________________________________ > > World J Gastroenterol. 2008 Jun 7;14(21):3360-3367 > > Autoimmune paediatric liver disease. > > Mieli-Vergani G, Vergani D > > Paediatric Liver Centre, Variety Club Children‚s Hospital, King‚s > College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. > giorgina.vergani@... > > Liver disorders with a likely autoimmune pathogenesis in childhood > include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis > (ASC), and de novo AIH after liver transplantation. AIH is divided > into two subtypes according to seropositivity for smooth muscle > and/or antinuclear antibody (SMA/ANA, type 1) or liver kidney > microsomal antibody (LKM1, type 2). There is a female predominance in > both. LKM1 positive patients tend to present more acutely, at a > younger age, and commonly have partial IgA deficiency, while duration > of symptoms before diagnosis, clinical signs, family history of > autoimmunity, presence of associated autoimmune disorders, response > to treatment, and long-term prognosis are similar in both groups. The > most common type of paediatric sclerosing cholangitis is ASC. The > clinical, biochemical, immunological, and histological presentation > of ASC is often indistinguishable from that of AIH type 1. In both, > there are high IgG, non-organ specific autoantibodies, and interface > hepatitis. Diagnosis is made by cholangiography. Children with ASC > respond to immunosuppression satisfactorily and similarly to AIH in > respect to remission and relapse rates, times to normalization of > biochemical parameters, and decreased inflammatory activity on follow > up liver biopsies. However, the cholangiopathy can progress. There > may be evolution from AIH to ASC over the years, despite treatment. > De novo AIH after liver transplantation affects patients not > transplanted for autoimmune disorders and is strikingly reminiscent > of classical AIH, including elevated titres of serum antibodies, > hypergammaglobulinaemia, and histological findings of interface > hepatitis, bridging fibrosis, and collapse. Like classical AIH, it > responds to treatment with prednisolone and azathioprine. De novo AIH > post liver transplantation may derive from interference by > calcineurin inhibitors with the intrathymic physiological mechanisms > of T-cell maturation and selection. Whether this condition is a > distinct entity or a form of atypical rejection in individuals > susceptible to the development of autoimmune phenomena is unclear. > Whatever its etiology, the recognition of this potentially life- > threatening syndrome is important since its management differs from > that of standard anti-rejection therapy. PMID: 18528933. > > http://www.ncbi.nlm.nih.gov/pubmed/18528933 > (follow the link to the full text article) > _________________________________ > > I hope this helps you in your quest for information. > > Best regards, > > Dave > (father of (23); PSC 07/03; UC 08/03) > > > > > > > Dave, > > > > Are you aware of any studies going on regarding IgA as both myself > > and my daughter are Dx with it. I have PSC and worry about my > > daughter, who at times has URQ pain and had to have her gallbladder > > removed at 14 due to sludge, which is also how mine went. So far > her > > LFT's have been normal except when they removed her gallbladder, > and > > there have been no other symptoms of PSC other then the URQ pain. > If > > there is a study out there that you are aware of would you please > > send me the information. > > > > Dawn > Quote Link to comment Share on other sites More sharing options...
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