EDITORIALS Genetic Distinctions in Patients With Primary Sclerosing Cholangitis: Immunoglobulin G4 Elevations and HLA Risk See “Association between HLA haplotypes and increased serum levels of IgG4 in patients with primary sclerosing cholangitis,” by Berntsen NL, Klingenberg O, Juran BD, et al, on page 924.
P
rimary sclerosing cholangitis (PSC) is frequently a devastating liver disease characterized by chronic inflammation focused on the biliary tree, the consequence of which is bile duct obstruction, liver fibrosis, and malignancy.1 The “textbook PSC patient” is of Northern European descent, male, in their 40s, with coexistent inflammatory bowel disease (IBD), who progresses to liver transplantation, and lives with a lifetime risk of fatal cholangiocarcinoma. However, disease is more heterogeneous than this,1 with a wide-ranging clinical presentation and outcome, and recognition that patients have differing needs for new therapies. The facets and challenges of disease are broad and include (a) the presence or absence of IBD, and the impact its phenotype has on disease course,2 (b) disease restricted to small bile ducts only,3 (c) overlapping presentations with autoimmune hepatitis,4 (d) risk of development of cholangiocarcinoma,5 (e) modification of disease severity associated with gender, age,6 and ancestry,7 and of relevance to the study by Berntsen et al in this edition of Gastroenterology,8 and (f) elevated immunoglobulin (Ig)G4 concentrations without overt IgG4-associated disease.9 Focusing on this latter stratifier of high-risk PSC, the Hov group have now applied HLA genotyping to demonstrate a replicated genetic distinction within representative PSC populations (of European ancestry), based on increases in IgG4. PSC, like other autoimmune diseases, is presumed to result from a coalescence of host genetic risk and environmental triggers. A number of mimics of disease (eg, secondary sclerosing cholangitis) provide tantalizing clues to pathways to biliary injury that span classical autoimmunity, bile toxicity, infections, and vascular changes. Genetically, large-scale studies in patients predominantly of European descent with IBD have shed light on common host genetic variations associated with disease, with the major histocompatibility complex on chromosome 6p21 representing by far the strongest genetic risk factor in PSC. The first reports of an HLA association in PSC indeed date back to the 1980s, yet the full realization of the meaning of such associations with disease remain quite enigmatic, unlike for example the advances seen bridging HLA risk and celiac disease10 or drug injury with Abacavir.11 Key PSC susceptibility alleles include HLA-B*08 and DRB1*03:01 and, in particular, the haplotypes HLA-DRB1*15:01-DQB1*06:02, HLA-DRB1*13:01-DCB1*06:03 and HLA-A1-B8-DRB1*
Gastroenterology 2015;148:886–900
03:01-DQB1*02:01. Simultaneously, a strong protective influence of the DRB1*04-DQB1*03:02 and DRB1*07:01DQB1*03:03 haplotypes has been reported. What is apparent is that the pattern of HLA association in PSC is highly reminiscent of autoimmune diseases such as celiac disease and type 1 diabetes, more so than it is of Crohn’s disease,12 which ultimately provides genetic evidence at least that PSC has significant prototypical autoimmune features despite a lack of a characteristic serologic marker, or response to immunosuppression. In part, our inability to understand how HLA risk is associated with PSC mechanistically reflects a failure to capture fully the immunologic history of our patients, such as may arise from deep sequencing, longitudinally, and from representative sites in the liver and bowel, of disease-specific activated T cells. With this in mind, the overlapping features of PSC with IgG4-associated diseases has provoked much interest, not least because in its classical form IgG4-associated cholangitis/IgG4-associated autoimmune pancreatitis is a steroid and/or rituximab (anti-CD20) responsive autoimmune disease.13 Insights into IgG4-related disease have focused on understanding how this systemic fibroinflammatory illness, characterized by increased IgG4 values and tissue infiltration by IgG4-positive plasma cells, is triggered. Recent studies have looked at environmental exposure risks for patients,14 and in addition have shown enhanced levels of polyclonal IgG4 to multiple antigens.15 To date, given the rarity of disease, extensive genetic studies of classic IgG4-related disease have not been conducted. The interest for PSC patients arises more so than from the need to exclude classic radiologic and histologic IgG4-related disease, but from the observations that in patients with PSC for whom IgG4 elevations are identified, their disease course is more aggressive.9 It remains unclear whether this risk marker can be used to define a different treatment paradigm for some patients. Berntsen et al8 have explored the clinical features and HLA background of PSC patients with high IgG4 concentrations. They included 263 Norwegian PSC patients in whom IgG4 concentrations were measured. They tested their hypothesis of a genetic basis for increased IgG4 in PSC by comparing PSC patients with high and low IgG4 values, and further validated findings using patients with PSC from Swedish and American cohorts. In so doing, the authors provide evidence that increased IgG4 values were associated with more advanced disease stage and reduced transplant-free survival from time of PSC diagnosis, as has been reported previously. They further showed that in PSC patients with high IgG4 values (IgG4 > 2.01 g/L) a significantly reduced frequency of HLA-B*08 was observed, which represents the strongest genetic risk factor in PSC, whereas the alleles HLA-B*07 and DRB1*15 were significantly more
EDITORIALS
Figure 1. Dissecting the pathogenesis of primary sclerosing cholangitis (PSC). PSC is characterized by an overwhelming association with the major histocompatibility complex (MHC), which is also known in humans as the human leukocyte antigen (HLA). A strong association with HLA-B*08, HLA-DRB1*03:01 and HLA-DRB1*15:01 alleles in PSC has been reported. However, the triggering (auto)antigen/s in PSC are unknown as is their route of entry. The role played by HLA-DR molecules in exogenous antigen presentation to CD4þ T-helper cells may help to explain their association with PSC disease. Exogenous peripheral antigens entering the liver are internalized via antigen-presenting cells (APC), degraded and preferentially bound by HLA class II molecules; the HLA class II–peptide complex is then transported to the cell surface for recognition by CD4þ T-helper T cells bearing the antigen-specific T-cell receptor (TCR). The adaptive immune response also selectively expands B cells; activated B cells differentiate into plasma cells producing immunoglobulins (IgG4, IgA, IgM, IgG) able to bind to the cognate antigen that caused the activation of the precursor B cell. (PSC HLA distinctions are based on previous reports).
prevalent in PSC patients with high than low IgG4. The significantly lower frequency of HLA-B*08 and the higher frequencies of HLA-B*07 and DRB1*15 in PSC patients with high IgG4 were confirmed in their independent replication cohorts from Sweden and the United States. The authors also show that HLA-DRB1*15 was only associated with PSC patients with high levels of IgG4 (>2.01 g/L) but not healthy controls in all 3 panels. An association of HLA-DR2 (DRB1*15) with PSC has been described before in a study where clinical differences also suggested that HLA-DR2 and DR3 could represent different etiologic subsets of PSC. This study thus deepens our understanding of the association of HLA-DR2 in PSC by stratification of patients
based on their serum IgG4 concentrations. Additional studies will no doubt take this further, including evaluating patients based on IgG4/IgG1 ratios, a proposal suggested to distinguish PSC from IgG4-associated cholangiopathy. The use of a ratio of IgG4 to IgG1 has logic because IgG4 may be increased specifically in IgG4-associated diseases, whereas in PSC it may also reflect nonspecific increases in IgG. Accurate patient phenotyping is relevant, therefore, to clinical practice as well as genetic stratification studies: a serum IgG4 of >1.4 g/L is reportedly not reliable enough to detect IgG4-associated disease in PSC patients with only moderately elevated IgG4 concentrations (>1.4 to 100 mg/g identified patients with endoscopic recurrence with 89% sensitivity and 58% specificity. The negative predictive value (NPV) of a FC of >100 mg/g was 91%. In this cohort, colonoscopy could have been avoided in 47% of patients without endoscopic recurrence, but at the cost of missing 11% of patients with endoscopic recurrence. A FC of
P
rimary sclerosing cholangitis (PSC) is frequently a devastating liver disease characterized by chronic inflammation focused on the biliary tree, the consequence of which is bile duct obstruction, liver fibrosis, and malignancy.1 The “textbook PSC patient” is of Northern European descent, male, in their 40s, with coexistent inflammatory bowel disease (IBD), who progresses to liver transplantation, and lives with a lifetime risk of fatal cholangiocarcinoma. However, disease is more heterogeneous than this,1 with a wide-ranging clinical presentation and outcome, and recognition that patients have differing needs for new therapies. The facets and challenges of disease are broad and include (a) the presence or absence of IBD, and the impact its phenotype has on disease course,2 (b) disease restricted to small bile ducts only,3 (c) overlapping presentations with autoimmune hepatitis,4 (d) risk of development of cholangiocarcinoma,5 (e) modification of disease severity associated with gender, age,6 and ancestry,7 and of relevance to the study by Berntsen et al in this edition of Gastroenterology,8 and (f) elevated immunoglobulin (Ig)G4 concentrations without overt IgG4-associated disease.9 Focusing on this latter stratifier of high-risk PSC, the Hov group have now applied HLA genotyping to demonstrate a replicated genetic distinction within representative PSC populations (of European ancestry), based on increases in IgG4. PSC, like other autoimmune diseases, is presumed to result from a coalescence of host genetic risk and environmental triggers. A number of mimics of disease (eg, secondary sclerosing cholangitis) provide tantalizing clues to pathways to biliary injury that span classical autoimmunity, bile toxicity, infections, and vascular changes. Genetically, large-scale studies in patients predominantly of European descent with IBD have shed light on common host genetic variations associated with disease, with the major histocompatibility complex on chromosome 6p21 representing by far the strongest genetic risk factor in PSC. The first reports of an HLA association in PSC indeed date back to the 1980s, yet the full realization of the meaning of such associations with disease remain quite enigmatic, unlike for example the advances seen bridging HLA risk and celiac disease10 or drug injury with Abacavir.11 Key PSC susceptibility alleles include HLA-B*08 and DRB1*03:01 and, in particular, the haplotypes HLA-DRB1*15:01-DQB1*06:02, HLA-DRB1*13:01-DCB1*06:03 and HLA-A1-B8-DRB1*
Gastroenterology 2015;148:886–900
03:01-DQB1*02:01. Simultaneously, a strong protective influence of the DRB1*04-DQB1*03:02 and DRB1*07:01DQB1*03:03 haplotypes has been reported. What is apparent is that the pattern of HLA association in PSC is highly reminiscent of autoimmune diseases such as celiac disease and type 1 diabetes, more so than it is of Crohn’s disease,12 which ultimately provides genetic evidence at least that PSC has significant prototypical autoimmune features despite a lack of a characteristic serologic marker, or response to immunosuppression. In part, our inability to understand how HLA risk is associated with PSC mechanistically reflects a failure to capture fully the immunologic history of our patients, such as may arise from deep sequencing, longitudinally, and from representative sites in the liver and bowel, of disease-specific activated T cells. With this in mind, the overlapping features of PSC with IgG4-associated diseases has provoked much interest, not least because in its classical form IgG4-associated cholangitis/IgG4-associated autoimmune pancreatitis is a steroid and/or rituximab (anti-CD20) responsive autoimmune disease.13 Insights into IgG4-related disease have focused on understanding how this systemic fibroinflammatory illness, characterized by increased IgG4 values and tissue infiltration by IgG4-positive plasma cells, is triggered. Recent studies have looked at environmental exposure risks for patients,14 and in addition have shown enhanced levels of polyclonal IgG4 to multiple antigens.15 To date, given the rarity of disease, extensive genetic studies of classic IgG4-related disease have not been conducted. The interest for PSC patients arises more so than from the need to exclude classic radiologic and histologic IgG4-related disease, but from the observations that in patients with PSC for whom IgG4 elevations are identified, their disease course is more aggressive.9 It remains unclear whether this risk marker can be used to define a different treatment paradigm for some patients. Berntsen et al8 have explored the clinical features and HLA background of PSC patients with high IgG4 concentrations. They included 263 Norwegian PSC patients in whom IgG4 concentrations were measured. They tested their hypothesis of a genetic basis for increased IgG4 in PSC by comparing PSC patients with high and low IgG4 values, and further validated findings using patients with PSC from Swedish and American cohorts. In so doing, the authors provide evidence that increased IgG4 values were associated with more advanced disease stage and reduced transplant-free survival from time of PSC diagnosis, as has been reported previously. They further showed that in PSC patients with high IgG4 values (IgG4 > 2.01 g/L) a significantly reduced frequency of HLA-B*08 was observed, which represents the strongest genetic risk factor in PSC, whereas the alleles HLA-B*07 and DRB1*15 were significantly more
EDITORIALS
Figure 1. Dissecting the pathogenesis of primary sclerosing cholangitis (PSC). PSC is characterized by an overwhelming association with the major histocompatibility complex (MHC), which is also known in humans as the human leukocyte antigen (HLA). A strong association with HLA-B*08, HLA-DRB1*03:01 and HLA-DRB1*15:01 alleles in PSC has been reported. However, the triggering (auto)antigen/s in PSC are unknown as is their route of entry. The role played by HLA-DR molecules in exogenous antigen presentation to CD4þ T-helper cells may help to explain their association with PSC disease. Exogenous peripheral antigens entering the liver are internalized via antigen-presenting cells (APC), degraded and preferentially bound by HLA class II molecules; the HLA class II–peptide complex is then transported to the cell surface for recognition by CD4þ T-helper T cells bearing the antigen-specific T-cell receptor (TCR). The adaptive immune response also selectively expands B cells; activated B cells differentiate into plasma cells producing immunoglobulins (IgG4, IgA, IgM, IgG) able to bind to the cognate antigen that caused the activation of the precursor B cell. (PSC HLA distinctions are based on previous reports).
prevalent in PSC patients with high than low IgG4. The significantly lower frequency of HLA-B*08 and the higher frequencies of HLA-B*07 and DRB1*15 in PSC patients with high IgG4 were confirmed in their independent replication cohorts from Sweden and the United States. The authors also show that HLA-DRB1*15 was only associated with PSC patients with high levels of IgG4 (>2.01 g/L) but not healthy controls in all 3 panels. An association of HLA-DR2 (DRB1*15) with PSC has been described before in a study where clinical differences also suggested that HLA-DR2 and DR3 could represent different etiologic subsets of PSC. This study thus deepens our understanding of the association of HLA-DR2 in PSC by stratification of patients
based on their serum IgG4 concentrations. Additional studies will no doubt take this further, including evaluating patients based on IgG4/IgG1 ratios, a proposal suggested to distinguish PSC from IgG4-associated cholangiopathy. The use of a ratio of IgG4 to IgG1 has logic because IgG4 may be increased specifically in IgG4-associated diseases, whereas in PSC it may also reflect nonspecific increases in IgG. Accurate patient phenotyping is relevant, therefore, to clinical practice as well as genetic stratification studies: a serum IgG4 of >1.4 g/L is reportedly not reliable enough to detect IgG4-associated disease in PSC patients with only moderately elevated IgG4 concentrations (>1.4 to 100 mg/g identified patients with endoscopic recurrence with 89% sensitivity and 58% specificity. The negative predictive value (NPV) of a FC of >100 mg/g was 91%. In this cohort, colonoscopy could have been avoided in 47% of patients without endoscopic recurrence, but at the cost of missing 11% of patients with endoscopic recurrence. A FC of
