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A novel immunoglobulin-immunoglobulin interaction in autoimmunity.

Kawa S, Kitahara K, Hamano H, Ozaki Y, Arakura N, Yoshizawa K, Umemura T, Ota M, Mizoguchi S, Shimozuru Y, Bahram S - PLoS ONE (2008)

Bottom Line: Indeed Western blotting clearly showed that IgG4 binds to IgG1 kappa, IgG2 kappa, IgG3 kappa myeloma proteins, as well as to IgG Fc, in line with a typical RF activity.Further experiments however unraveled the unexpected fact that unlike hitherto known RF, IgG4 does not engage IgG Fc through its Fab, but its very own Fc.In the future, the relevance of NRF, beyond autoimmune pancreatitis, in both diagnosis/prognosis as well as pathophysiology of autoimmune and other systemic diseases where IgG4's role seems paramount, needs to be systematically assessed.

View Article: PubMed Central - PubMed

Affiliation: Center for Health, Safety and Environmental Management, Shinshu University, Matsumoto, Japan. skawapc@hsp.md.shinshu-u.ac.jp

ABSTRACT
Well over six decades since its first description, the Rheumatoid Factor (RF)-autoantibodies recognizing Fc (constant) portion of IgG through their own Fab (antigen binding variable segments)-is believed to have come of age. Autoimmune pancreatitis is a unique form of pancreatitis, biologically characterized by an elevated serum IgG4 concentration. Given the fact that IgG4 myeloma proteins can act as RF, we initially hypothesized that IgG4 in autoimmune pancreatitis might do likewise, hence potentially contributing to disease pathogenesis. Indeed Western blotting clearly showed that IgG4 binds to IgG1 kappa, IgG2 kappa, IgG3 kappa myeloma proteins, as well as to IgG Fc, in line with a typical RF activity. Further experiments however unraveled the unexpected fact that unlike hitherto known RF, IgG4 does not engage IgG Fc through its Fab, but its very own Fc. These data therefore collectively describe a Novel RF (NRF) in autoimmune pancreatitis. In the future, the relevance of NRF, beyond autoimmune pancreatitis, in both diagnosis/prognosis as well as pathophysiology of autoimmune and other systemic diseases where IgG4's role seems paramount, needs to be systematically assessed.

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Scattergram of serum levels of IgG4 bound to IgG1κ myeloma protein.Similar results were seen with assay systems for IgG4 bound to IgG2 κ and IgG3 κ myeloma proteins.
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pone-0001637-g003: Scattergram of serum levels of IgG4 bound to IgG1κ myeloma protein.Similar results were seen with assay systems for IgG4 bound to IgG2 κ and IgG3 κ myeloma proteins.

Mentions: This Fc-Fc interaction is a novel finding and therefore we have decided to name it Novel RF (NRF) in contrast to the “original” RF hereafter termed Classical RF (CRF). It was now worthwhile to investigate the relevance of NRF in vivo. We first sought to confirm by ELISA that each autoimmune pancreatitis patient's serum IgG4 does act as a Novel RF, by examining its binding capacity to human IgG1 or IgG2 or IgG3. Serum IgG4 bound to IgG1 was undetectable (or at very low levels) in 130 healthy controls as well as patients with other autoimmune diseases (n = 119; cf. supra) including autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, systemic lupus erythematosus and Sjögren's syndrome (Figure 3, Table 1) or other pancreatic affections i.e. chronic pancreatitis and pancreatic cancer; all in contrast to a cohort of autoimmune pancreatitis patients which harbored a significantly elevated concentration of IgG4. Figure 4 clearly depicts two important facts with regards to IgG4: firstly that indeed it does show NRF activity in the sense that its serum concentration is in near perfect correlation with its capacity to bind IgG1 (Figure 4a) and that this NRF activity is in total discordance with that of the CRF i.e. no correlation with IgG1 binding and CRF (Figure 4b). Given the almost perfect correlation of IgG4 concentration to that of the functional IgG1 binding we chose to pursue with this latter as it depicts a functional activity rather than just a “passive” concentration (Figure 4). As depicted in Figure 3 and Table 1 high serum IgG4 concentrations able to bind to IgG1 were detected in most samples from the patients with autoimmune pancreatitis (median 269, range 0–4,185 mg/dl), and the concentrations were significantly higher than those observed in other selected diseases (Figure 3, Table 1). Finally, assays of IgG4 bound to IgG2 or IgG3 showed results that were similar to the results of the assays of IgG4 bound to IgG1 (Table 1). Inversely however neither IgG1, 2 or 3 did show any NRF activity (unpublished data) i.e. IgG subclasses other than IgG4 did not have the ability to bind to IgG1–4.


A novel immunoglobulin-immunoglobulin interaction in autoimmunity.

Kawa S, Kitahara K, Hamano H, Ozaki Y, Arakura N, Yoshizawa K, Umemura T, Ota M, Mizoguchi S, Shimozuru Y, Bahram S - PLoS ONE (2008)

Scattergram of serum levels of IgG4 bound to IgG1κ myeloma protein.Similar results were seen with assay systems for IgG4 bound to IgG2 κ and IgG3 κ myeloma proteins.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2249926&req=5

pone-0001637-g003: Scattergram of serum levels of IgG4 bound to IgG1κ myeloma protein.Similar results were seen with assay systems for IgG4 bound to IgG2 κ and IgG3 κ myeloma proteins.
Mentions: This Fc-Fc interaction is a novel finding and therefore we have decided to name it Novel RF (NRF) in contrast to the “original” RF hereafter termed Classical RF (CRF). It was now worthwhile to investigate the relevance of NRF in vivo. We first sought to confirm by ELISA that each autoimmune pancreatitis patient's serum IgG4 does act as a Novel RF, by examining its binding capacity to human IgG1 or IgG2 or IgG3. Serum IgG4 bound to IgG1 was undetectable (or at very low levels) in 130 healthy controls as well as patients with other autoimmune diseases (n = 119; cf. supra) including autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, systemic lupus erythematosus and Sjögren's syndrome (Figure 3, Table 1) or other pancreatic affections i.e. chronic pancreatitis and pancreatic cancer; all in contrast to a cohort of autoimmune pancreatitis patients which harbored a significantly elevated concentration of IgG4. Figure 4 clearly depicts two important facts with regards to IgG4: firstly that indeed it does show NRF activity in the sense that its serum concentration is in near perfect correlation with its capacity to bind IgG1 (Figure 4a) and that this NRF activity is in total discordance with that of the CRF i.e. no correlation with IgG1 binding and CRF (Figure 4b). Given the almost perfect correlation of IgG4 concentration to that of the functional IgG1 binding we chose to pursue with this latter as it depicts a functional activity rather than just a “passive” concentration (Figure 4). As depicted in Figure 3 and Table 1 high serum IgG4 concentrations able to bind to IgG1 were detected in most samples from the patients with autoimmune pancreatitis (median 269, range 0–4,185 mg/dl), and the concentrations were significantly higher than those observed in other selected diseases (Figure 3, Table 1). Finally, assays of IgG4 bound to IgG2 or IgG3 showed results that were similar to the results of the assays of IgG4 bound to IgG1 (Table 1). Inversely however neither IgG1, 2 or 3 did show any NRF activity (unpublished data) i.e. IgG subclasses other than IgG4 did not have the ability to bind to IgG1–4.

Bottom Line: Indeed Western blotting clearly showed that IgG4 binds to IgG1 kappa, IgG2 kappa, IgG3 kappa myeloma proteins, as well as to IgG Fc, in line with a typical RF activity.Further experiments however unraveled the unexpected fact that unlike hitherto known RF, IgG4 does not engage IgG Fc through its Fab, but its very own Fc.In the future, the relevance of NRF, beyond autoimmune pancreatitis, in both diagnosis/prognosis as well as pathophysiology of autoimmune and other systemic diseases where IgG4's role seems paramount, needs to be systematically assessed.

View Article: PubMed Central - PubMed

Affiliation: Center for Health, Safety and Environmental Management, Shinshu University, Matsumoto, Japan. skawapc@hsp.md.shinshu-u.ac.jp

ABSTRACT
Well over six decades since its first description, the Rheumatoid Factor (RF)-autoantibodies recognizing Fc (constant) portion of IgG through their own Fab (antigen binding variable segments)-is believed to have come of age. Autoimmune pancreatitis is a unique form of pancreatitis, biologically characterized by an elevated serum IgG4 concentration. Given the fact that IgG4 myeloma proteins can act as RF, we initially hypothesized that IgG4 in autoimmune pancreatitis might do likewise, hence potentially contributing to disease pathogenesis. Indeed Western blotting clearly showed that IgG4 binds to IgG1 kappa, IgG2 kappa, IgG3 kappa myeloma proteins, as well as to IgG Fc, in line with a typical RF activity. Further experiments however unraveled the unexpected fact that unlike hitherto known RF, IgG4 does not engage IgG Fc through its Fab, but its very own Fc. These data therefore collectively describe a Novel RF (NRF) in autoimmune pancreatitis. In the future, the relevance of NRF, beyond autoimmune pancreatitis, in both diagnosis/prognosis as well as pathophysiology of autoimmune and other systemic diseases where IgG4's role seems paramount, needs to be systematically assessed.

Show MeSH
Related in: MedlinePlus