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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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Related in: MedlinePlus

A Novel RF. Schematic representation of two distinct modes of Ig-Ig interaction.On the left: IgG4 Fc interacts with Ig Fc. On the right: IgM RF recognizes IgG in a “classical” Fab-Fc recognition.
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pone-0001637-g005: A Novel RF. Schematic representation of two distinct modes of Ig-Ig interaction.On the left: IgG4 Fc interacts with Ig Fc. On the right: IgM RF recognizes IgG in a “classical” Fab-Fc recognition.

Mentions: Western blot analysis showed that IgG4 did indeed bind to IgG1κ, IgG2κ, IgG3κ and IgG Fc, hence acting, till this stage, as a de facto RF. However, and surprisingly, IgG4 binding to IgG Fc was due to its Fc, rather than to its Fab. This is formally inconsistent with the simplest definition of an autoantibody that is an immunoglobulin recognizing a self antigen through its variable, antigen binding Fab, and consequently that of a RF i.e. an autoantibody recognizing IgG Fc. Based on this contention, but unwilling to introduce yet a new nomenclature, we propose for this new Ig-Ig interaction to be called Novel RF (NRF) in contrast to the original finding [27], [28], subsequently called Classical RF (CRF) (it should be noted that originally, the term RF was used as an alternate for “Rheumatoid Arthritis Serum” prior to any knowledge as to its fine identity and structural mode of action; see [29]). Importantly however, any overlap between NRF and CRF could be excluded based on the following arguments: (a) Western blotting shows no IgG4 Fab- Ig Fc (CRF) interaction and (b) ELISA showed that serum level of IgG4 bound to each IgG subclass correlated well with the serum IgG4 level itself (i.e. the totality of IgG4-Ig interaction is through Fc-Fc engagement), and (c) the reciprocal absence of any link between IgG-bound IgG4 levels and RF, excluding therefore any CRF reactivity (Figure 5). It should be also reminded that a previous report, albeit in vitro, did show through domain swapping experiments that the binding of a monoclonal IgG4 RF (isolated this time from a rheumatoid arthritis patient) to IgG is through their respective constant segments and not Fab-Fc [40]. This is in direct support of our results obtained on total seric, polyclonal, IgG4. Finally the fact that IgG4 anti-immunoglobulin antibodies have been found in all human beings puts the pathophysiological relevance of the here presented data into perspective [41]. It is equally noteworthy that this IgG4 Fc–Ig Fc interaction extends beyond man to a number of other animal IgG. Some such as mouse, rabbit, guinea pig, bovine and goat, showed strong reactivity with human IgG4. On the other hand, sheep, horse and rat IgG showed scarce reactivity to human IgG4 (unpublished data).


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)

A Novel RF. Schematic representation of two distinct modes of Ig-Ig interaction.On the left: IgG4 Fc interacts with Ig Fc. On the right: IgM RF recognizes IgG in a “classical” Fab-Fc recognition.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001637-g005: A Novel RF. Schematic representation of two distinct modes of Ig-Ig interaction.On the left: IgG4 Fc interacts with Ig Fc. On the right: IgM RF recognizes IgG in a “classical” Fab-Fc recognition.
Mentions: Western blot analysis showed that IgG4 did indeed bind to IgG1κ, IgG2κ, IgG3κ and IgG Fc, hence acting, till this stage, as a de facto RF. However, and surprisingly, IgG4 binding to IgG Fc was due to its Fc, rather than to its Fab. This is formally inconsistent with the simplest definition of an autoantibody that is an immunoglobulin recognizing a self antigen through its variable, antigen binding Fab, and consequently that of a RF i.e. an autoantibody recognizing IgG Fc. Based on this contention, but unwilling to introduce yet a new nomenclature, we propose for this new Ig-Ig interaction to be called Novel RF (NRF) in contrast to the original finding [27], [28], subsequently called Classical RF (CRF) (it should be noted that originally, the term RF was used as an alternate for “Rheumatoid Arthritis Serum” prior to any knowledge as to its fine identity and structural mode of action; see [29]). Importantly however, any overlap between NRF and CRF could be excluded based on the following arguments: (a) Western blotting shows no IgG4 Fab- Ig Fc (CRF) interaction and (b) ELISA showed that serum level of IgG4 bound to each IgG subclass correlated well with the serum IgG4 level itself (i.e. the totality of IgG4-Ig interaction is through Fc-Fc engagement), and (c) the reciprocal absence of any link between IgG-bound IgG4 levels and RF, excluding therefore any CRF reactivity (Figure 5). It should be also reminded that a previous report, albeit in vitro, did show through domain swapping experiments that the binding of a monoclonal IgG4 RF (isolated this time from a rheumatoid arthritis patient) to IgG is through their respective constant segments and not Fab-Fc [40]. This is in direct support of our results obtained on total seric, polyclonal, IgG4. Finally the fact that IgG4 anti-immunoglobulin antibodies have been found in all human beings puts the pathophysiological relevance of the here presented data into perspective [41]. It is equally noteworthy that this IgG4 Fc–Ig Fc interaction extends beyond man to a number of other animal IgG. Some such as mouse, rabbit, guinea pig, bovine and goat, showed strong reactivity with human IgG4. On the other hand, sheep, horse and rat IgG showed scarce reactivity to human IgG4 (unpublished data).

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