PMID- 18339427
OWN - NLM
STAT- MEDLINE
DCOM- 20080702
LR  - 20080415
IS  - 0161-5890 (Print)
IS  - 0161-5890 (Linking)
VI  - 45
IP  - 10
DP  - 2008 May
TI  - Human F(ab')2-containing immune complexes together with anti-hinge natural 
      antibodies stimulate complement amplification in vitro and in vivo.
PG  - 2951-61
LID - 10.1016/j.molimm.2008.01.029 [doi]
AB  - The systemic inflammatory response syndrome (SIRS) is triggered by C5a generation 
      following an excessive complement amplification, but it has remained unclear how 
      complement amplification is stimulated. It is known that neutrophilic elastase 
      can cleave IgG to F(ab')(2) and that F(ab')(2)-containing immune complexes 
      (F(ab')(2)-IC) stimulate complement amplification together with an unidentified 
      plasma factor. We show that absorption of plasma on F(ab')(2) from human IgG 
      removed this factor and prevented F(ab')(2)-IC from stimulating complement 
      amplification. The required factor was purified from pooled whole human IgG 
      (IVIG) as those naturally occurring antibodies (NAbs) that bind to F(ab')(2), but 
      not to intact IgG. These "anti-hinge NAbs" restored complement amplification by 
      F(ab')(2)-IC in absorbed plasma. Anti-hinge NAbs must have formed secondary, 
      rigidified IC from F(ab')(2)-IC, because the F(ab')(2) fragments evidently 
      captured dimeric C3b, known as a potent C3 convertase precursor. This process may 
      also stimulate complement amplification in vivo, because plasma from septic 
      patients at the onset of SIRS indeed contained F(ab')(2) fragments. The 
      concentrations of F(ab')(2) and that of factor Bb, an unbiased measure of 
      complement amplification, correlated linearly with that of released elastase. 
      Moreover, the F(ab')(2) fragments migrated on gelfiltration columns together with 
      anti-hinge NAbs as ICs with MW of up to approximately 750kDa, as verified on 
      plasma of each of the nine patients studied. These findings provide for the first 
      time a plausible mechanism of how F(ab')(2)-containing immune complexes stimulate 
      complement amplification together with anti-hinge NAbs. The same mechanism may 
      contribute to complement overreaction at the onset of SIRS.
FAU - Fumia, Sandra
AU  - Fumia S
AD  - Institute of Biochemistry, ETH Zurich, Schafmattstrasse 18, Zurich, Switzerland.
FAU - Goede, Jeroen S
AU  - Goede JS
FAU - Fischler, Manuel
AU  - Fischler M
FAU - Luginbuhl, Alexander
AU  - Luginbuhl A
FAU - Frick, Sonia
AU  - Frick S
FAU - Fodor, Patricia
AU  - Fodor P
FAU - Lutz, Hans U
AU  - Lutz HU
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080314
PL  - England
TA  - Mol Immunol
JT  - Molecular immunology
JID - 7905289
RN  - 0 (Antibodies)
RN  - 0 (Antigen-Antibody Complex)
RN  - 0 (Immunoglobulin Fab Fragments)
RN  - 80295-43-8 (Complement C3b)
RN  - EC 3.4.21.36 (Pancreatic Elastase)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibodies/*immunology
MH  - Antigen-Antibody Complex/*immunology
MH  - Complement Activation/*immunology
MH  - Complement C3b/immunology
MH  - Female
MH  - Humans
MH  - Immunoglobulin Fab Fragments/blood/*immunology
MH  - Male
MH  - Middle Aged
MH  - Models, Immunological
MH  - Molecular Weight
MH  - Pancreatic Elastase
MH  - Systemic Inflammatory Response Syndrome/blood
EDAT- 2008/03/15 09:00
MHDA- 2008/07/03 09:00
CRDT- 2008/03/15 09:00
PHST- 2007/12/07 00:00 [received]
PHST- 2008/01/16 00:00 [revised]
PHST- 2008/01/19 00:00 [accepted]
PHST- 2008/03/15 09:00 [pubmed]
PHST- 2008/07/03 09:00 [medline]
PHST- 2008/03/15 09:00 [entrez]
AID - S0161-5890(08)00030-8 [pii]
AID - 10.1016/j.molimm.2008.01.029 [doi]
PST - ppublish
SO  - Mol Immunol. 2008 May;45(10):2951-61. doi: 10.1016/j.molimm.2008.01.029. Epub 
      2008 Mar 14.