IgA is by far the most abundant
immunoglobulin in humans. It is found in serum and in secretions (
SIgA). Unlike any other class of
immunoglobulin, each form of
IgA occurs naturally in different polymerisation states. In serum, the predominant form of
IgA is
IgA1 of which around 90% is monomeric and 10% is dimeric or polymeric. The proportion of dimeric/
polymeric IgA increases in a number of important diseases, such as
IgA nephropathy and in chronic
liver disease. In both, there is evidence that further aggregation of dimeric/
polymeric IgA is the cause of the characteristic tissue deposition. To investigate the effect of role of
IgA polymerisation on the structure and function of
IgA, we purified different molecular forms of
IgA1 from myeloma serum (monomer, dimer and trimer) and SIgA1 from colostrum. Structural features of these different
IgA1 forms were examined following proteolysis using Neisseria gonorrhoeae
IgA1 type 2
protease and Streptococcus pneumoniae
IgA1 protease. These
IgA1 proteases cleave
IgA1 at the hinge region and produce Fcalpha and
Fab fragments. Western blot analysis demonstrated that the Fcalpha fragments of serum dimeric and trimeric but not monomeric
IgA1 aggregated to form multimers resistant to disruption in SDS-PAGE under non-reducing conditions. Size exclusion chromatography under native conditions of cleaved serum dimeric
IgA1 demonstrated that aggregation occurs because of structural changes in the
IgA per se and was not an effect of the SDS-PAGE system. In the same assay, SIgA1 (dimeric) did not aggregate after digestion. The results suggest an important, previously unrecognised, property of dimeric/polymeric serum
IgA1, which might explain its propensity to aggregate and deposit in tissues.