Recently, I have been reading Janeway's immunobiology and had a question on immunoglobin A. I read that IgA activates the complement pathway using the Fab fragment of the IgA. How does IgA do that? I can't seem to find an information on that in the book or online.
I found some reports on it (like reference 1) but there is an oddly little amount of publications on this topic. then I found this review in Mucosal Immunology (reference 2, interesting to read) which doubts this activation. It says:
Interaction with complement
IgA lacks the residues identified in the Fc regions of IgG or IgM that bind to C1q, and consequently IgA does not activate the classical complement pathway. Although several papers have reported activation of the alternate pathway by heat-aggregated, denatured, or recombinantly generated IgA, this seems to be essentially artifactual, and intact native IgA antibodies complexed with antigen inhibit complement activation induced by IgG or IgM antibodies. This effect is also replicated by Fabα fragments generated by cleavage of IgA1 antibodies with IgA1 protease. It is telling that mixed aggregates of heat-denatured IgG and IgA activate the alternate pathway in proportion to the content of IgG, and that C3b becomes covalently linked to the IgG heavy chains, not to IgA. Intriguing reports that IgA antibodies promote complement-dependent lysis or opsonization of encapsulated bacteria probably also arise from facilitation of alternate pathway activation by bacterial polysaccharides
It names three papers to underline this (which are number 45-47 in the reference list of the article), which can be found as references 3-5. So the question here is not only how the mechanism looks like, but also if this is real or an artefact.
- Activation of complement by human serum IgA, secretory IgA and IgA1 fragments.
- Structure and function relationships in IgA
- Anti-inflammatory activity of human IgA antibodies and their Fabα fragments: inhibition of IgG-mediated complement activation
- IgA blocks IgM and IgG-initiated immune lysis by separate molecular mechanisms.
- Activity of human IgG and IgA subclasses in immune defense against Neisseria meningitidis serogroup B.
Roos et al (Journal of Immunology, 2001, reference below) suggests that IgA binds MBL, and activates complement by facilitating the lectin binding pathway for complement activation rather than being a major player in the alternate pathway.
Another group of researchers (Daha et al, in Nephrology Dialysis Transplantation, 2006) discusses a potential fourth method for complement activation, as well as describing IgA nephropathy as a result of both alternate- and lectin-activated complement activity. (second reference)