Sunday, 2 September 2012

C1q activation and schizophrenia

The Doorman @ Wikipedia
I'm back to schizophrenia with this post based on another very interesting paper by Dr Emily Severance and colleagues* describing some of the potential ins and outs of C1q activation, diet and immune function.

Regular readers of this blog might remember the last offering from Dr Severence et al on gastrointestinal (GI) inflammation and immune activation in cases of schizophrenia (see here**). The net finding suggesting that inflammation might tie into permeability of the GI membrane and onwards to the appearance of antibodies to various foodstuffs. Not a million miles away from the suggestions of the late Curt Dohan and his ideas about schizophrenia and food*** it has to be said.

Perhaps a brief description first?

The complement system is something that has also cropped up on this blog previously with reference to the C4b null allele work carried out by the late Reed Warren and colleagues (here). Basically this is a system charged with aiding in the clearance of pathogens. The complement protein C1q alongside its siblings (C1r and C1s) is a sort of first line in the classical complement pathway, functioning as a recognition unit as it binds to already antigen bound immunoglobulin complexes such as IgG or IgM. I suppose its a sort of nightclub bouncer of the immune system which gets rid of immunoglobulins which have already found an antigenic friend - "you and your friend, out of here".

C1q is a pretty important molecule given that a lack of it has been linked to issues of autoimmunity such as systemic lupus erythematosus (SLE)**** suggested as a result of the reduced clearance of apoptotic cells (which brings us back to those very interesting executioner molecules, the caspases). It is also noteworthy that C1q might have another disposal function with regards to synaptic pruning***** (full-text).

All very important I'm sure you'll agree. So what about the latest paper?

  • Blood samples were drawn from various groups of participants: n=61 non-recent onset schizophrenia (SZ), n=38 recent onset schizophrenia (ROSZ) and n=63 controls. Mean ages and gender splits were quite literally all over the place alongside other demographic information like the percentages of smokers/non-smokers across the groups.
  • Analysis of serum was undertaken for: (a) total IgG antibody binding to C1q, (b) C1q seropositivity and (c) C1q immune complexes containing food antigens.
  • Results: C1q antibody levels were highest in the ROSZ group and moderately elevated in the SZ group compared with controls.
  • Based on cut-off values, C1q seropositivity was associated with both ROSZ and SZ groups with corrected odds ratios (ORs) of 8.02 and 3.15 respectively alongside some quite wide-ranging confidence intervals.
  • Looking at milk casein and wheat gluten as being potential sources of C1q immune complexes, there was indeed a sizable presence of C1q milk casein or wheat gluten antigen complexing to be had. Indeed, particularly for the SZ group - the chronically affected group - "the presence of an immune complex containing C1q and a casein or gluten food antigen yielded a significant odds ratio for disease association".
  • There was no significant positive association between C1q and other antigens including an old friend, T.gondii (well, not so much of a friend).
  • Although not formally part of this experiment, the authors also report that in the SZ group at least "C1q was associated with a marker of GI inflammation, ASCA" with reference to the anti-Saccharomyces cerevisiae IgG antibodies (ASCA) that formed part of their last paper.

So, in their cohort at least, the authors found quite a strong presence of C1q activation in cases of schizophrenia meaning that this was a system hard at work trying to get rid of those immunoglobulin-antigen complexes. Added to the fact that milk and wheat were quite significantly a part of those immunoglobulin-antigen C1q complexes.

Another detail from this paper interests me. Mention is made of the possibility of C1q autoantibodies as an explanation for the strong C1q immunoreactivity noted in both schizophrenia groups particularly the ROSZ group. I'm very intrigued by this prospect given the emerging evidence on a possible role for autoimmunity in cases of other conditions like autism and indeed some direction in the current paper towards the work of Ari Vojdani and colleagues and their anti-gluten and anti-casein peptide antibodies******. 

For quite a few years now, its often been at the back of quite a few people's minds that the whole gluten and casein peptide theory of autism might actually result not just in a direct pharmacological 'opioid' effect from such peptides as per the speculations of Sun and Cade*******, but also an immune system effect as the body starts to recognise such peptides outside of places like the GI tract (as a result of enhanced gut permeability). It is speculative but we've already kinda seen hints of this in other areas with for example, the Sutterella IgG findings in cases of autism (see here) and so-called bacterial translocation. So how about peptide translocation similar to that speculated in coeliac disease?

All in all I am once again mightily impressed with the work coming out of Johns Hopkins in this area and yet again dream about how this platform and methodology could so readily be tested in cases of autism and lots of other related conditions too.

To finish, I'm in the mood for something a bit different, so how about The Cincy Brass covering a Gaga classic?


* Severance EG. et alComplement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia. Neurobiology of Disease. 2012. July 2012.
DOI: 10.1016/j.nbd.2012.07.005

** Severance EG. et al. Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophrenia Research. 2012; 138: 48-53.
DOI: 10.1016/j.schres.2012.02.025

*** Dohan FC. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophrenia Bulletin. 1988; 14: 489-494.

**** Horák P. et al. C1q complement component and -antibodies reflect SLE activity and kidney involvement. Clinical Rheumatology. 2006; 25: 532-536.

***** Stevens B. et al. The classical complement cascase medicates CNS synapse elimination. Cell. 2007; 131: 1164-1178.

****** Vojdani A. et al. Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. International Journal of Immunopathology & Pharmacology. 2003; 16: 189-199.

******* Sun Z. & Cade JR. A peptide found in schizophrenia and autism causes behavioural changes in rats. Autism. 1999; 3: 85-89.

---------- Severance EG, Gressitt K, Halling M, Stallings CR, Origoni AE, Vaughan C, Khushalani S, Alaedini A, Dupont D, Dickerson FB, & Yolken RH (2012). Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia. Neurobiology of disease PMID: 22801085