Autoimmune disease monitoring - how to use complement testing results

Analysis of complement in autoimmune disease is important for the diagnosis and monitoring particularly in SLE where increased activation of the classical pathway is a typical finding. Also in several other autoimmune diseases increased complement activation is seen. This is the case in for example rheumatoid arthritis (RA) where complement activation is part of the inflammatory process in the affected joints.

Analysis of complement when an autoimmune disease is suspected should always include functional assays of the activation pathways (for example by Wielisa) in order to detect deficiency cases (ref. 1). This is important since classical pathway deficiencies confer high risk for development of SLE. To measure only selected complement proteins, most often C3 and C4 is not sufficient in this situation. The functional assays will reveal a complement deficiency but a low value may also indicate an ongoing activation and consumption.

To assess activation of complement measurement of

a) individual complement proteins,

b) fragments formed by activation and

c) complexes formed by activation can be used.

a) Low serum level of C1q and C4 indicate classical pathway activation. The concentration is however influenced by other factors, for example are both C3 and C4 levels raised in inflammation (acute phase reactants) which may hide consumption.

b) Cleavage fragments of C3, both C3a and C3d are much used as a measure of activation. Since C3 is common to the three major activation pathways these fragments are good markers. The level of the fragments should be assessed in relation to the level of C3 (ref. 2). Other fragments to distinguish between the pathways are available for research purposes mainly.

c) During activation several complexes between complement proteins are formed. When the activation proceeds through the terminal sequence to formation of the C5b-C9 complex also a soluble terminal complement complex (TCC) is formed through interaction with vitronectin. Measurement of TCC is commonly used since this complex reflects activation after C5 and this complex has also a relatively long serum half life.

Autoantibodies against complement proteins may also be found in autoimmune disease. In SLE with low level of C1q IgG antibodies against C1q is often found. About one third of SLE patients have anti-C1q antibodies and they are typically found in patients with hypocomplementemic urticaria vasculitis syndrome (HUVS). These antibodies are in some cases also found in other conditions and when C1q level is normal. 

Examples of typical test results in patients

Analysis SLE RA HUVS
Classical pathway function Low Normal    Low
Alternative pathway function Normal Normal Normal
C1q Low Normal Low
C4 Low Normal – Increased Low – Normal
C3 Normal Normal – Increased Normal
C3d Increased Normal – Increased Normal – Increased
Anti-C1q Negative/Positive Not measured Positive


Page References

1. Mollnes TE, Jokiranta S, Truedsson L, Nilsson B, Rodrigues de Cordoba S, Kirschfink M: Complement analysis in the 21st century. Molecular Immunology, 44:3838-3849, 2007.

2.  Nilsson B, Ekdahl KN: Complement diagnostics: concepts, indications, and practical guidelines. Clinical and Developmental Immunology. Volume 2012, Article ID 962702, 11 pages, doi:10.1155/2012/962702.

 aHUS complement tests

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