Background: The complement system, a network of proteins regulating immune and inflammatory responses, has been implicated in intervertebral disc degeneration (IDD) pathogenesis. Tissue-specific complement activation in degenerated discs is well-established, but systemic expression in IDD patients' plasma is less understood. This study investigates the levels of complement proteins in disease plasma to understand their implications during the disease progression.

Purpose: To understand the (dis)similarities between the proteome profiles of HV-plasma (healthy volunteers) and DD-plasma (patients with degenerative disc disease).

Materials and Methods: Eleven healthy volunteers (HV) and 39 patients with disc degeneration (DD) were recruited. Plasma samples from the HV group served as controls. A high-throughput mass spectrometric approach was used for plasma proteome profiling.

Results: Demographic data showed comparable sex ratios, BMI, blood profiles, and dietary patterns between healthy volunteers (HV) and DD patients. Elevated levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in the DD group indicated significant inflammation (p < 0.05). Proteomic analysis identified 691 proteins in DD-plasma and 526 in HV plasma, with 470 proteins common to both. The corresponding DD-tissue samples revealed 1842 proteins. The PLS-DA model demonstrated a 19.4% variance between HV-plasma and DD-plasma proteins. Further Pathway enrichment analysis highlighted the involvement of 47 complement proteins in the complement and coagulation cascades. Analysis of complement pathways revealed significant upregulation of classical pathway components, C4BPA, C4a, C4b, C2, C3, and C3/C5 convertase, with a notable downregulation of C1q. The lectin pathway showed significant upregulation of MASP1. The alternate pathway exhibited upregulation of MAC constituents (C5, C6, C7, C8A, C8B) and regulatory proteins (CFH, CFI), suggesting their role in immune defense. Interestingly in the corresponding disease tissue, we observed downregulation of all the complement proteins discussed above except for C1q which is upregulated.

Conclusion: This study profiled the proteomes of HV-plasma, DD-plasma, and DD-tissue, revealing altered complement activation (C1q, C1r, and C1s) during degeneration. Upregulation of MAC constituents and regulatory proteins suggests involvement in inflammation. The correlation between complement levels inside the DD-tissue and in the DD-plasma has to be studied further to understand the actions of complement proteins in an IDD context.

Clinical Significance: The inverse correlation between C1q levels in plasma and tissue of IVDD patients could serve as a promising candidate for the prognosis of IVDD progression. C1q expression levels need to be studied in various disease stages in a larger population to be recommended as a therapeutic target.

Keywords: IVDD, proteomics, complement system, plasma proteins, inflammatory markers, CRP, ESR