Complement Activation Related to IgG: Mechanisms and Management
IgG-mediated complement activation is a critical immune defense mechanism that can also drive harmful inflammation in autoimmune diseases, requiring targeted management strategies including immunosuppression, complement inhibitors, and treatment of underlying disorders. 1
Mechanisms of IgG-Mediated Complement Activation
Classical Pathway Activation
- IgG activates complement primarily through the classical pathway by binding of C1q to the Fc regions of IgG antibodies, forming the initial step in the complement cascade 1, 2
- Specific noncovalent interactions between Fc segments of IgG antibodies result in the formation of ordered antibody hexamers after antigen binding on cell surfaces, which efficiently recruit and activate C1 3
- The hexamer formation is critical for optimal complement activation and can be manipulated to enhance or inhibit complement activation 3
IgG Subclass Differences
- Among the four IgG subclasses, IgG4 is considered the least inflammatory and poorly activates the complement system compared to other subclasses 4
- IgG4 can activate complement only at high antigen and antibody concentrations, and this activation is influenced by glycosylation patterns 4
- Bispecific, monovalent IgG4 resulting from Fab arm exchange is a less potent activator of complement than monospecific IgG4 4
Alternative and Lectin Pathway Involvement
- Beyond the classical pathway, antibodies can also play a role in activating both the alternative and lectin pathways of complement 2
- Auto-antibodies can activate the alternative pathway and induce cell lysis and tissue damage, as demonstrated in mouse models 2
Clinical Manifestations of IgG-Complement Activation
Immune Complex-Mediated Glomerulonephritis (ICGN)
- IgG immune complexes can deposit in glomeruli, activate complement, and cause membranoproliferative glomerulonephritis (MPGN) pattern of injury 5
- Immunofluorescence findings on kidney biopsy can help distinguish between monoclonal deposition diseases, autoimmune IC diseases, and infection-associated diseases 5
- Complement dysregulation may occur in immune complex glomerular diseases, leading to a complex interplay between antibodies and complement 5
Monoclonal Gammopathy-Related Complement Activation
- Monoclonal IgG proteins can affect the complement cascade and present as complement-mediated disorders, including hemolytic uremic syndrome (HUS) 5
- In patients over 50 years with C3 glomerulopathy (C3G), monoclonal gammopathies should be considered as potential triggers of complement dysregulation 5
- Monoclonal gammopathies can initiate C3G without glomerular deposition of immunoglobulin 5
Diagnostic Approach
Laboratory Evaluation
- Measure serum complement levels (C3, C4, CH50, AH50) to assess complement activation and pathway involvement 5
- Evaluate for both genetic and immune complement dysregulation, even in the absence of hypocomplementemia 5
- In patients with MPGN pattern and monoclonal immunoglobulin deposits, perform serum and urine electrophoresis, immunofixation, and free light chain analysis to evaluate for hematologic malignancy 5
Specialized Testing
- Comprehensive complement analysis may be necessary for accurate diagnosis of complement-mediated disorders 5
- Consider specialized complement tests such as complement factor levels, autoantibodies to complement components, and genetic testing for complement regulatory proteins 5
- In cases of suspected complement-mediated TMA, evaluate ADAMTS13 activity to distinguish from thrombotic thrombocytopenic purpura (TTP) 5
Management Strategies
Treatment of Underlying Causes
- For monoclonal immunoglobulin-associated diseases, focus on controlling the clone of B cells or plasma cells responsible for production of the monoclonal immunoglobulin 5
- For autoimmune diseases, immunosuppression is most often the treatment of choice 5
- For infection-associated glomerular diseases, control the underlying infection 5
Immunosuppressive Therapy
- For idiopathic ICGN with proteinuria <3.5 g/d and normal eGFR, supportive therapy with RAS inhibition alone may be sufficient 5
- For idiopathic ICGN with nephrotic syndrome and normal or near-normal serum creatinine, a limited course of glucocorticoids can be tried 5
- For more severe cases, mycophenolate mofetil (MMF) has been shown to decrease progression to kidney failure compared to other immunosuppressives 5
Complement Inhibition
- Eculizumab, a monoclonal antibody that specifically binds to complement protein C5, inhibits terminal complement-mediated effects and can be used in complement-mediated disorders 6
- Eculizumab has been used in patients with C3G who fail to respond to MMF, though with variable results 5
- In antibody-mediated rejection (AMR) with complement activation, eculizumab may be considered as a second-line therapy to inhibit complement activation 5
Intravenous Immunoglobulin (IVIG)
- IVIG has an attenuating effect on complement amplification in vivo, despite inducing classical complement pathway activation 7
- IVIG can be considered as part of treatment for complement-mediated disorders, with doses up to 1.6 g/kg in split doses over 2-3 days 5
- The anti-inflammatory potential of IVIG works through inhibiting complement activation, blocking antibody Fc fragments and macrophage Fc receptors, and neutralizing cytokines 5
Plasmapheresis
- In cases of antibody-mediated rejection with complement activation, plasmapheresis with or without IVIG may be beneficial 5
- Plasma exchange increases the clearance of eculizumab approximately 250-fold, requiring supplemental dosing when used concurrently 6
Special Considerations
Monitoring and Follow-up
- Regular monitoring of complement levels (C3, C4) and specific antibody levels can help assess treatment response 5
- In patients receiving complement inhibitors, monitor for increased risk of infections, particularly from encapsulated organisms 6
- Vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b is recommended before initiating complement inhibitor therapy 6