What does the presence of Immunoglobulin G (IgG) + Complement component 3 (C3) indicate?

Understanding IgG + C3 Immunofluorescence Pattern in Renal Pathology

The presence of both Immunoglobulin G (IgG) and Complement component 3 (C3) on immunofluorescence microscopy indicates immune complex-mediated glomerulonephritis with activation of the classical complement pathway, suggesting underlying conditions such as infections, autoimmune diseases, or monoclonal gammopathies. 1

Pathophysiological Significance

• IgG + C3 co-deposition represents activation of the classical complement pathway, where IgG immune complexes bind C1q, leading to sequential activation of C4, C2, and ultimately C3 1
• This pattern suggests antigen-antibody complex formation with subsequent complement fixation, creating covalent C3b-IgG complexes that mark antigens for immune clearance 2
• The presence of both markers indicates that antibodies are binding to antigens (either foreign or self) and activating complement as part of the immune response 1

Common Disease Associations

Infectious Causes:

• Hepatitis B and C viral infections 1
• Bacterial endocarditis and infected ventriculo-atrial shunts 1
• Chronic microbial infections (fungal, parasitic, protozoal, mycoplasma, mycobacterial) 1

Autoimmune Disorders:

• Systemic lupus erythematosus (SLE) 1
• Mixed cryoglobulinemia 1
• Sjögren syndrome and rheumatoid arthritis 1

Neoplastic Conditions:

• Monoclonal gammopathies and plasma cell dyscrasias 1
• Leukemia (particularly chronic lymphocytic leukemia) 1
• Lymphoma and solid organ carcinomas 1

Other Conditions:

• Castleman disease (angiofollicular lymph node hyperplasia) 1
• Sarcoidosis, celiac disease, and sickle cell disease 1
• Alpha-1-antitrypsin deficiency 1

Diagnostic Implications

• The IgG + C3 pattern helps differentiate immune complex-mediated glomerulonephritis from complement-mediated diseases (C3 glomerulopathy) and non-immune processes 1
• This pattern is commonly seen in membranoproliferative glomerulonephritis (MPGN) with immune complex deposition 1
• The finding warrants a thorough evaluation for underlying causes of antigenemia that can trigger the classical complement pathway 1, 3

Recommended Diagnostic Workup

• Serum complement levels (C3, C4, CH50) to assess complement consumption 3
• Complete urinalysis with sediment evaluation for dysmorphic hematuria and casts 3
• 24-hour urine protein quantification (significant if >500 mg/day) 3
• Renal function tests (creatinine, BUN) 3
• Infectious disease workup: hepatitis B/C serology, blood cultures if endocarditis suspected 1
• Autoimmune evaluation: ANA, anti-dsDNA, ANCA, rheumatoid factor 1, 3
• Paraprotein studies: serum and urine electrophoresis, immunofixation, and free light chain analysis 1

Clinical Pearls and Pitfalls

• In adults over 50 years with IgG + C3 pattern, always evaluate for monoclonal gammopathies even if other conditions are identified 1, 3
• The presence of light chain restriction or IgG subclass restriction on immunofluorescence strongly suggests a monoclonal process requiring hematology consultation 1
• Before labeling a case as "idiopathic," comprehensive evaluation for complement dysregulation should be performed even in the absence of hypocomplementemia 1
• Complement and IgG can form covalent complexes (C3b-IgG), which are important for immune complex clearance and can be detected as specific bands on electrophoresis 2, 4
• The IgG + C3 pattern can sometimes be seen in post-infectious glomerulonephritis even after 8 weeks, so clinical correlation is essential 3

Treatment Considerations

• Treatment should primarily target the underlying cause rather than the immune complex deposition itself 1
• For infectious causes, appropriate antimicrobial therapy is the cornerstone of management 1
• For autoimmune diseases, immunosuppression is typically required 1
• For monoclonal gammopathies, treatment focuses on controlling the clone of B cells or plasma cells responsible for production of the monoclonal immunoglobulin 1
• For truly idiopathic cases with nephrotic syndrome and declining kidney function, immunosuppression with cyclophosphamide or mycophenolate mofetil plus corticosteroids may be considered 1