Major Mechanisms of Glomerulonephritis Development
The major mechanism associated with the development of glomerulonephritis is immune-mediated injury, primarily involving immune complex deposition, autoantibody formation, or dysregulation of the complement system.
Immune-Mediated Mechanisms
Immune Complex Deposition
- Immune complexes form when antibodies bind to antigens, either self or foreign
- These complexes deposit in the glomerular basement membrane and mesangium
- Once deposited, they activate the complement cascade and recruit inflammatory cells 1
- This mechanism is central to many forms of glomerulonephritis, including:
- Post-infectious glomerulonephritis
- Lupus nephritis
- IgA nephropathy
- Cryoglobulinaemic glomerulonephritis
Autoantibody Production
- Autoantibodies may target specific glomerular structures
- Examples include:
- Anti-glomerular basement membrane (anti-GBM) antibodies
- Anti-neutrophil cytoplasmic antibodies (ANCA)
- These antibodies can cause direct damage or trigger inflammatory responses 1
Complement System Dysregulation
- The complement system plays a crucial role in glomerular inflammation
- Dysregulation can occur through:
- Genetic mutations in complement regulatory proteins
- Acquired autoantibodies against complement factors
- Inappropriate activation by immune complexes
- C3 glomerulopathy represents a prime example of complement-mediated glomerular injury 1
Pathophysiological Consequences
Inflammatory Cell Recruitment
- Following immune complex deposition or autoantibody binding:
- Neutrophils are often the first responders 2
- Monocytes/macrophages infiltrate the glomeruli
- T and B lymphocytes may also be recruited
- These cells release inflammatory mediators, including cytokines and chemokines 3
Mesangial Cell Activation
- Mesangial cells respond to immune complexes and inflammatory signals by:
- Proliferating (mesangioproliferative response)
- Producing extracellular matrix components
- Releasing chemokines that attract more inflammatory cells 3
- This contributes to the characteristic mesangial expansion seen in many forms of glomerulonephritis
Podocyte Injury
- Podocytes are specialized epithelial cells crucial for glomerular filtration
- Immune-mediated injury to podocytes leads to:
- Proteinuria
- Foot process effacement
- Eventual podocyte loss and glomerulosclerosis
Classification Based on Immune Mechanisms
Immune Complex-Mediated Glomerulonephritis
- Characterized by granular deposits of immunoglobulins and complement
- Examples include:
- IgA nephropathy
- Lupus nephritis
- Post-infectious glomerulonephritis
- Membranoproliferative glomerulonephritis (MPGN) with immune complexes 1
Pauci-immune Glomerulonephritis
- Minimal or absent immune deposits
- Associated with ANCA
- Examples include:
- Granulomatosis with polyangiitis
- Microscopic polyangiitis
- Eosinophilic granulomatosis with polyangiitis 1
Anti-GBM Glomerulonephritis
- Linear deposition of antibodies along the glomerular basement membrane
- Causes Goodpasture syndrome when lungs are also affected 1
Complement-Mediated Glomerulonephritis
- Characterized by C3 deposits with minimal or no immunoglobulin deposits
- Examples include:
- C3 glomerulopathy
- Dense deposit disease 1
Special Considerations
Monoclonal Gammopathy-Related Glomerulonephritis
- Monoclonal immunoglobulins can cause various forms of glomerular injury
- Examples include:
- Monoclonal immunoglobulin deposition disease
- Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID)
- Fibrillary glomerulonephritis 1
Infection-Related Glomerulonephritis
- Infections can trigger glomerulonephritis through:
- Direct deposition of microbial antigens
- Formation of immune complexes with microbial antigens
- Molecular mimicry leading to autoantibody production
- Hepatitis B and C are notable causes of secondary glomerulonephritis 1
Understanding these immune-mediated mechanisms is crucial for appropriate diagnosis and targeted therapy of glomerulonephritis, ultimately affecting patient morbidity, mortality, and quality of life.