Introduction
Nephritic factors are a group of autoantibodies generated in the complement system against neoepitopes, causing their dysregulation. A neoepitope is an antigenic determinant (epitope) that is a part of an antigen or a portion of a foreign protein that has not been encountered by the immune system previously. Nephritic factors are associated with various kidney diseases like C3 glomerulopathy, acquired partial lipodystrophy, membranoproliferative glomerulonephritis, and systemic lupus erythematosus.
What Are Nephritic Factors?
Nephritic factors are a group of autoantibodies generated in the complement system. It is a heterogeneous group of autoantibodies that are generated against the neoepitopes, causing their dysregulation. They stabilize the enzymes produced in the complement system. The C3 nephritic factor stabilizes the C3 convertase enzyme in the alternative pathway of the complement system. The C5 convertase of the alternative pathway is stabilized by the C5 nephritic factor. Autoantibodies are also produced against the C3 or C5 convertase of the classical and lectin pathways. These autoantibodies are associated with renal diseases like C3 glomerulopathy and membranoproliferative glomerulonephritis. It is also seen in other conditions, such as infections and autoimmune disorders like systemic lupus erythematosus and acquired partial lipodystrophy.
What Is a Complement System?
The complement system is a molecular system that is complex. It plays a fundamental role in defense mechanisms, apoptotic cell clearance, immune complex elimination, and adaptive immunity modulation. It also differentiates between foreign agents and self-components. The complement system detects the foreign agents through a molecular tagging system and eliminates them by cell lysis or opsonophagocytosis.
The complement system is activated by three mechanisms, namely, the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). The initial activation step is different for each pathway, but all the pathways converge in the C3 molecule activation through the generation of C3 convertase (an unstable protease complex).
What Is the Role of the Nephritic Factors in the Complement System?
The binding of antigen-antibody complexes and the recognition of mannose groups on the surface of the bacteria stimulate the activation of the CP and LP pathways. This activation results in the generation of the C3 convertase complex, which splits C3 into C3a and C3b. The activation steps progress and result in the generation of C5 convertase, which splits C5 into C5a (a pro-inflammatory anaphylatoxin) and C5b, which is incorporated into the formation of the membrane attack complex (MAC) along with C6, C7, C8, and C9 molecules on the cell surface. The AP is initiated by the spontaneous activation of the C3 molecule in plasma. This membrane attack complex attacks the cell membrane if it is not stopped.
The C3 and C5 convertase complexes are vital because they dissociate in a few minutes to prevent autologous tissue injury. The nephritic factors stabilize C3 and C5 convertase, preventing its dissociation, increasing its half-life, and causing tissue injury. A group of complement regulatory proteins functions to prevent this damage. Proper control between activation and regulation of the complement system is essential to prevent various diseases. Deficiency in these proteins or the presence of nephritic factors causes diseases, namely membranoproliferative glomerulonephritis, C3 glomerulopathy, acquired partial lipodystrophy, or systemic lupus erythematosus.
What Are C3, C5, and C4 Nephritic Factors?
Nephritic factors are autoantibodies that bind to convertases of the complete system and cause its dysregulation. A nephritic factor stabilizes C3 convertase in either the cell-bound or fluid phase of the alternative pathway (AP) by incorporating it into the C3 convertase. This nephritic factor that stabilizes C3 convertase is named as C3 nephritic factor, an autoantibody. C3 nephritic factor binds to a neoepitope on the C3 convertase of the alternative pathway. This prevents the dissociation of C3 and increases its half-life and consumption.
The C3 nephritic factor is responsible for the activation of the C5 convertase. C5 nephritic factors stabilize the C5 convertase of the alternative pathway. The C5 nephritic factor binds to a neoepitope on the C5 convertase of the alternative pathway, preventing its decay and increasing its half-life. The C5 nephritic factor exists as a unique factor or coexists with the C3 nephritic factor.
C4 nephritic factors are autoantibodies that bind to neoepitope on the C3 convertase of the CP or LP and stabilize it and increase its half-life. It also stabilizes the C5 convertase and prevents its decay.
What Are the Diseases Associated With Nephritic Factors?
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C3 Glomerulopathy or Membranoproliferative Glomerulonephritis - This rare kidney disease is caused by the dysregulation of the alternative pathway. It is characterized by C3 deposition in the glomeruli of the kidneys.
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Acquired Partial Lipodystrophy - It is a rare autoimmune disease characterized by the presence of C3 hypocomplementemia with C3 nephritic factor.
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Systemic Lupus Erythematosus - C3 nephritic factors have been detected in this disease and other infections like meningococcal infections.
How Are Nephritic Factors Detected?
Various renal diseases are caused by complement dysregulation. Definitive diagnosis requires a microscopic examination of kidney biopsy. However, following laboratory tests are performed to diagnose nephritic factors. Serums from patients are screened for auto antibodies that cause complement dysregulation. Nephelometry or Turbidimetryare automated methods to detect the presence of serum C3 and C4 levels. Genetic screening is performed in C3 glomerulopathy patients to screen for alternative pathway regulators.
How Are the Patients With Nephritic Factors Managed?
The presence of nephritic factors is considered the autoimmune cause of the diseases, namely C3 glomerulopathy and membranoproliferative glomerulonephritis. Treatment done is the same as other autoimmune diseases, and also complement-blocking drugs are used.
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Plasmapheresis - Plasma exchange therapy is performed to remove the nephritic factors from the serum of the patients.
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Immunosuppressants - Immunosuppressant drugs like glucocorticoids and mycophenolate mofetil are given to reduce the production of nephritic factors.
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Monoclonal Antibody Therapy - Antibody-producing B cell targeted therapies are effective in patients with C3 nephritic factors.
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Complement Directed Therapies - Complement blocking agents like Eculizumab have been tried in patients with nephritic factors.
Conclusion
Nephritic factors are a group of autoantibodies that cause dysregulation of the complement system. The complement system is essential for defense mechanisms, apoptotic cell clearance, immune complex elimination, and adaptive immunity modulation. Nephritic factors are associated with various diseases. Diagnosing the nephritic factors and proper treatment can help in managing the diseases associated with it.
