What is the significance of elevated Immunoglobulins (Ig) and low Complement component 3 (C3) and Complement component 8 (C8) levels?

From the Guidelines

Elevated immunoglobulins with low C3 and C8 complement levels are indicative of an active autoimmune process, and immediate evaluation and treatment are crucial to prevent further tissue damage and improve patient outcomes. The patient's presentation suggests an underlying condition such as systemic lupus erythematosus (SLE), mixed cryoglobulinemia, or certain forms of vasculitis, which are characterized by immune complex formation and activation of the complement cascade 1.

Key Considerations

• The patient's low C3 and C8 levels indicate complement consumption due to immune complex formation and activation of the complement cascade.
• Elevated immunoglobulins suggest an active autoimmune process, which requires prompt evaluation and treatment.
• A complete autoimmune workup, including ANA, anti-dsDNA, anti-Smith antibodies, rheumatoid factor, and ANCA testing, is essential to determine the underlying diagnosis.
• Additional testing, such as serum protein electrophoresis, cryoglobulin levels, and urinalysis, should be performed to rule out monoclonal gammopathy and assess for renal involvement.

Treatment Approach

• Treatment depends on the underlying diagnosis but often includes immunosuppressive therapy, such as prednisone (starting at 0.5-1 mg/kg/day with gradual taper), hydroxychloroquine (200-400 mg daily) for SLE, or rituximab (375 mg/m² weekly for 4 weeks) for certain vasculitides.
• Patients should be monitored regularly with complement levels, complete blood counts, and renal function tests to assess treatment response.
• Antibiotic prophylaxis and immunization can be applied for recurrent infections, as complement deficiencies can increase the risk of bacterial respiratory tract infections 1.

Pathophysiology

• The formation of antibody-antigen complexes activates and depletes complement components, particularly C3 and C8, leading to inflammation and tissue damage in affected organs.
• The activation of the complement cascade contributes to the development of autoimmune diseases, such as SLE and vasculitis.
• Understanding the pathophysiology of complement activation and consumption is essential for developing effective treatment strategies and improving patient outcomes.

From the Research

Complement System and Immunoglobulins

• The complement system is a powerful cascade of the innate immunity and also acts as a bridge between innate and acquired immune defence 2.
• Complement activation can occur via three distinct pathways, the classical, alternative and lectin pathways, each resulting in the common terminal pathway 2.
• Immunoglobulins can mediate complement activation, and both monoclonal and polyclonal immunoglobulin contingents can contribute to complement dysregulation in certain diseases 3.

C3 and C8 Complement Components

• Low C3 levels have been observed in various diseases, including autoimmune hemolytic anemia (AIHA) and C3 glomerulopathy (C3G) 4, 3.
• Elevated sC5b-9, a biomarker of C3 and C5 convertase activation, was present in 78% of patients with MIg-C3G 3.
• C3 plays a versatile role in the complement response, acting as a point of convergence of activation pathways and fueling the amplification of the complement response 5.

Relationship between Immunoglobulins and Complement Components

• Autoantibodies targeting complement components have been described to alter expression and/or function of target protein resulting in a dysregulation of the delicate equilibrium between activation and inhibition of complement 2.
• The detection of autoantibodies targeting complement components is performed in specialized laboratories, but there is no consensus on detection methods and standardization of the assays is a real challenge 2.
• Both polyclonal and monoclonal Ig can contribute to complement dysregulation in MIg-C3G, and the monoclonal immunoglobulin can enhance C3 convertase activity 3.

Clinical Implications

• Low C3 levels have been associated with an increased risk of healthcare-associated infections (HAIs) in intensive care patients 6.
• Elevated complement C3 levels may be associated with a reduced incidence of HAIs in ICU patients 6.
• The study findings may be helpful in not only unraveling the mechanism underlying hemolysis in AIHA but also diagnosing AIHA and selecting targeted treatment strategies 4.