What is the pathophysiology of autoimmune hemolytic anemia (AIHA) mediated by Immunoglobulin G (IgG) antibodies?

Pathophysiology of IgG-Mediated Autoimmune Hemolytic Anemia

In autoimmune hemolytic anemia (AIHA) mediated by IgG antibodies, the primary mechanism of red blood cell destruction occurs through extravascular hemolysis in the spleen, with complement playing a supporting but not essential role in this process.

Autoantibody Production and Characteristics

• AIHA is characterized by the production of IgG autoantibodies directed against self red blood cell (RBC) surface antigens 1
• In warm AIHA (the most common type of IgG-mediated AIHA):
  • Autoantibodies are typically polyclonal high-affinity IgG that react optimally at 37°C 2
  • These autoantibodies are produced by non-malignant B lymphocytes through a T-cell-mediated mechanism 2
  • The etiology underlying the production of these autoantibodies involves complex immunological dysregulation 3

Immunological Breakdown Leading to AIHA

The pathogenesis of IgG-mediated AIHA involves several immunological abnormalities:

1. Defective antigen presentation to immunocompetent cells 1
2. Insufficient T-lymphocyte tolerance to RBC autoantigens 1
3. Functional abnormalities of B and T cells resulting in polyclonal lymphocyte activation 3
4. Alteration of cytokine production affecting immune regulation 3
5. Dysfunction of immunoregulatory T cells that normally prevent autoimmunity 3

Mechanism of RBC Destruction

Primary Mechanism: Extravascular Hemolysis

1. IgG Opsonization: IgG autoantibodies bind to RBC surface antigens, coating (opsonizing) the cells 2, 3
2. Fc Receptor Recognition: The Fc portion of IgG antibodies on RBCs is recognized by Fc receptors on macrophages in the spleen and liver 2
3. Antibody-Dependent Cellular Cytotoxicity (ADCC): IgG-opsonized RBCs are destroyed via ADCC mechanisms 2
4. Phagocytosis: Macrophages in the spleen engulf portions of the RBC membrane (trogocytosis) or the entire RBC 4
5. Sequestration: The spleen traps and sequesters antibody-coated RBCs, removing them from circulation 4

Role of the Complement System

The complement system plays a variable role in IgG-mediated AIHA:

• Complement Activation: Some IgG subclasses (particularly IgG1 and IgG3) can activate the classical complement pathway 2
• C3b Deposition: When complement is activated, C3b is deposited on RBC surfaces, enhancing recognition by macrophages that have C3b receptors 2
• Incomplete Complement Cascade: In IgG-mediated AIHA, complement activation typically stops at C3, rarely proceeding to the formation of the membrane attack complex (MAC) 2
• Complement-Independent Destruction: Notably, many cases of IgG-mediated AIHA can proceed without significant complement activation, as the Fc-mediated phagocytosis is often sufficient for RBC destruction 4

Role of the Spleen

The spleen is the primary site of RBC destruction in IgG-mediated AIHA:

• Specialized Macrophages: The spleen contains specialized macrophages with high expression of Fc receptors 4
• Slow Blood Flow: The splenic architecture with its slow blood flow allows optimal interaction between antibody-coated RBCs and macrophages 4
• Hemagglutination: In some cases, IgG antibodies can cause RBC agglutination in the spleen, leading to mechanical trapping and sequestration 4
• Therapeutic Relevance: The central role of the spleen explains why splenectomy can be an effective treatment in refractory cases, with success rates up to 70% in idiopathic warm AIHA 3

Additional Pathophysiological Mechanisms

• Vesiculation: Recent evidence suggests that RBC vesiculation may be an additional pathogenic mechanism in some cases of AIHA, potentially contributing to complement activation and disease severity 5
• Eryptosis: In some cases, antibody binding may induce programmed cell death of RBCs (eryptosis), though this appears to be a less common mechanism 4

Clinical Implications

The understanding of these pathophysiological mechanisms has direct therapeutic implications:

• Glucocorticoids: First-line therapy that suppresses autoantibody production and macrophage function 3
• Splenectomy: Second-line therapy that removes the primary site of extravascular hemolysis 3, 4
• Rituximab: Targets CD20+ B cells to reduce autoantibody production, effective in approximately 60% of refractory cases 3

Understanding the predominant role of extravascular hemolysis in the spleen and the variable contribution of complement helps guide appropriate therapeutic interventions in patients with IgG-mediated AIHA.