What primarily forms complexes that precipitate in tissues due to self-antigens, B cells or autoantibodies?

Autoantibodies Form Complexes That Precipitate in Tissues in Autoimmune Diseases

Autoantibodies, not B cells themselves, are the primary entities that form complexes with self-antigens that precipitate in tissues, causing tissue damage in autoimmune diseases. 1, 2

Mechanism of Autoantibody-Mediated Tissue Damage

Production of Autoantibodies

• Autoreactive B cells produce autoantibodies when self-tolerance mechanisms fail 1
• In autoimmune diseases, B cells break tolerance to self-antigens due to:
  • Environmental triggers (viral infections, xenobiotics)
  • Ineffective regulation by T regulatory cells (nTregs and iTregs)
  • Lack of effective B regulatory cell (Breg) inhibition 1

Formation of Immune Complexes

• Autoantibodies bind to self-antigens forming immune complexes 2
• These complexes can:
  • Precipitate in tissues
  • Activate complement pathways
  • Engage Fc receptors on inflammatory cells 3

Tissue Deposition and Damage

• Immune complex deposition in tissues leads to:
  • Complement activation
  • Recruitment of inflammatory cells
  • Local inflammation
  • Tissue damage and organ dysfunction 2

Evidence from Specific Autoimmune Diseases

Systemic Lupus Erythematosus (SLE)

• Anti-dsDNA autoantibodies form immune complexes that deposit in tissues, particularly in the kidneys 1, 2
• These complexes are associated with lupus nephritis and other organ manifestations 2
• The American College of Rheumatology recommends anti-dsDNA testing for SLE diagnosis and monitoring disease activity 2

Autoimmune Hepatitis (AIH)

• Autoantibodies produced by B cells contribute to the pathogenesis of AIH 1
• The immunopathogenesis involves:
  1. Break in self-tolerance to hepatocyte autoantigens
  2. Production of autoantibodies by B cells
  3. Formation of immune complexes
  4. Progressive hepatic necroinflammation and fibrogenesis 1

Pathogenicity Factors of Autoantibodies

Antibody Isotype and Subclass

• Different IgG subclasses have varying pathogenic potential 3:
  • IgG2a and IgG2b are most pathogenic (activate Fc receptors and complement)
  • IgG3 is moderately pathogenic (activates complement)
  • IgG1 is least pathogenic 3

Glycosylation Patterns

• The terminal sialylation of IgG oligosaccharide chains affects pathogenicity
• More sialylated IgG autoantibodies have limited Fc-associated effector functions 3

Clinical Relevance

Diagnostic Applications

• Detection of specific autoantibodies is crucial for diagnosis of autoimmune diseases 2
• Anti-dsDNA testing using a double-screening strategy with solid-phase assay followed by Crithidia luciliae immunofluorescence test maximizes sensitivity and specificity 2

Monitoring Disease Activity

• Autoantibody levels, particularly anti-dsDNA, correlate with disease activity in SLE 2
• Regular monitoring of autoantibody levels helps assess treatment response 2

Therapeutic Implications

• B cell-targeted therapies like rituximab work by depleting B cells that produce pathogenic autoantibodies 4
• Rituximab binds to CD20 on B cells, mediating B cell lysis through complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity 4

Important Caveats

• While B cells produce the autoantibodies, it's the antibodies themselves that form the immune complexes with self-antigens 1, 2
• Not all autoantibodies are pathogenic; their pathogenicity depends on:
  • Specificity for the target antigen
  • Isotype and subclass
  • Ability to activate complement
  • Ability to engage Fc receptors 3
• The presence of autoantibodies alone is not sufficient for disease; other factors like genetic predisposition and environmental triggers contribute to disease development 1

Understanding this distinction between B cells and their antibody products is crucial for developing targeted therapies for autoimmune diseases.