Complement Activation May Drive the Pathogenicity of Anti-α6 and Anti-β4 Integrin Antibodies In Vivo

Area of Science:

• Immunodermatology
• Autoimmunity
• Integrin Biology

Background:

• Autoantibodies targeting α6β4 integrin are found in mucous membrane pemphigoid (MMP).
• Anti-α6 integrin antibodies correlate with oral lesions, while anti-β4 integrin antibodies are linked to ocular involvement.
• The precise pathogenic mechanisms of these autoantibodies remain unclear.

Purpose of the Study:

• To investigate the pathogenic potential of IgG autoantibodies against α6 and β4 integrin.
• To elucidate the in vitro and in vivo effects of these autoantibodies.

Main Methods:

• Immune complexes of anti-α6 and anti-β4 integrin were used to stimulate human leukocytes and murine keratinocytes.
• Repeated injections of anti-β4 and anti-α6 integrin IgG were administered to C57BL/6 mice.
• Histopathological analysis and direct immunofluorescence microscopy were performed on affected tissues.
• Complement fixation assays were conducted to assess complement activation.

Main Results:

• In vitro, anti-α6 and anti-β4 integrin immune complexes induced reactive oxygen species release and CXCL2 secretion.
• In vivo, mice injected with anti-β4 integrin IgG developed conjunctival swelling, and those with anti-α6 integrin IgG showed mild oral lesions.
• Histopathology revealed subepithelial inflammation without tissue splitting.
• Direct immunofluorescence showed IgG deposition at the basement membrane zone, but minimal C3 deposition, indicating inefficient complement activation.

Conclusions:

• IgG autoantibodies against α6 and β4 integrin possess pathogenic activity.
• These antibodies can induce mild in vivo disease manifestations, particularly oral and ocular symptoms.
• The pathogenic effects in this model may be partly attributed to inefficient complement activation by these autoantibodies.