Principles of autoimmune disease: pathogenesis, genetics and specific immunotherapy

Area of Science:

• Immunology
• Genetics

Background:

• The immune system produces diverse lymphocyte clones to combat pathogens.
• Autoimmune diseases arise from "forbidden clones" that mistakenly target host antigens.
• Burnet's concept of forbidden clones has been overlooked in immunology for decades.

Purpose of the Study:

• To re-emphasize Burnet's "forbidden clone" theory in the context of modern immunology.
• To explain the genetic mechanisms (V and H genes, somatic mutations) underlying forbidden clone formation.
• To highlight the potential for targeted immunotherapy by identifying these self-reactive clones.

Main Methods:

• Review of established immunological principles regarding V and H genes.
• Explanation of somatic hypermutation in lymphocyte development.
• Analysis of microbial triggers in autoimmune disease pathogenesis.

Main Results:

• Somatic mutations in V genes during immune responses can generate self-reactive "forbidden clones".
• Histocompatibility (H) genes normally delete self-reactive clones but imperfectly.
• Microbial infections can initiate cascades leading to forbidden clone expansion and autoimmune disease.

Conclusions:

• Autoimmune diseases result from specific lymphocyte clones with self-reactivity, arising from V gene mutations.
• Understanding the genetic basis of forbidden clones is crucial for autoimmune disease research.
• Targeting these forbidden clones offers a promising avenue for future immunotherapy strategies.