Conclusion: Self-defense Versus Autoimmunity
The critical function of the immune system is to discriminate self- from non-self and maintain tolerance against self-antigens. Therefore, the immune system must deplete the self-reactive lymphocytes that produce AutoAb. B cells develop from hematopoietic stem cells. B cell maturation involves the rearrangement of the immunogloboulin (Ig) heavy chain, which is independent of the antigen and requires interactions with bone marrow stromal cells leading to the generation of the pre-BCR (central tolerance). The BCR complexes regulate the continuous B-cell development and define its reactivity. BCR cross-linking by the self-antigens initiates BCR editing, which rearranges the Ig light chain genes to substitute the self-reactive receptors with the non-self-reactive receptors. The B cells that display auto-reactive Igs after BCR editing are removed by apoptosis, and the surviving B cells migrate to the periphery and mature to become immune-competent naïve B cells. However, the selection involves only the antigens expressed in the central lymphoid organs. The auto-reactive B cells that encounter self-antigens in the periphery must also be removed (peripheral tolerance). Nevertheless, a negative selection mechanism exists to delete auto-reactive B cell clones. Unless a B cell engaged with a self-antigen interacts with a T helper cell, it will be led to apoptosis. This indicates that auto-reactive T helper cells are critically involved in the breakdown of B cell tolerance, leading to the production of AutoAb. Thus B-cell proliferation in response to self-antigen depends on the cooperation of both B and T cells. Secretion of AutoAbs indicates the breakdown of tolerance in which both B and T cells escape the sensing process.
The peripheral mechanisms that maintain immune tolerance are not completely understood. Failure of both central and peripheral tolerance results in self-reactive B cells and generation of AutoAbs, favoring the development of autoimmune diseases. Efficient clearance of apoptotic cells is crucial to avoid generation of autoimmune cells and maintain tolerance, which requires a large spectrum of NAbs. To generate this NAb diversity, Ig genes undergo recombinations in which a huge number of intact Ig genes are assembled by assorting a relatively small number of gene segments. On the other hand, NAbs can still potentially contribute to harmful immune reactions, though the presence of NAb alone is not enough to lead to autoimmunity. The switches between self-defense and autoimmune response remain to be clarified.
The CNS is relatively isolated by several barrier systems including the BBB, which adds additional features to immune responses that target self-antigens of the CNS. The cloning of monoclonal natural human IgMs that recognize neural self-antigens provides powerful tools for understanding the generation of immunity against the CNS, and will benefit both research and therapeutics.