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This chapter offers a new theory in order to explain the triggering of an immune response, called the “continuity theory.” According to this theory, the triggering of an immune response is due to a strong modification of the antigenic patterns with which the organism’s immune receptors continuously interact. The continuity theory is built upon the two observations made in the previous chapter in order to reject the self-nonself theory, that is, normal autoreactivity and immune tolerance. One of the main advantages of the continuity theory is that it gathers under a unique explanation phenomena that have until now received different explanations, and even sometimes ad hoc explanations: immune responses to tumor cells, the phagocytosis of dying cells, or the triggering of immune regulatory mechanisms, among others. I show how the continuity theory explains a wide range of phenomena, and how it can be applied to every organism, including unicellulars.

This chapter offers a critique of the self-nonself theory. I first analyze data on autoreactivity and normal autoimmunity, in particular phagocytosis and regulatory cells, in order to reject the idea that self constituents do not trigger immune responses. In a second step, thanks to a description of immune tolerance to genetically foreign entities, including the fetus and huge amounts of commensal and symbiotic bacteria, I reject the idea that every nonself triggers an immune response of rejection. I show that every organism is “impure” in so far as it contains a great number of “nonself” constituents. I conclude that the self-nonself theory is experimentally inadequate, and conceptually too vague to still be used as a satisfying scientific framework to explain the triggering of immune responses.

Multiple sclerosis (MS) is considered an autoimmune chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal damage. The view of MS as a “two-stage disease”, with a predominant inflammatory demyelination in the early phase (relapsing-remitting MS form) and a subsequent secondary neurodegeneration in the early phase (secondary or primary progressive MS) of the disease, is now challenged by the demonstration that axonal destruction may occur independently of inflammation and may also produce it. Therefore, as CNS inflammation and degeneration can coexist throughout the course of the disease, MS may be a “simultaneous two-component disease”, in which the combination of neuroinflammation and neurodegeneration promotes irreversible disability. This chapter discusses factors that contribute to the pathogenesis of MS, immune surveillance in the CNS, regulation of immune responses in the inflamed CNS, initiation of T helper 1 (Th1)-mediated immune reactions in the inflamed CNS, amplification of Th1-mediated immune responses in inflamed CNS and tissue damage, and development of autoimmunity in MS.