Effectors and determinants of the innate and adaptive immune responses

Introduction Multicellular organisms must protect themselves against a plethora of exogenous enemies surrounding them. In the case of microbes, the body relies on several, scaled strategies. Firstly, there are external membranes, such as the skin and mucous membranes, that ward offmost potential intruders. The physical barriers are highly efficient, but not perfect; at any time, a few potential pathogens can leak through and invade the tissues. These invaders are dealt with by an intricate system of internal defense, the immune system, which identifies the foreign pathogen and mounts a response with the ultimate aim to neutralize and eliminate it. There are principally two classes of immune responses, one, the innate immune response, is based on response elements preformed within the body, and thus is immediately available upon contact with a microbial target. The other response type, adaptive immunity, develops following the first contact with the pathogen. It produces specific effector cells and humoral antibodies, which are exclusively programmed to exterminate infectious agents, and it provides an immunological memory (Table 1.1). Importantly, however, innate and adaptive immune reactions are not strictly separated, but tightly interconnected (Medzhitov, 2001). Thus, in the course of early innate immune reactions, the presentation of antigens to cells of the adaptive immune system is enhanced, while, conversely, ongoing adaptive reactions can trigger or enhance innate reactivity. The general rules of immune response are of proven validity for most of the body’s organs and tissues. They also govern protection of the central nervous system (CNS), although in a modified version that takes into account the particular requirements of these very special tissues. This chapter will discuss how innate and adaptive immune responses function in the CNS to maintain health and to modulate different diseases. Innate immunity Innate immune reactivity is the oldest version of immunity. It acts throughout phylogeny, in insects as in mammals, even in plants. Like its adaptive counterpart, the innate immune system must be able to distinguish between foreign structures, which are to be discarded, and the various components of the “self”, which must be tolerated. Recognition of infectious non-self is mediated by a limited number of germlineencoded pattern-recognition receptors (PRRs), that recognize structural motifs typical for microbial agents, and which trigger rapid inflammatory responses (Medzhitov and Janeway, 1997). Some PRRs can also recognize endogenous “danger signals” (Wagner, 2006), such as mitochondrial components leaking out of a destroyed cell. These receptors alert the immune system to cell damage, independent of microbial infection. Activation of innate immune pathways occurs in the brain classically in infectious diseases of the CNS, but also under “sterile” conditions (Wyss-Coray and Mucke, 2002). Brain injury, neurodegeneration, ischemia, autoimmunity and neoplasia can all give rise to innate immune responses within the CNS tissues. The consequences of innate immune activation in non-infectious CNS diseases are ambiguous. Dependent on the context, the reactions can eithermediate damage to neurons or, in contrast, protect them from exogenous insult.