**2.1 Innate immune system**

414 Amyotrophic Lateral Sclerosis

1984 the presence of an autoimmunity component in ALS was proven when immunoglobulin depositories have been described in spinal cord (Donnenfeld et al., 1984). At present the implication of the neuronal and non-neuronal immunological cells and activation of the inflammatory processes have been extensively described in ALS

Starting from literature data about implication of the innate and adaptive immunity in ALS, we would like to point out the role of the TNF alpha (TNF-) system and its interactions in ALS pathway with particular attention to SOD1 protein, the most important player in the ALS pathogenesis. We will focus this book section on TNF- cytokine because its involvement both in immunological pathways and in oxidative stress is known in ALS disease. Moreover we will try to define the immunological actors that exert a protective

In the last decades, increasing numbers of experimental and clinical observations have reported inflammatory reactions in ALS tissues which indicate the involvement of both the innate and adaptive immune responses (Fig. 1) (McGeer & McGeer, 2006; Moisse & Strong,

So far it is not clear how immune system is involved in ALS disease, whether the adaptive or innate immunity has a major role and whether immunity is part of damaging or

(Engelhardt et al., 1995; Henkel et al., 2004; Troost et al., 1990).

function and how they could be used in a possible therapy.

**2. ALS and immunity** 

2006; Sta et al., 2011; Weydt et al., 2002).

Fig. 1. Innate and adaptive immunity.

neuroprotective response to the pathological process.

*INNATE ADAPTIVE*

Innate immunity is naturally present and is not stimulated by antigens or mediated by antibodies. It is therefore non-specific and is executed by a variety of cells: granulocytes, as eosinophils and basophils, white blood cells as natural killer and mast cells. Instead, microglia belongs to the central nervous system and is involved in the local innate immunity. Inflammation is one of the aspects of the innate immune response.

Interactions between innate immune system, brain and neurodegenerative diseases are known (Ghezzi et al., 1998; Gowing et al., 2006) and it has been reported that mast cells, macrophages, dendritic cells, microglia, complement and cytokines participate in limiting the damage (Calvo et al., 2010).

Innate system was found activated in central and in peripheral system of ALS patients (Chandels et al., 2001; Elliott et al., 2001; Sta et al., 2011).

Several studies regarding peripheral innate immune system changes in sporadic ALS reveal that there are increased levels of circulating monocytes and macrophages (Harman et al., 1991; Hemnani et al, 1998). The presence of T cells, IgG, activated microglia, macrophages, and reactive astrocytes, as well as other indications of inflammation are found in ALS spinal cord tissue (Henkel et al., 2004; Engelhardt et al., 1995; Troost et al., 1990).

In ALS there is morphological and neurochemical evidence for the proliferation and activation of microglia in areas of significant motor neuron loss, as spinal cord (Henkel et al., 2004; Kawamata et al., 1992; Moisse et al., 2006). This activation may be a consequence of stressed neurons that induced proliferation and activation of microglial cells activating complement system and pro-cytokine response involved in neuronal death (Fig. 2). Motor neuron loss and immune system activation may increase neuron stress leading to increase of neuroinflammation.

Fig. 2. Hypothesis of activation of innate immunity in ALS.
