**4. Conclusion**

464 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

Additionally, microglia are also compromised in PD, they tend to produce high levels of MHCII antigen leukocyte antigen-DR (HLA-DR) and inflammatory molecules including IL-1β, IL-6 and TNF-α and express ICAM-1 and LFA-1 (McGeer and McGeer, 2008; McGeer et al., 2001). The activated microglia portray high levels of ICAM-1 and LFA-1, thus these molecules in SN may also be implicated in the influx of immune cells in the affected areas (Imamura et al., 2003). In the CNS microglia are responsible for, antigen presentation, removal damaged and apoptotic cells and secretion of pro-inflammatory and neurotrophic factors. These factors can either be protective or toxic to the CNS environment (Sawada et al., 2006), thus microglias have two contradictory roles in the CNS, depending on the CNS environment. Microglia become activated when they come into contact with damaged or lingering neuron when this occurs the microglia will assist in repairing and restoring these damaged neurons. These microglia express TNF-α and IL-6, these cytokines have neurotrophic components (Diogenes and Outeiro, 2010; Gash et al., 2007; Reale et al., 2009). Neurotoxic effects of microglias underlie some of the detrimental effects conferred on neurons in the CNS, neurotixic microglia increase the levels of pro-inflammatory cytokines, neurotrophins, reactive oxygen species and reactive nitrogen species (Long-Smith et al., 2009). They can become harmful when they synthesise and secrete molecules that increase synaptic overactivity and thus increase the damage already present. They may also alter excitotoxicity, abort apoptosis and encourage the growth of neurite in the injured CNS (Barger et al., 1995; Berezovskaya et al., 1995; Imamura et al., 1990; Lazarov-Spiegler et al., 1996; Prewitt et al., 1997; Rabchevsky and Streit, 1997; Toku et al., 1998). Activated microglias are present in other areas of the CNS and therefore initiate and promote inflammation in different brain regions including the putamen, substantia nigra and cingulated cortex where they are responsible for the generation of lewy bodies (Li et al., 2010; McKeith and Mosimann, 2004; Varani et al., 2010). TNF-α and IL-1β have similar signalling mechanisms and induce neurodegeneration in the CNS by activating NKFκB, thus facilitating oxidative damage and consequently neuronal damage (Wahner et al., 2007). The toxic effects of IL-1β and TNF-α can also be attributed to their ability to increase the expression of leukocyte adhesion molecules on the surfaces of the endothelial cells. This elevates inflammation in the CNS affecting neuronal survival (Whitton, 2007). At the molecular level mitochondrial and cytoskeletal dysfunction, oxidative damage, neuroinflammation and abnormal protein accumulation contribute to the progression of PD

Inducible nitric oxide synthase (iNOS), and NADP-oxidase secreted by activated microglia increase the production of NO and reactive oxygen species causing neurodegeneration. VIP is able to reduce microglial activation thereby preventing the release and damaging effects of these factors (Delgado and Ganea, 2003). Additionally in the CNS, the release of IFN-γ by activated microglia tends to be rather harmful. IFN-γ binds to its receptor sets off a cascade of events involving transphosphorylation of the receptor-associated janus tyrosine kinases (Jak)1 and 2. This facilitates the recruitment and phosphorylation of signal transducer and activator of transcription (STAT1) (Dell'Albani et al., 2001). These sequences of events stimulate IFN-γ, inducible protein 10, iNOS, CD40 and IL-12. VIP and PACAP together reduce microglia pro-inflammatory activities through VIP and PACAP binding to VPAC1 and dampening the phosphorylation and formation of the Jak1-2/STAT1 complex. This prevents the synthesis of IRF-1, and inhibits IFN-γ and iNOS expression from microglia in the striatum and also in the substantia nigra. These inhibitory effects are facilitated by the

(Winner et al., 2009).

cAMP pathway (Delgado, 2003).

In summary, it is apparent that VIP and PACAP are vital for the enhancement of antiinflammatory reactions in autoimmune diseases with compromises to neuro-endocrineimmune mechanism. These fundamental anti-inflammatory responses assist in decreasing pro-inflammatory reactions observed in most autoimmune diseases including RA, MS, PD and AD. Thus VIP and PACAP are important in suppressing elevated amounts of IFN-γ, TNF-α, IL-6 and IL1β. Modulation of these factors to optimal levels promotes and preserves the survival of cells and tissues affect these diseases. A decrease in their receptors is a common finding in most autoimmune disorders and this is often correlated with decreases in cAMP. Additionally, Th1/Th2/Th17 disequilibrium is noticed in the above mentioned diseases. VIP and PACAP are able to reverse and regulate these shifts in inflammatory cytokines. Their ability to maintain both peripheral and CNS homeostasis highlights their importance in physiological processes.

VIP and PACAP are therefore potential candidates for treating autoimmune disorders. Their administration may substantially reduce symptoms and improve the quality of life of patients with RA, MS, PD and ALS. As VIP and PACAP activate cAMP pathways, therapies that remove inhibitors of cAMP may be important. These inhibitors include Phosphosdiesterase enzymes. Phosphosdiesterase enzymes inhibitors (PDEIs) may have potential advantage in the treatment of autoimmune disorders. PDEIs may also increase the effectiveness of these VNs as they can increase the intracellular cAMP and therefore initiate anti-inflammatory mechanisms. Incidentally, PDEIs are known to prolong life and reduce cytokines, demyelination and inflammation. Hence further studies are required to examine the most effective therapies for these autoimmune disorders.

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**24** 

*Russia* 

**Antibody-Proteases in the Pathogenesis of** 

**Autoimmune Demyelination and Monitoring** 

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) resulting in axon loss and development of disability. (Gabibov et al., 2011) Autoantibodies (autoAbs) are one of the major features and crucial mechanisms in MS pathogenesis known to illustrate this autoagression. The major component in the pathogenesis of MS is primary myelin damage, which is mediated by autoAbs, which trigger the release of separate and pathogenically valuable myelin-associated epitopes into the bloodstream. These molecules acting as a group of sensitizing factors may provoke the immune system and drive disease progression. Being identified at the pre- or early stages or

Natural catalytic antibodies (*catAbs*) or natural *abzymes* today are one of the principal effectors of the adaptive immune system. In constructive sense, catAbs are multivalent immunoglobulins (Igs), presumably, of IgG and IgM isotypes, endowed with a capacity to

Traditionally, the basic structure of the Ab molecule is essentially *Y*-shaped, with the two tips (*Fab*-fragments) designed to recognize and bind non-self agents or cells. Moreover, the catalytic capacity is also present in *Fab*-fragments of the molecule. In general, the mechanisms of Ab-mediated catalytic action include nucleophilic catalysis, induction of conformational strain, coordination with ions, and stabilization of transition states (TS). Agspecific or targeted catAbs are preferentially found in the Ig repertoire of patients with a broad scope of diseases to act as pathogenically valuable tools. Since the discovery of catAbs, a wide spectrum of the disease-related abzymes regardless to their natural history or engineering protocols has been described. Moreover, the immune system was shown to express an intrinsic drive to generate natural abzymes in different pathological states in humans. Among them, proteolytic (*Ab-proteases*) and DNA-hydrolyzing (*DNA-abzymes*)

the demyelination, such autoAbs dominate during the whole course of the disease.

**1. Introduction** 

hydrolyze an antigenic substrate.

autoAbs are of a special practical value.

**Patients with Multiple Sclerosis** 

Aleksandr Gabibov4 and Sergey Suchkov1,2 *1I.M. Sechenov First Moscow Medical State University 2Moscow State University of Medicine and Dentistry 3National Research Center "Kurchatov Institute"* 

*Chemistry, Russian Academy of Sciences* 

Dmitry Kostyushev1, Dmitry Gnatenko1, Mikhail Paltsev3,

*4M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic* 

