**Recent Advances in the Treatment of Neurological Autoimmune Disorders**

Jagat R. Kanwar\*, Bhasker Sriramoju and Rupinder K. Kanwar

*Laboratory of Immunology and Molecular Biomedical Research (LIMBR), Centre for Biotechnology and Interdisciplinary Biosciences (BioDeakin), Institute for Technology in Nanomedicine & Research Innovation, Deakin University Waurn Ponds, Geelong, Australia* 

#### **1. Introduction**

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

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Tanaka H, Tsugawa K, Oki E, Suzuki K & Ito E (2008b) Mizoribine intermittent pulse

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Autoimmune diseases are a complex group of diseases arising because of the breakdown of narrow margin that exists between the immunity and tolerance. In simpler terms either T or B-cells or both are activated in the absence of a progressive infection or any other noticeable cause (Davidson & Diamond, 2001). Unable to distinguish self from non self, the renegade immune cells pose a serious threat to self molecules leading to severe destruction. The precise mechanisms that drive this event are still unclear but, most of the studies identified that genetics, environment and infections will have a role in triggering the autoimmune attack (Smith et al., 1999). An approximate of 5% of the population in western countries are currently the victims of these diseases and in this component, a major proportion of them are females displaying a higher risk of incidence (Jacobson, 1997; Kanwar, 2005). Added to this, the general ailments of the humans like atherosclerosis and gastrointestinal disturbances are found to be associated with an autoimmune component, predisposing the risk of developing an autoimmune disease (Ross, 1990, Galperin & Gershwin 1997).The influence of hormones cannot be neglected as preclinical studies have witnessed the role of oestrogen in the emergence of autoimmune diseases while testosterone was found to lower the risk in lupus prone mice (Sakic, 1998; Roubinian et al., 1978). Few epidemiological studies also revealed the preponderance of autoimmune diseases mediated by the nocturnal hormone, melatonin (Cutolo, 2003). In addition, cortisol levels and the secondary events like stress were also found to influence the autoimmune disease generation (Webster et al, 1998). Since ages, the basic principle of immunology has been the concept of clonal deletion of autoreactive immune cells and generation of a mature T & B-cell repertoire that could distinguish self from non self. The formation and survival of mature immune repertoire, always demands prolonged auto antigen exposure acknowledging the physiological importance of autoreactivity (Goldrath & Bevan, 1999; Gu et al., 1991). Though structural resemblances exist between self and non self antigens the attack is directed against self antigens under stimulatory conditions like the presence of infections, cytokines etc (Silverstein & Rose, 2000; Kanwar, 2005; Kanwar et al, 2009). Thus it is always fascinating to find answers for how the physiology of autoimmunity is turned to pathology and how the immune cells enforce their attack. This review focuses on introduction to immunity, pathology of autoimmune diseases and their treatments along with recent advancements.

Recent Advances in the Treatment of Neurological Autoimmune Disorders 291

memory cells unleash an accelerated immune attack upon antigen re-exposure (Swain, 2003;

Because of the expression of vast diversity of antigen recognition sites on T and B-cells, molecules that are considered as self also may find chances of binding with the immune cells. Hence, a diverse range of tolerance mechanisms have been developed that train the T & B-cells to differentiate self from nonself. This process is tightly controlled in the primary lymphoid organs and is continuous to inhibit the various modes of auto reactive lymphocyte generation and activation. The basic mechanisms dealt are clonal deletion, clonal anergy and inhibition of self reactive lymphocytes (Yoshida & Gershwin, 1993;

The tolerance mechanisms that develop in the primary lymphoid organs like thymus and bone marrow respectively for T and B cells constitute central tolerance. The naive T-cells originated from haematopoietic stem cells are devoid of CD4 and CD8 cell surface markers. Once migrated to the thymus, the TCR gene rearranges to develop double positive T-cells that display CD4+ and CD8+. Then these cells are positively selected as CD4+ and CD8+ cells based on their interactions with the MHC class II and Class I respectively. The cells with TCR, that fail to bind or interact MHC with little affinity undergo death and are positively selected based on weaker interactions between TCR and MHC carrying self antigens. T-cells are killed if found to interact strongly with a self antigen displayed by MHC and thus selected negatively (Palmer, 2003; Starr, 2006; Bretscher & Cohn, 1970; Kanwar et al, 2004; Kanwar, 2005). As a matter of enhanced protection from immune attack, the T-cells receiving stronger signals through TCR are deleted and this inactivation is much more sensitive compared to activation of T-cells that demand a stronger interaction between TCR and self antigen-MHC complex (Kappler, 1987; Pircher et al., 1991; Yagi & Janeway, 1990). Similar tolerance mechanisms exist for B-cell repertoire, as they are negatively selected if the BCR is found to interact strongly with the self antigens. However, active investigation is recommended to determine the existence of positive selection for B-cells. Interestingly, successful T-lymphocyte tolerance cuts down the signals for few autoreactive B-cells and thus induces B-cell tolerance (Bretscher & Cohn, 1970). During the course of their maturation, the pre B-cell receptor (BCR) cross links several avid auto-antigens. This event stimulates the rearrangement of light chain genes of the Ig's thus, driving the process of receptor editing where self antigens are replaced with non self ones (Ana et al., 2010). B-cells are deleted by apoptotic mechanism if found to interact strongly with self antigens (this happens mostly in bone marrow) and anergised if bound with little affinity (this happens mostly in periphery) (Monroe et al., 2003; Hodgkin & Basten, 1995). T-cells have a potential role in the generation and progression of chemical and spontaneously induced autoimmune diseases and the same was also demonstrated successfully in the animal studies (Singer & Theofilopoulos, 1990; Druet, 1989; Pettinelli & McFarlin, 1989; Waldor et al., 1985). Few autoreactive T-cells may escape tolerance mechanisms and spread in the periphery but, they are naive and do not hold any threat unless APCs turn active. Potential problem persists

Bishop et al., 2003).

**3. Tolerance** 

Rajewsky, 1996).

**3.1 T and B cell tolerance** 
