**2. Basics of immune system**

The immune system comprises of a complex array of immune cells tailored to defend the body against a variety of substances that are considered as foreign including pathogenic microbes and tumors while remaining nonreactive towards the self. Immune cells are originated from the haematopoietic stem cells and are classified as lymphoid and myeloid cells comprising B & T-lymphocytes, Natural killer cells (NKs), dendritic cells and polymorphonuclear leukocytes, monocytes, mast cells, macrophages respectively (Delves, 2006). The immune cells constantly patrol the body and involve specific and non specific mechanisms in executing immune attack upon finding a foreign substance. The specificity rests particularly with T and B-cells as they display the receptors capable of recognising non self molecules from the self.

The specific attack is also complimented before by the strategic non specific immune responses generated by polymmorphonucelar cells, NKs, macrophages, co-stimulatory molecules like cytokines and serves as the initial site of attack upon finding the foreign entities. The abnormal levels of cytokines have a strong impact in the initiation and progression of autoimmune diseases. Also, therapeutic interventions with exogenous cytokines were found to be associated with the disease process, suggesting their key role in mediating the disease (Hooks et al., 1982; Trembleau et al., 1995; McKall-Faienza et al., 1998; Schattner, 1994; Kanwar et al, 1999; Kanwar et al, 2005; Kanwar et al, 2009). The complex network of immune cells is classified into subpopulations based on the expression of surface markers, functional characteristics, regions where they mature and activate. Likewise, Tcells include helper cells (Th) displaying CD4+ marker and involve in modulating the immune responses. Further they comprise subsets of Th1 cells that aid other T-cells and Th2 subtype mediates the antibody generation. Cytotoxic cells (Tc) with CD8+ marker are killer cells with lethal effect on intracellular pathogens, infected and tumor cells. Lastly, suppressor cells (Ts) down regulate and monitor the immune reactions. The naive T-cells undergo maturation in the thymus (hence the name T-cells) and are able to respond only to the processed antigens. Most of the nucleated cells of the mammalian system function as the antigen presenting cells (APCs) and dendrites are unique in this category expressing major histocompatibility complex proteins (MHC) and generating co stimulatory gestures for Tcell activation. APCs process the antigen and represent them in association with cell surface MHCs for T-cell recognition. These MHCs categorised as class I and Class II are crucial in the selection process of cytotoxic and helper cells respectively.

The T-cells bear an antigen recognition site on their surface called as T-cell receptor (TCR) and the initiation of T-cell mediated immunity requires the complex association of the antigen, MHC and the TCR. B-cells are specialised immune cells that act as APCs along with a prime function of antibody generation. The immature B-cells initially express a pre-B cell receptor (pre-BCR) on their surface and upon maturation they produce antibodies that act as antigen receptors towards the native antigen (Yang & Santamaria, 2006; Austyn, 2000; Roitt et al., 1998; Janeway & Travers, 1998). Both the T and B-cells express specific receptors for each antigen and this diversity is exhibited by the rearrangement of receptor gene sequences in the somatic cells rather than acquired through the inheritance (Gellert, 2002). In order to mount immune responses, the T and B-cells are activated through corresponding receptors in the presence of co-stimulatory molecules (Crow, 2004; Kanwar et al, 2000; Kanwar et al, 2003; Kanwar et al, 2005). Another essential feature of both these cells is that, upon initial exposure to an antigen both these cells generate memory cells that expand clonally. These memory cells unleash an accelerated immune attack upon antigen re-exposure (Swain, 2003; Bishop et al., 2003).

#### **3. Tolerance**

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

The immune system comprises of a complex array of immune cells tailored to defend the body against a variety of substances that are considered as foreign including pathogenic microbes and tumors while remaining nonreactive towards the self. Immune cells are originated from the haematopoietic stem cells and are classified as lymphoid and myeloid cells comprising B & T-lymphocytes, Natural killer cells (NKs), dendritic cells and polymorphonuclear leukocytes, monocytes, mast cells, macrophages respectively (Delves, 2006). The immune cells constantly patrol the body and involve specific and non specific mechanisms in executing immune attack upon finding a foreign substance. The specificity rests particularly with T and B-cells as they display the receptors capable of recognising non

The specific attack is also complimented before by the strategic non specific immune responses generated by polymmorphonucelar cells, NKs, macrophages, co-stimulatory molecules like cytokines and serves as the initial site of attack upon finding the foreign entities. The abnormal levels of cytokines have a strong impact in the initiation and progression of autoimmune diseases. Also, therapeutic interventions with exogenous cytokines were found to be associated with the disease process, suggesting their key role in mediating the disease (Hooks et al., 1982; Trembleau et al., 1995; McKall-Faienza et al., 1998; Schattner, 1994; Kanwar et al, 1999; Kanwar et al, 2005; Kanwar et al, 2009). The complex network of immune cells is classified into subpopulations based on the expression of surface markers, functional characteristics, regions where they mature and activate. Likewise, Tcells include helper cells (Th) displaying CD4+ marker and involve in modulating the immune responses. Further they comprise subsets of Th1 cells that aid other T-cells and Th2 subtype mediates the antibody generation. Cytotoxic cells (Tc) with CD8+ marker are killer cells with lethal effect on intracellular pathogens, infected and tumor cells. Lastly, suppressor cells (Ts) down regulate and monitor the immune reactions. The naive T-cells undergo maturation in the thymus (hence the name T-cells) and are able to respond only to the processed antigens. Most of the nucleated cells of the mammalian system function as the antigen presenting cells (APCs) and dendrites are unique in this category expressing major histocompatibility complex proteins (MHC) and generating co stimulatory gestures for Tcell activation. APCs process the antigen and represent them in association with cell surface MHCs for T-cell recognition. These MHCs categorised as class I and Class II are crucial in

The T-cells bear an antigen recognition site on their surface called as T-cell receptor (TCR) and the initiation of T-cell mediated immunity requires the complex association of the antigen, MHC and the TCR. B-cells are specialised immune cells that act as APCs along with a prime function of antibody generation. The immature B-cells initially express a pre-B cell receptor (pre-BCR) on their surface and upon maturation they produce antibodies that act as antigen receptors towards the native antigen (Yang & Santamaria, 2006; Austyn, 2000; Roitt et al., 1998; Janeway & Travers, 1998). Both the T and B-cells express specific receptors for each antigen and this diversity is exhibited by the rearrangement of receptor gene sequences in the somatic cells rather than acquired through the inheritance (Gellert, 2002). In order to mount immune responses, the T and B-cells are activated through corresponding receptors in the presence of co-stimulatory molecules (Crow, 2004; Kanwar et al, 2000; Kanwar et al, 2003; Kanwar et al, 2005). Another essential feature of both these cells is that, upon initial exposure to an antigen both these cells generate memory cells that expand clonally. These

the selection process of cytotoxic and helper cells respectively.

**2. Basics of immune system** 

self molecules from the self.

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; Rajewsky, 1996).

#### **3.1 T and B cell tolerance**

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

Recent Advances in the Treatment of Neurological Autoimmune Disorders 293

diseases was also reported and this etiology could be due to the family history associated with the genetic vairaitons. In addition, a variety of MHC and non-MHC susceptible genes are identified in the genome wide studies of MS, SLE and RA while, few studies reported that many autoimmune diseases have a common genetic etiology operating (Glinda, 1999). Likewise, the association of intracellular tyrosine phosphatise, PTPN22 was shared in the pathologies of Type-1diabetes, RA and myasthenia gravis (Bottini, 2004; Begovich, 2004; Vandiedonck et al., 2006). In brief, genetics underscore a significant risk factor for the

In the early stages of development some of the self antigens might escape recognition from the T-cell populations. This could happen because, they might not have been formed at the time of T-cell development or they might be separated from T-cell access due to remote anatomical existence (e.g. myelin basic protein) or due to the presence of membrane barriers or they might be inappropriately presented by the MHC proteins (Manoury, 1998). These cryptic antigens hinder the tolerance mechanisms and drive the autoimmune attack if they are encountered by the T-cells upon membrane barrier disruption for e.g. orchiditis upon vasectomy (Flickinger, 1994; Jarow et al., 1994) infections (Type 1 diabetes upon coxsackie B virus infection) or any other mechanism that exposes them (Yoon et al., 1979). A striking feature of auto antigens is that they are not specific to any tissue and form the integral

Infections have an interesting role to play in the induction of autoimmune diseases and there are several interesting mechanisms where infections mediate them. In the instances of microbial infections, immune cells cannot differentiate antigenic sequences from self proteins if structural similarities are found. This molecular mimicry unleashes the immune attack that is directed towards self and nonself leading to tissue destruction. For e.g. hepatitis B virus polymerase resembles myelin basic protein and generates auto antibodies that destroy myelin leading to multiple sclerosis (Fujinami & Oldstone, 1989; Oldstone, 1998; Fujinami & Oldstone, 1985). Infections are associated with interesting mechanisms that may enhance the severity of autoimmune diseases. Among these, epitope spreading is an instance where in an inflammatory burst, the avid APCs over process and presents the antigens to activate the large T-cell populations lowering the threshold to the disease onset. The other mechanism is termed as polyclonal activation where abundant B-cell populations are activated generating loads of antibodies along with immune complexes that pose serious threat to the tissues. The next mechanism involves the over activation and indiscriminate expansion of self reactive T-cells that are initially considered to be inefficient but can cause the disease in the presence of elevated levels of cytokines. Finally, microbes express super antigens on their surfaces that are unique in coupling T-cells with MHC complexes irrespective of their relativities (Barzilai et al., 2007a, 2007b). On the contrary when correlations were made between autoimmune diseases and infections, the incidences were found to be increased in the subjects who are at reduced risk of infections. The same holds true as autoimmune diseases have a rampant growth in western countries where the infectious incidences are lower compared to less developed nations (Bach, 2002; Patterson et al., 1996) substantiating the concept of hygiene hypothesis which states that the microbial

exposure enhances the body's defence mechanisms ( Bjorksten B, 1994).

autoimmune etiology and presents a new area to explore.

components of all various cell types (Tan et al., 1987).

**4.2 Auto antigens** 

**4.3 Role of infections** 

incase of molecular mimicry (where pathogenic antigens resemble self antigens) as APCs turn active and trigger T-cell attack that is indiscriminate towards self and nonself. The same also holds true for B-cells (Damian, 1964; Oldstone, 1998). On the whole, generation of autoimmune diseases is based on the narrow margin that exists between tolerance and immunity executed by deletion and survival of self reactive lymphocytes. Too much deletion compromises the immunity and too little deletion follows subsequent autoimmunity. The following figure is an ideal representation of healthy and pathologic immunity and the differentiation between tolerance and autoimmunity.

Fig. 1. Showing the comparison of healthy and pathologic immune system. A healthy T-cell upon exposure to self antigens undergo specific mechanisms of inactivation like deletion or clonal anergy constituting peripheral tolerance while an autoreactive T-cell is dysregulated with indiscriminate attack on self and non self antigens because of the lack of tolerance in autoimmunity.
