**Four Aspects of Autoimmunity and How to Regain Tolerance to Self from an Autoimmune Disease Utilizing the Modified Vaccination Technique**

Arpad Z. Barabas1, Chad D. Cole2, Arpad D. Barabas1, Rene Lafreniere1 and Donald M. Weir3 *1Department of Surgery, University of Calgary, Calgary, Alberta, 2Department of Neurosurgery, University of Utah, Salt Lake City, Utah, 3University of Edinburgh Medical School, Edinburgh, 1Canada 2USA 3Scotland* 

#### **1. Introduction**

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

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> The cells of the immune system are exposed to two broad types of antigenic challenges – challenges from the external environment (bacteria, viruses, etc.), and challenges from the internal environment of the host (from both normal and abnormal self). The immune system functions throughout life to preserve the integrity of the organism, allowing its various organs and systems to carry out their intended functions, and maintaining normal health. The cells of the immune system have intimate knowledge of self and non-self. Normal self is allowed to live and function, whereas abnormal self or non-self, e.g. degraded cellular products or abnormal cells, are recognized as non-self and removed by the cells and products of the immune system and processed into reusable small MW peptides (Manson et al., 2005; Quartier et al., 2005; Wermeling et al., 2009). Occasionally, modified self will affect the normally functioning immune system and stimulate a pathogenic immune response causing an autoimmune disease (Barabas et al., 2004c; Heymann et al., 1959). In other instances, because of the minimal antigenicity of cancer specific antigens (ags) on cancer cell surfaces, cancer is not recognized as non-self and is allowed to grow and cause harm (Berinstein, 2007; Engelhard et al., 2002).

> The question of how to correct immunological mishaps that not only compromise the normal functioning of an affected organ but can even threaten the life of the host has engaged numerous investigators in the search for curative solutions. So far the options available for treating ailments caused by autoimmune disorders have been mainly limited to drugs (Cattran, 1988; Matsukawa et al., 1992; Penny et al., 1998), which in general have undesirably over-broad effects. Yet there are encouraging signs that targeted, specific cures might be achieved by immunological means (Andreakos et al., 2002; Berinstein, 2007;

Four Aspects of Autoimmunity and How to Regain Tolerance to Self

health, then premature death due to organ failure can ensue.

**3. Autoimmunity conventional definition** 

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Autoimmunity is conventionally defined in the scientific literature as abnormal immune response against self resulting in autoimmune disease. As such, autoimmunity is viewed as a self-destructive process, involving aberrant immune responses against self by the cells and products of the immune system, along with the wide spectrum of resulting autoimmune diseases which are generally chronic and progressive in nature. An autoimmune process is often irreversible, and currently the only readily available treatment is with drugs. In most cases the prognosis is guarded at best; even with the best medical care the symptoms of autoimmune conditions can generally only be minimized. Autoimmunity can result in morphological changes, including structural alterations in affected organs, that compromise and even destroy the normal functioning of the affected part. For example, in an experimental autoimmune kidney disease called Heymann nephritis (HN), we observe: a collection of symptoms including proteinuria, the presence in the circulation of pathogenic IgG autoantibodies (aabs) directed against the brush border (BB) region of the proximal renal tubules, massive deposition of immune complexes (ICs) in the glomeruli, and overall morphological and functional changes in affected regions of the kidney (Alousi et al., 1969; Andres et al., 1986; Edgington et al., 1967; Farquhar et al., 1995; Heymann et al., 1959; Kerjaschki, 1993; Kerjaschki & Farquhar, 1982; Singh & Kasinath, 1993). As in the case of HN, if the affected part is vitally important to the host and can no longer contribute to

It is a common belief that once an autoimmune response is triggered it continues *in perpetuum* (Manz et al., 2002). However, many autoimmune diseases exhibit remission or exacerbation of disease processes, with or without drug treatment. Generally speaking it is not understood why. Autoimmune diseases are treated with immunosuppressive agents (Cattran, 1988; Fox & McCune, 1994; Fox & Ransohoff, 2004; Matsukawa et al., 1992) that have side effects and do not act specifically to terminate disease processes (Perna et al., 2004). In addition, as a result of their non-selective inhibition of the overall function of the immune system, these immunosuppressants expose patients to infection and related complications. The conventional understanding of how immunopathological processes cause autoimmune diseases (Davidson & Diamond, 2001; Feldmann & Steinman, 2005; Hill & Sarvetnick, 2002) does not allow for the possibility of reversing disease processes and reestablishing normalcy (Dorner et al., 2009) by the application of a vaccination technique.

**4. Autoimmunity within the concept of beneficial and harmful aspects of** 

Autoimmunity properly understood denotes a complex interconnected network of immune responses against self that are not pathological in the first instance, but rather are designed to maintain the structural and functional integrity of the host's internal environment throughout life. The cells and products of the autoimmune system keep the internal environment of the host in a state of homeostasis. As a result of the proper functioning of the autoimmune system, intracytoplasmic components released from damaged cells (by burns, drugs, infectious agents, ischemia, toxic compounds, etc.) and from normal cells at the end of their life span are assisted in their removal by non-pathogenic IgM aabs (Avrameas, 1991; Casali & Notkins, 1989; Chen et al., 1995; Weir et al., 1966; Weir, 1966) and phagocytic cells (Barabas et al., 2004a; Helmy et al., 2006; Mevorach et al., 1998; UytdeHaag

**immune responses against self in the light of new evidence** 

Hasegawa et al., 2001; Lollini & Forni, 2002; Yokoyama et al., 1999). Studies have shown that the method of presentation of the ag – whether it be exogenous or endogenous – to the cells of the immune system determines the immune response outcome.

Medical science has learned, over the course of the developmental history of vaccination, how to present antigenic components in an inoculate to stimulate protective immune responses in the vaccinated host against exogenous ags. However, the possibility of using vaccination to achieve protective or curative outcomes in patients with disorders caused by endogenous ags, without causing side effects, has remained elusive (Ben Yehuda et al., 1988; Fox & McCune, 1994; Golbus & McCune, 1994; Hu et al., 2009; Nepom, 2002; Perosa et al., 2005; Thaiss et al., 1989).

Our investigations into the etiology and pathogenesis of an experimental autoimmune kidney disease have resulted in a new immunological approach involving the presentation of native autoimmune disease related ags to evoke a predetermined corrective immune response in the host (Barabas et al., 2004b; Barabas et al., 2006c; Barabas et al., 2006b; Barabas & Lafreniere, 2005). The approach consists of a new vaccination method called modified vaccination technique (MVT) (Barabas et al., 2007b; Barabas et al., 2007a; Barabas et al., 2008a; Barabas et al., 2009a; Barabas et al., 2009b). The MVT involves the injection of a mixture of antibody (ab) inducing components which are predetermined based on the required outcome. So far the MVT has been implemented:

 to prevent an experimental autoimmune kidney disease, and to terminate the already present disease (Barabas et al., 2004b; Barabas et al., 2006c; Barabas et al., 2006b; Barabas & Lafreniere, 2005); and

 to achieve a powerful immune response against an exogenous ag (Barabas et al., 2007d); Below we give a detailed account of how and why the MVT has the potential of specifically preventing and curing certain chronic disorders such as autoimmune disease and disease caused by chronic infection.
