**3. Autoimmunity conventional definition**

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

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

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.,

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

 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

 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

Vaccination is the most cost-effective way to protect the public against undesirable medical conditions that can result in acute or chronic ailments. Vaccination by active immunization can prevent serious infectious and contagious diseases from occurring; and vaccination by passive immunization can neutralize existing disease causing/contributing agents (Hjelm et al., 2006; Imbach et al., 1981; Leandro & de, I, 2009; Levesque, 2009; Pirofsky & Kinzey, 1992; Segal et al., 1999). However, neither vaccination technique has been successfully implemented to date to achieve preventative or curative immune response outcomes in endogenous ag initiated and maintained disorders. It has been evident for a number of years that a technique other than those applied to diseases caused by exogenous ags is needed. The danger of using components derived from endogenous ags and causing added complications (e.g. autoimmune disease) has presented obstacles in the search for solutions (Finn & Forni, 2002; Peakman & Dayan, 2001). However, a better understanding of naturally occurring immune events, particularly pathogenic and non-pathogenic immune responses against self (Barabas et al., 2008b) - where the terms "pathogenic" and "non-pathogenic" do not equate with the terms "harmful" and "beneficial" - within the concept of autoimmunity promises to provide a framework for creating new possibilities for designing prophylactic

and therapeutic vaccines for mishaps caused by or involving endogenous ags.

of the immune system determines the immune response outcome.

required outcome. So far the MVT has been implemented:

2005; Thaiss et al., 1989).

& Lafreniere, 2005); and

caused by chronic infection.

**2. Vaccination** 

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

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

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

Four Aspects of Autoimmunity and How to Regain Tolerance to Self

exacerbated and will manifest in a chronic progressive disease.

**4.1.2 Removal of abnormal cell lines** 

2009).

The autoimmune system's specific IgM aab production cell line will lose its ability to carry out its intended beneficial function in such circumstances where the modifying agent is continuously present in the system and maintains a pathogenic immune response. Its work may also be compromised in cases where the immune system is dysfunctional or has low IgM aab production because of old age, ill health, genetic predisposition, malnutrition, immune suppression, ineffective phagocytosis, etc. (Schulze et al., 2008; Wermeling et al.,

Just as intracytoplasmic waste is recognized as unwanted self and assisted in its removal by physiological non-pathogenic IgM aabs, cells with non-self markers, i.e., cancer cells, are also recognized by lymphocytes and their products – NK cells, cytolytic IgG aabs, etc. – and

**4.1.1 Removal of cellular waste** 

from an Autoimmune Disease Utilizing the Modified Vaccination Technique 573

Cells damaged by various agents or events (e.g. chemicals, drugs, ischemia, trauma, toxic compounds, UV irradiation, etc.) release their intracytoplasmic components into intra- and extravascular spaces. These cellular wastes are assisted in their removal by specific nonpathogenic IgM aabs (Avrameas, 1991; Weir, 1964; Weir et al., 1966; Weir, 1969; Zwart et al., 2004) and subsequently phagocytosed and broken down into reusable small MW peptides (Ciurana et al., 2004; Manson et al., 2005; Ogden et al., 2005; Quartier et al., 2005). It was shown by Weir and associates that in a physiological sense we are not *per se* tolerant to our own intracytoplasmic components, and specific IgM aabs are present in the circulation throughout life to clear the system of cellular breakdown products (Weir et al., 1966; Weir & Elson, 1969; Weir & Pinckard, 1967). Specific IgM aab production increases following excessive release of aags (secondary ab response) from an organ damaged by toxic agents, pathogenic IgG aabs, or ischemia at the site of rapid tumour growth etc. (Barabas et al., 2003; Pinckard & Weir, 1966; Weir, 1966). Circulating specific IgM aabs also contribute to rapid and efficient removal of cellular wastes to prevent not only their toxic accumulation in the system but also their possible chemical modification, which could trigger a tissue to be targeted and damaged by a pathogenic IgG aab response, an event which has the potential to initiate an autoimmune disease (Weir, 1969; Weir & Elson, 1969). IgM aabs are able to assist in the removal from the intracytoplasmic space not only of normal native aags released into the intra- and extravascular spaces but also of native-like ags (molecular mimicry) and native aags that are chemically or otherwise modified (Barabas et al., 2004b). Specific IgM aabs in the circulation are present with high titres measurable during the chronic phase of an autoimmune disease, as they assist in the removal of both disease causing and maintaining aags (modified aags that stimulate pathogenic IgG aab production) and disease contributing aags (target aags from the targeted organ) (Barabas et al., 2003; Barabas et al., 2004b). These cross-reactive specific IgM aabs are greatly responsible for the maintenance of tolerance to self during life by efficiently clearing the system of native and modified aags. If they can effectively clear the system of both native and modified aags during an autoimmune disease, then remission will occur, as manifested in signs of improvement and diminished symptoms (Barabas et al., 2004b; Barabas et al., 2006c; Barabas et al., 2006b; Barabas & Lafreniere, 2005). If the stimulus agent – that produces the modified self – ceases to be present in the system then spontaneous remission and termination of the autoimmune disease process will follow. However, as long as the modifying agent remains present in the system and is able to alter the chemical nature of self into non-self, the immune responses that cause the disease will continue, and the condition will be

et al., 1991; Wermeling et al., 2009). Likewise, abnormal cells and cell lines having non-self antigenic surface markers (e.g. cancer cells) are also recognized and removed (Cheent & Khakoo, 2009; Foss, 2002; Topham & Hewitt, 2009). These are the two beneficial aspects of autoimmunity, by which it endeavours to keep the internal environment, composed as it is of endogenous ags, free of change. It is a major undertaking since several factors, both internal and external, have the potential to create an imbalance and cause harmful pathogenic immune responses against self, especially if the right triggers are present.

A well functioning autoimmune system averts most attempts by internal and external agents to create a harmful autoimmune response resulting in autoimmune disorders such as autoimmune disease and cancer (which themselves may be considered the two negative aspects of autoimmunity). It stands to reason that in order to protect against the kinds of insults that could lead to autoimmune disorders, we should engage in healthful consumption and healthful avoidance, eating healthy diets (consisting of fruits, vegetables, etc.) that contain chemicals or trace elements that boost the immune system or contribute to the prevention of cancer, and minimizing exposure to noxious agents (cigarette smoke, legal and illegal drugs, alcohol, and other toxic or infectious agents) that can chemically alter autoantigens (aags) and initiate autoimmune diseases (Greenwald et al., 2001; Howells et al., 2007; Nair et al., 2007). However it would also be advantageous to know more about the workings of the beneficial aspects of the autoimmune system, how it operates, how it maintains tolerance to self, how it might be influenced by naturally occurring or medically induced events to correct harmful immune responses and restore the organism to a normal state of health.

Observation tells us that the autoimmune system has the inbuilt ability to self-correct – with or without medical intervention – and restore the host to health, provided the correction occurs prior to overwhelming injury to the host's immune system and/or organs, tissues, or cells. We have conducted several recent experiments in this area, and have observed through these experiments that corrective immune responses can in fact be initiated by providing the right "information" to the cells of the autoimmune system. We have shown that with a vaccination technique that induces a predetermined immune response, autoimmune diseases can not only be prevented, but also, when present, terminated (Barabas et al., 2004b; Barabas et al., 2006c; Barabas et al., 2006b).

#### **4.1 Beneficial aspects of autoimmunity resulting in tolerance to self**

There are two beneficial aspects of autoimmunity, both characterized by maintenance of the integrity of the host's internal environment (homeostasis/healthy state) and involving the clearing and elimination of cellular waste and abnormal cell lines that are not conducive to the morphological and functional unity of the organism. Immunological cell lines are dedicated to surveyance and recognition of self and difference, or self and non-self (Kreuwel & Sherman, 2001; Sakaguchi, 2000). When difference is recognized there is usually enough time for the host to mount an immune response to avoid the establishment of an autoimmune disorder. Such protective immune responses are carried out by the normally functioning autoimmune system and as such the host is not aware of them. On the other hand, if the autoimmune system's natural ability to correct mishaps is compromised by age, dysfunction, suppression, misinformation, etc. then there exists a stronger likelihood of the host not being able to regain tolerance to self, and the host has a greater chance of experiencing ill health in the form of an autoimmune disorder.

#### **4.1.1 Removal of cellular waste**

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

et al., 1991; Wermeling et al., 2009). Likewise, abnormal cells and cell lines having non-self antigenic surface markers (e.g. cancer cells) are also recognized and removed (Cheent & Khakoo, 2009; Foss, 2002; Topham & Hewitt, 2009). These are the two beneficial aspects of autoimmunity, by which it endeavours to keep the internal environment, composed as it is of endogenous ags, free of change. It is a major undertaking since several factors, both internal and external, have the potential to create an imbalance and cause harmful

A well functioning autoimmune system averts most attempts by internal and external agents to create a harmful autoimmune response resulting in autoimmune disorders such as autoimmune disease and cancer (which themselves may be considered the two negative aspects of autoimmunity). It stands to reason that in order to protect against the kinds of insults that could lead to autoimmune disorders, we should engage in healthful consumption and healthful avoidance, eating healthy diets (consisting of fruits, vegetables, etc.) that contain chemicals or trace elements that boost the immune system or contribute to the prevention of cancer, and minimizing exposure to noxious agents (cigarette smoke, legal and illegal drugs, alcohol, and other toxic or infectious agents) that can chemically alter autoantigens (aags) and initiate autoimmune diseases (Greenwald et al., 2001; Howells et al., 2007; Nair et al., 2007). However it would also be advantageous to know more about the workings of the beneficial aspects of the autoimmune system, how it operates, how it maintains tolerance to self, how it might be influenced by naturally occurring or medically induced events to correct harmful immune responses and restore the organism to a normal

Observation tells us that the autoimmune system has the inbuilt ability to self-correct – with or without medical intervention – and restore the host to health, provided the correction occurs prior to overwhelming injury to the host's immune system and/or organs, tissues, or cells. We have conducted several recent experiments in this area, and have observed through these experiments that corrective immune responses can in fact be initiated by providing the right "information" to the cells of the autoimmune system. We have shown that with a vaccination technique that induces a predetermined immune response, autoimmune diseases can not only be prevented, but also, when present, terminated

There are two beneficial aspects of autoimmunity, both characterized by maintenance of the integrity of the host's internal environment (homeostasis/healthy state) and involving the clearing and elimination of cellular waste and abnormal cell lines that are not conducive to the morphological and functional unity of the organism. Immunological cell lines are dedicated to surveyance and recognition of self and difference, or self and non-self (Kreuwel & Sherman, 2001; Sakaguchi, 2000). When difference is recognized there is usually enough time for the host to mount an immune response to avoid the establishment of an autoimmune disorder. Such protective immune responses are carried out by the normally functioning autoimmune system and as such the host is not aware of them. On the other hand, if the autoimmune system's natural ability to correct mishaps is compromised by age, dysfunction, suppression, misinformation, etc. then there exists a stronger likelihood of the host not being able to regain tolerance to self, and the host has a greater chance of

(Barabas et al., 2004b; Barabas et al., 2006c; Barabas et al., 2006b).

experiencing ill health in the form of an autoimmune disorder.

**4.1 Beneficial aspects of autoimmunity resulting in tolerance to self** 

pathogenic immune responses against self, especially if the right triggers are present.

state of health.

Cells damaged by various agents or events (e.g. chemicals, drugs, ischemia, trauma, toxic compounds, UV irradiation, etc.) release their intracytoplasmic components into intra- and extravascular spaces. These cellular wastes are assisted in their removal by specific nonpathogenic IgM aabs (Avrameas, 1991; Weir, 1964; Weir et al., 1966; Weir, 1969; Zwart et al., 2004) and subsequently phagocytosed and broken down into reusable small MW peptides (Ciurana et al., 2004; Manson et al., 2005; Ogden et al., 2005; Quartier et al., 2005). It was shown by Weir and associates that in a physiological sense we are not *per se* tolerant to our own intracytoplasmic components, and specific IgM aabs are present in the circulation throughout life to clear the system of cellular breakdown products (Weir et al., 1966; Weir & Elson, 1969; Weir & Pinckard, 1967). Specific IgM aab production increases following excessive release of aags (secondary ab response) from an organ damaged by toxic agents, pathogenic IgG aabs, or ischemia at the site of rapid tumour growth etc. (Barabas et al., 2003; Pinckard & Weir, 1966; Weir, 1966). Circulating specific IgM aabs also contribute to rapid and efficient removal of cellular wastes to prevent not only their toxic accumulation in the system but also their possible chemical modification, which could trigger a tissue to be targeted and damaged by a pathogenic IgG aab response, an event which has the potential to initiate an autoimmune disease (Weir, 1969; Weir & Elson, 1969). IgM aabs are able to assist in the removal from the intracytoplasmic space not only of normal native aags released into the intra- and extravascular spaces but also of native-like ags (molecular mimicry) and native aags that are chemically or otherwise modified (Barabas et al., 2004b). Specific IgM aabs in the circulation are present with high titres measurable during the chronic phase of an autoimmune disease, as they assist in the removal of both disease causing and maintaining aags (modified aags that stimulate pathogenic IgG aab production) and disease contributing aags (target aags from the targeted organ) (Barabas et al., 2003; Barabas et al., 2004b). These cross-reactive specific IgM aabs are greatly responsible for the maintenance of tolerance to self during life by efficiently clearing the system of native and modified aags. If they can effectively clear the system of both native and modified aags during an autoimmune disease, then remission will occur, as manifested in signs of improvement and diminished symptoms (Barabas et al., 2004b; Barabas et al., 2006c; Barabas et al., 2006b; Barabas & Lafreniere, 2005). If the stimulus agent – that produces the modified self – ceases to be present in the system then spontaneous remission and termination of the autoimmune disease process will follow. However, as long as the modifying agent remains present in the system and is able to alter the chemical nature of self into non-self, the immune responses that cause the disease will continue, and the condition will be exacerbated and will manifest in a chronic progressive disease.

The autoimmune system's specific IgM aab production cell line will lose its ability to carry out its intended beneficial function in such circumstances where the modifying agent is continuously present in the system and maintains a pathogenic immune response. Its work may also be compromised in cases where the immune system is dysfunctional or has low IgM aab production because of old age, ill health, genetic predisposition, malnutrition, immune suppression, ineffective phagocytosis, etc. (Schulze et al., 2008; Wermeling et al., 2009).

#### **4.1.2 Removal of abnormal cell lines**

Just as intracytoplasmic waste is recognized as unwanted self and assisted in its removal by physiological non-pathogenic IgM aabs, cells with non-self markers, i.e., cancer cells, are also recognized by lymphocytes and their products – NK cells, cytolytic IgG aabs, etc. – and

Four Aspects of Autoimmunity and How to Regain Tolerance to Self

eliminated by non-pathogenic IgM aabs (secondary ab response).

response may fail to occur for the following reasons:

1999; Tureci et al., 2006) (Figure 1).

inducement; or

al., 1997).

Kim et al., 2007).

from an Autoimmune Disease Utilizing the Modified Vaccination Technique 575

In order for the autoimmune system to respond for the benefit of the host, the cancer specific ags on cancer cell surfaces must be readily available for immune processing. In this regard, the cancer specific ag must be somehow detached, chemically degraded, and made available separately from normal cell membrane components or other normal self molecules shared with normal cells to stimulate immune cell lines to produce pathogenic lytic IgG aabs (primary ab response) against the cancer cell line bearing that specific ag. If this process occurs and pathogenic lytic IgG aabs are produced, then regardless of where those cancer cells are located in the body they will be lysed and the cellular breakdown products

It is noteworthy that in cancer defence one of the most important aspects of autoimmunity is manifested in a pathogenic IgG aab response against a self-like group of cells (Jager et al.,

Pathogenic autoimmune response against altered self (i.e., cancer specific ag on cancer cells) is clearly a highly beneficial aspect of autoimmunity. In such circumstances tolerance to self (to a self-like group of cells) is lost, but the host's internal environment is protected from possible changes that could result in tumour growth. However, pathogenic lytic IgG ab

 the cancer specific ag is minimally antigenic (Foss, 2002; Lollini & Forni, 2002) (and a small MW protein), is closely associated with normal cell surface components, and does not detach easily to allow its recognition as non-self for pathogenic immune response

 the host's immune system is prevented from functioning against an apparent self ag by inbuilt protective regulatory cells and molecules (Cheent & Khakoo, 2009; Musiani et

There are two harmful aspects of autoimmunity, both of which have the potential to manifest in disease states, one being an adverse immune response against normal self, causing an autoimmune disease; and the other being tolerance of an abnormal cell line, so that cancer growth is permitted. These disease states, or autoimmune disorders, come about when the immune system's surveying ability is mislead into situations of improper response or non-response to changes in self. It is observed in many autoimmune diseases that modified self initiates and/or maintains pathogenic aab responses against a target ag, causing a disease state (Barabas et al., 2004c; Heymann et al., 1959), whereas in cancer, ags identifiable as cancer specific are minimally antigenic and not recognized as unwanted self, and therefore fail to induce an immune response that eliminates the cancer cells (Foss, 2002;

In many respects the autoimmune system responds correctly during the development and maintenance of autoimmune disorders. In fact, the immune system does what it is instructed to do or not to do by the "information" it receives. In the case of self reaction, for instance, the cells and the products of the cells of the autoimmune system are virtually predestined to react against altered self, in that altered self is non-self and non-self should provoke a pathogenic immune response. Unfortunately, such an immune response against altered self can cause an autoimmune disease, as the developing pathogenic aabs are crossreactive, i.e., in addition to reacting against the modified self ag that initiates and maintains their production, they also react with normal self, causing harm to the tissue and providing

**4.2 Harmful aspects of autoimmunity resulting in autoimmune disorders** 

are eliminated from the system (Cheent & Khakoo, 2009; Kim et al., 2007; Topham & Hewitt, 2009). Such naturally occurring autoimmune responses are necessary to maintain the morphological and functional integrity of the host's organs, tissues, cells, etc. Without this beneficial aspect of autoimmunity, normal cells exposed to carcinogens, genetic influences, or even to normal aging could become cancerous, non-functional tissue, infiltrating the body and compromising its health. It is well documented that the incidence of cancer in the young is considerably lower than in the elderly, presumably because in the young a more efficient autoimmune system recognizes and responds to changes more readily, and/or cell cycles are more precisely regulated. (However, the autoimmune system's beneficial function of recognizing and eliminating cancer can be compromised at any age by a hazardous lifestyle [diets known to cause cancer, smoking, drinking, excessive exposure to the sun], genetic predisposition, exposure to certain infectious agents, malnutrition, immune suppression, etc. (Arver et al., 2000; Baniyash, 2006; Beral et al., 1991; Birkeland et al., 1995; Greenwald et al., 2001; Khuder et al., 1998).

Fig. 1. A normally functioning immune system's immune responses against exogenous ags, exogenous-like and endogenous aags.

The IS is designed to remove exogenous ags, exogenous-like aags, and cellular breakdown products of normal cells from the system to maintain homeostasis and tolerance to self. However, prolonged exposure to exogenous ags can result in chronic infections, exogenouslike aags can induce autoimmune diseases, and deficient processing of cancer specific aags on the surface of cancer cells can permit the growth of cancer.

Abbreviations: aabs, autoantibodies; aags, autoantigens; abs, antibodies; ags, antigens; IgG, immunoglobulin G; IgM, immunoglobulin M; IS, immune system

are eliminated from the system (Cheent & Khakoo, 2009; Kim et al., 2007; Topham & Hewitt, 2009). Such naturally occurring autoimmune responses are necessary to maintain the morphological and functional integrity of the host's organs, tissues, cells, etc. Without this beneficial aspect of autoimmunity, normal cells exposed to carcinogens, genetic influences, or even to normal aging could become cancerous, non-functional tissue, infiltrating the body and compromising its health. It is well documented that the incidence of cancer in the young is considerably lower than in the elderly, presumably because in the young a more efficient autoimmune system recognizes and responds to changes more readily, and/or cell cycles are more precisely regulated. (However, the autoimmune system's beneficial function of recognizing and eliminating cancer can be compromised at any age by a hazardous lifestyle [diets known to cause cancer, smoking, drinking, excessive exposure to the sun], genetic predisposition, exposure to certain infectious agents, malnutrition, immune suppression, etc. (Arver et al., 2000; Baniyash, 2006; Beral et al., 1991; Birkeland et al., 1995; Greenwald et

Fig. 1. A normally functioning immune system's immune responses against exogenous ags,

The IS is designed to remove exogenous ags, exogenous-like aags, and cellular breakdown products of normal cells from the system to maintain homeostasis and tolerance to self. However, prolonged exposure to exogenous ags can result in chronic infections, exogenouslike aags can induce autoimmune diseases, and deficient processing of cancer specific aags

Abbreviations: aabs, autoantibodies; aags, autoantigens; abs, antibodies; ags, antigens; IgG,

al., 2001; Khuder et al., 1998).

exogenous-like and endogenous aags.

on the surface of cancer cells can permit the growth of cancer.

immunoglobulin G; IgM, immunoglobulin M; IS, immune system

In order for the autoimmune system to respond for the benefit of the host, the cancer specific ags on cancer cell surfaces must be readily available for immune processing. In this regard, the cancer specific ag must be somehow detached, chemically degraded, and made available separately from normal cell membrane components or other normal self molecules shared with normal cells to stimulate immune cell lines to produce pathogenic lytic IgG aabs (primary ab response) against the cancer cell line bearing that specific ag. If this process occurs and pathogenic lytic IgG aabs are produced, then regardless of where those cancer cells are located in the body they will be lysed and the cellular breakdown products eliminated by non-pathogenic IgM aabs (secondary ab response).

It is noteworthy that in cancer defence one of the most important aspects of autoimmunity is manifested in a pathogenic IgG aab response against a self-like group of cells (Jager et al., 1999; Tureci et al., 2006) (Figure 1).

Pathogenic autoimmune response against altered self (i.e., cancer specific ag on cancer cells) is clearly a highly beneficial aspect of autoimmunity. In such circumstances tolerance to self (to a self-like group of cells) is lost, but the host's internal environment is protected from possible changes that could result in tumour growth. However, pathogenic lytic IgG ab response may fail to occur for the following reasons:

