**8. Phase 2 characteristics**

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

elevation of glutamine and moderate elevation of GABA take place in the initial steps. However, in the course of time the concentration of glutamic acid begins to decrease, while that of GABA increases; however, autoAbs are not generated even under these conditions. Subsequent decreases of glutamic acid and GABA are noted only against the background of increasing titers of anti-GAD65 and anti-insulin autoAbs (seroconversion). After T1D passes to the clinical diagnosis stage, auto-Abs titers begin to decrease gradually to a nearly

Fig. 6. The dynamics of changes in the concentrations of Glu / GABA / GADA and insulin Abs in the period between the commencement of the effect of the irreversible diabetesinducing factor and first clinical manifestations of T1D. There is a clear seroconversion sequence Glu / GABA / GADA with a period of about 1 year. By the moment of appearance of first clinical manifestations, some antibodies detected several years theretofore, may be

There is evidence that in addition to the aforesaid metabolites T1D is characterized by fluctuations in the levels of succinic acid, phosphatidylcholine (even in newborns),

Estimation of the role of environmental factors in triggering one or another pathology and development of adequate approaches to diagnosis within maximally short intervals of time is one of currently central problems in preclinical medicine. Here, it is necessary to draw a demarcation line between autoimmune disorders and background events in order to select optimal diagnostic procedures and reliable criteria, since clinical tests do not always provide unfailing results that are crucial for diagnosis. Therefore, development of strict elaborate protocols is of vital importance for identification and analysis of environmental factors.

missing. (Noteworthy, each individual case may be different from the average).

triglycerides and phospholipids.

**7. Environmental factors triggering T1D** 

undetectable level (this widely occurring phenomenon usually lasts 10 to 20 years).

#### **8.1 Viral infections as triggering factors in type 1 diabetes**

The large body of evidence (serological, epidemiological, biological, etc.) obtained thus far testifies to the ability of certain viruses to provoke type 1 diabetes mellitus (T1D) in human beings. Among the immense diversity of other disease-provoking factors, enteroviruses, retroviruses, reoviruses, parotiditis viruses, cytomegalovirus, Epstein-Barr virus and a clinical variant of the diabetogenic encephalomyocarditis virus are the most likely candidates for T1D-triggering factors.

Viral infections provoke diabetes by operating at different regulatory levels, e.g., by disregulating immune mechanisms, by stimulating the activity of pathological systems or by interfering with the normal course of regulatory processes occurring in the organism.

The risks of viral infection and T1D development correlate with the functional stability of the organism and its genetic and immune backgrounds. It is well known that morbidity from seasonal (especially, in the winter period) virus-borne infections correlates with very high incidence of autoimmune diseases including T1D. The reason is in shorter (in comparison with summertime) duration of the daylight period and, as a consequence, low level of vitamin D synthesis and increased morbidity from viral infections and autoimmune disorders. Additional support in favor of this hypothesis can be derived from much greater incidence of T1D in North European countries in comparison with Southern Europe.

#### **8.2 Bacterial infections as triggering factors of T1D**

Recent advances in immunologic research and numerous animal and human model studies shed new light on the role of enteric bacteria in triggering autoimmune reactions. It was shown, in particular, that certain bacteria (e.g., *Bacteroides ovatus*) induce diabetes in young children predisposed to T1D. The mechanisms whereby bacterial agents interfere with immune homeostasis and provoke diabetes are still poorly understood; it is known, however, that intestinal bacteria trigger autoimmune responses that initiate destructive insulitis. The strongest argument in favor of this viewpoint is an ever increasing (by 20% in comparison with control) number of affected individuals infected with sporadic variants of these bacteria. The extent of bacterial infection is especially apparent in young children whose autoimmune microbiome is the least stable and diversified. Continuous sophistication and diversification of the microbiome with ageing point to the decreasing role of bacteria in initiating diabetes in adult individuals. (Giongo et al., 2010)

#### **8.3 Nutritional factors**

For quite a long period of time, viruses were considered to be the only etiogenic external factors in T1D. Today, there is evidence that nutritional factors also play a role in T1D development. Although the pathogenetic mechanisms of the disease are not yet completely

Preclinical and Predictive Algorithms in Monitoring

and fetus pregnancy.

over a period of three decades.

**9. Medicaments as potential T1D inducers** 

**passive immunization in T1D development** 

manufacturers. (Classen JB & Classen DC, 1999)

2001; Blom et al., 2001)

Patients with Autoimmune Diseases and Their Relatives-at-Risks 211

alternative hypothesis states that higher X-linked genetic predisposition of females to autoimmune diseases is a result of unbalanced X chromosome inactivation. The Xinactivation skew theory was recently corroborated for dermatosclerosis and autoimmune thyroiditis. Yet another possible mechanism is small-scale exchange of cells between mother

At the same time, the current views on the role of environmental factors in T1D are often diametrally opposite and many practitioners in medicine are inclined to think that the stably increasing incidence of this severe autoimmune disease is unrelated to external factors. For example, a mass-scale retrospective investigation was carried out in Saudi Arabia in the period between 1980–2009. In this study, 119 patients with T1D were divided into six groups depending on early clinical manifestations of the disease. There was no correlation between the impact of environmental factors and the incidence of T1D

For many decades, it was believed that certain chemical substances including patented medicaments are harmful for the pancreas and provoke T1D. The mechanisms whereby chemical drugs exert their hazardous effects vary widely and are not clearly understood. Active drug components accumulated in body cells slow down the functional processes in different body tissues and organs and trigger pathological reactions, e.g., by providing tropism of certain pathogens or restructuring the systemic architectonics of body organs including the pancreas. The presence, in such active components, of sequestered or cryptic epitopes provokes negative phenomena, such as molecular mimicry. Not infrequently, medicinal drugs trigger a series of immunoregulatory and immunoeffector shifts, which

culminate in immune disorders including autoimmune destruction of the pancreas.

**10. T1D and vaccination: Is there a correlation between them? The role of** 

There exist quite a few hypotheses concerning the role of vaccination in triggering autoimmune diseases including T1D. This fact notwithstanding, only few instances proved to display a clearcut correlation between vaccination and development of autoimmune syndromes. (Ethan Rubinstein, 2004) In the meantime, heated discussions about association between autoimmune disorders and vaccination do not abate. Advocates of the "autoimmunization" hypothesis refer to recent flagrant global-scale spreading of autoimmune diseases with a particular on responsibility of children's vaccines

There is evidence that T1D indeed develop in response to immunization. At the same time, in newborn infants vaccinated at the age of several months the incidence of T1D did not exceed the morbidity level in children immunized with a single vaccinating dose at the age of 2 years. (Karvonen et al., 1999) Mass-scale serial investigations carried out in the USA did not establish any associativity between these two events. Similarly, studies into the role of vaccination and vaccination timing as risk factors in childhood diabetes failed to establish a correlation between vaccination and the risk for autoimmune diseases. (DeStefano et al.,

understood, the role of T1D as one of the most essential links in the human immune system leaves no doubt, particularly with regard to its tolerance to food antigens.

As a rule, tolerance to food antigens largely depends on peculiarities of local immune reactions whose functional role consists in suppression of immune responses formed under the influence of several factors, viz., (i) oral tolerance, (ii) controlled chronic inflammation (so-called "physiological inflammation") and (iii) local secretion of IgA.

Disturbances in the coordinated functioning of these mechanisms stimulate the appearance of characteristic manifestations of food allergy. Measurements of blood plasma levels of Abs against various food antigens in patients with clinically confirmed T1D revealed high titers of IgA and IgG against cow's milk Ags (bovine serum albumin, BSA), beta lactoglobulin, BLG) and some other food Ags, e.g., ovalbumin, OVA. It should be noted, however, that in this particular case we deal with the so-called abuse tolerance, which can hardly be compared to food allergies associated with high levels of circulating IgE. (Kohno et al., 2002; Luopajärvi et al., 2008)

#### **8.3.1 Nitrosamines**

There is a statistic association between nitrosamines and diabetes as can be judged from some biochemical data on destructive effects of nitrosamines on pancreatic Langerhans islet beta cells. In a statistical study, nitrosamine levels were determined in foods consumed by children under 14 at risk of diabetes. It was found that in children with low dietary nitrosamine levels the Odds Ratio (OR) was equal to 1.0 (cf. 1.7 OR and 2.6 OR in children with medium and high levels of dietary nitrosamine). (Dahlquist et al., 1990)

Statistic analysis established a correlation between the quality and quantity of consumed food, on the one hand, and susceptibility for diabetes, on the other hand. However, this correlation is purely statistical, since biological, biochemical and immunological mechanisms responsible for this phenomenon demand further investigation and analysis. (Essien & Akpan, 2006)

#### **8.4 Age**

The growing tendency in the past decades is towards higher incidence of T1D in young people and children. In the first place, this is due to negative influences of environmental factors. The first peak of T1D is normally observed between the 4th and 6th years of life; the second peak is associated with hormonal transformations in the pubertal period (10–12 years).

On the other hand, there exists a special form of diabetes termed as latent autoimmune diabetes in adults (above 30) (LADA). Its most characteristic features are moderate clinical manifestations and slow progression of the autoimmune process. The finding that 6% of patients with LADA carry protective haplotypes responsible for more slow progression and less severe (in comparison with IDDM1) manifestations of the disease indicates that LADA appears to be a more widespread form of diabetes than its classical form, viz., T1D. This and the aforementioned data emphasize the need for elaborating novel effective criteria and approaches to treatment of patients with diagnosed LADA. (Bermúdez et al., 2010)

#### **8.5 Gender**

Analysis of sex steroids revealed that clinical manifestations of many autoimmune diseases vary widely depending on the hormonal status of the organism, e.g., menstrual cycle, administration of oral contraceptives, etc. Pregnancy should also be included in this list. The

understood, the role of T1D as one of the most essential links in the human immune system

As a rule, tolerance to food antigens largely depends on peculiarities of local immune reactions whose functional role consists in suppression of immune responses formed under the influence of several factors, viz., (i) oral tolerance, (ii) controlled chronic inflammation

Disturbances in the coordinated functioning of these mechanisms stimulate the appearance of characteristic manifestations of food allergy. Measurements of blood plasma levels of Abs against various food antigens in patients with clinically confirmed T1D revealed high titers of IgA and IgG against cow's milk Ags (bovine serum albumin, BSA), beta lactoglobulin, BLG) and some other food Ags, e.g., ovalbumin, OVA. It should be noted, however, that in this particular case we deal with the so-called abuse tolerance, which can hardly be compared to food allergies associated with high levels of circulating IgE. (Kohno et al., 2002;

There is a statistic association between nitrosamines and diabetes as can be judged from some biochemical data on destructive effects of nitrosamines on pancreatic Langerhans islet beta cells. In a statistical study, nitrosamine levels were determined in foods consumed by children under 14 at risk of diabetes. It was found that in children with low dietary nitrosamine levels the Odds Ratio (OR) was equal to 1.0 (cf. 1.7 OR and 2.6 OR in children

Statistic analysis established a correlation between the quality and quantity of consumed food, on the one hand, and susceptibility for diabetes, on the other hand. However, this correlation is purely statistical, since biological, biochemical and immunological mechanisms responsible for this phenomenon demand further investigation and analysis.

The growing tendency in the past decades is towards higher incidence of T1D in young people and children. In the first place, this is due to negative influences of environmental factors. The first peak of T1D is normally observed between the 4th and 6th years of life; the second peak is

On the other hand, there exists a special form of diabetes termed as latent autoimmune diabetes in adults (above 30) (LADA). Its most characteristic features are moderate clinical manifestations and slow progression of the autoimmune process. The finding that 6% of patients with LADA carry protective haplotypes responsible for more slow progression and less severe (in comparison with IDDM1) manifestations of the disease indicates that LADA appears to be a more widespread form of diabetes than its classical form, viz., T1D. This and the aforementioned data emphasize the need for elaborating novel effective criteria and

Analysis of sex steroids revealed that clinical manifestations of many autoimmune diseases vary widely depending on the hormonal status of the organism, e.g., menstrual cycle, administration of oral contraceptives, etc. Pregnancy should also be included in this list. The

with medium and high levels of dietary nitrosamine). (Dahlquist et al., 1990)

associated with hormonal transformations in the pubertal period (10–12 years).

approaches to treatment of patients with diagnosed LADA. (Bermúdez et al., 2010)

leaves no doubt, particularly with regard to its tolerance to food antigens.

(so-called "physiological inflammation") and (iii) local secretion of IgA.

Luopajärvi et al., 2008)

(Essien & Akpan, 2006)

**8.4 Age** 

**8.5 Gender** 

**8.3.1 Nitrosamines** 

alternative hypothesis states that higher X-linked genetic predisposition of females to autoimmune diseases is a result of unbalanced X chromosome inactivation. The Xinactivation skew theory was recently corroborated for dermatosclerosis and autoimmune thyroiditis. Yet another possible mechanism is small-scale exchange of cells between mother and fetus pregnancy.

At the same time, the current views on the role of environmental factors in T1D are often diametrally opposite and many practitioners in medicine are inclined to think that the stably increasing incidence of this severe autoimmune disease is unrelated to external factors. For example, a mass-scale retrospective investigation was carried out in Saudi Arabia in the period between 1980–2009. In this study, 119 patients with T1D were divided into six groups depending on early clinical manifestations of the disease. There was no correlation between the impact of environmental factors and the incidence of T1D over a period of three decades.
