**12. Multiple Sclerosis (MS)**

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

T1D is often concomitant with local or systemic autoimmune disturbances, which further progress to complex autoimmune diseases or polyglandular syndromes via the crossreactivity mechanism. By illustration, in many patients T1D is associated with autoimmune thyroiditis (24.5%/autoAbs vs 47.5%), celiac disease (1.4%/autoAbs to gliadin and IgA to tissue transglutaminase vs 18.7%), MS (0.5-2%/autoAbs vs 7%), Addison's disease (1.4%/adrenal cortex autoAbs vs 0.7%), autoimmune gastritis (6.9-7.2%/parietal cell

Secondary autoimmune disorders associated with later steps of T1D have a number of specific features. Thus, autoimmune thyroiditis (AIT) (autoimmune polyglandular syndrome 3A version (APS3Av)) is diagnosed in 12-15% of T1D patients; its clinical manifestations correlate positively with age, gender (AIT is more frequent in females (8.6%) than in males (3.4%)), duration of T1D (mean age of AIT patients varies between 5 and 15 years), serum levels of the thyroid-stimulating hormone (TSH), etc. Both diseases have a common familial hereditary background, but can also be present in a single individual suggesting a crucial role of genetic predisposition in the development of polyglandular syndromes. Furthermore, high incidence of AIT among first-degree relatives of T1D patients points to a significant contribution of genetic factors to immune system failures (see above).

Noteworthy, the predominant form of AIT in patients of both sexes is hypothyroidism (8.1%), but in males with anti-thyroid Abs AIT is prevalent (85.7% vs 37.5% in females). the total incidence of hypothyroidism in T1D patients with anti-thyroid Abs is 52.2%. The interval between the onset of T1D and the appearance of first clinical manifestations of AIT varies from one year to 5–6 years, while the first thyroid autoAbs appear in the period between 6 months and 5–3 years before the onset of the disease. Blood sera of patients with APS3Av (AIT and T1D) (Hunger-Battefeld et al., 2009) contain circulating anti-thyroid peroxidase and anti-thyroglobulin Abs emerging soon after emergence of GADA (10% and 8% of cases, respectively); more than 6% of such patients contain both types of autoAbs. As mentioned earlier in this chapter, MS is also associated with T1D. In this case, morbidity from MS among male patients exceeds that in females nearly fourfold (2% vs. 0.5%). According to statistic reports, non-diabetic sisters run five times higher risks for MS than other cohorts of the general population. Consequently, adult females with T1D can be assigned to the highest risk group for associated autoimmune disorders (e.g., MS). (Bussone

The association between T1D and RA is not so apparent as in the case of T1D and MS. In depth studies established that about 13% of patients whose first-degree relatives suffer from T1D have clinical signs of RA. According to other authors, no such linkage does not exist.

Based on these findings, we can state with assurance that T1D increases the risk for autoimmune disorders through triggering the formation of autoimmune clusters and polyglandular autoimmune syndromes. As a rule, circulating autoAbs begin to appear in the blood serum as early as several years before the development of severe secondary disorders and absolute clinical manifestations of the disease. The genetic data provide the physician with a broad spectrum of autoimmune diseases that are likely to develop in patients with T1D. Time-lapse monitoring of patients' blood sera not only affords reliable

**11. Associativity between T1D and autoimmune diseases. Polyglandular** 

autoAbs vs 20.9%), etc. (Somers et al., 2009; Villano et al., 2009; De Block et al., 2006)

(Severinski et al., 2003; Hunger-Battefeld et al., 2009)

et al., 2009; Otto-Buczkowska et al., 2009)

(Hakala et al., 1992)

**autoimmune syndromes** 

### **12.1 State-of-art models of multiple sclerosis**

Multiple sclerosis (MS), a remitting and relapsing autoimmune disease of the central nervous system (CNS), represents a generalized degenerative inflammatory process. Its main causative factors are demyelination, degradation of oligodendrocytes and degeneration of axons.

The clinical course of MS includes three stages, viz., the preclinical stage, the autoimmune inflammation stage and the neurodegeneration stage. Some basically important targets (including gene-oriented ones) emerging in the course of MS evolution can be used in the design of novel preclinical diagnostic tools. Expression of gene products including functionally important transcripts is currently employed in the design of proteomes. The use of these constructs (commonly referred to as diagnostic microchips) as early as at the preclinical pathology stage allows multifarious manipulations with specific targets in the course of immune attacks. Impaired structure of the myelin sheath (demyelination) and degradation of axons take place at the very earliest stages of preclinical MS, i.e., long before the clinical onset of the disease. This generates a need for innovative preclinical diagnosis protocols and, in a more distant perspective, preventive treatment of MS. In this context, genetic tests acquire special importance as valuable analytical tools for predicting and estimating risks in MS. In terms of present-day classifications, the genes supporting predisposition to MS are divided into three main groups, viz., immune system genes (DRB1, OPN, CD44, CD24, CCR5-Δ32), myelin metabolism genes (MBP, CTLA4, ICAM1) and cytokins (TGFβ1, TNF). AutoAbs to the basic protein of myelin are amont the key autoaggression markers for demyelination-related pathologies. Some of these Abs have functional resources of their own, e.g., proteolytic activity towards the Ag substrate. The dynamics of Abs spectra in patients with MS reflect etiogenic peculiarities of MS evolution. It is now well established that pre-early stages of MS are accompanied by the appearance of specific Abs against two categories of determinants, viz., mimicking and myelin epitopes. After termination of the preclinical phase, serum titers of mimicking Abs show a tendency to decrease, while those of antimyelin and antineural autoAbs increase in contrast. This upward trend points to escalation of antitissue autoaggression and formation of a typical clinical picture of the disease including a complete set of clinical and serological criterial features of PIFAS. Early emergence and long persistence of antimyelin autoAbs in MS patients points to a correlation between serum positivity and duration of the disease. (Sepiashvili et al., 2010; Martynov et al., 2010)

### **13. Aortic aneurisms**

Aortic aneurisms (AA) are related to the category of socially important diseases involving a high risk for lethality. Its main causal factors are degradation of elastin (e.g., by proteases), pronounced structural changes in medial smooth muscle cells (SMC), aortic vasculature atrophies and formation of the *preclinical* pathological syndrome. The main clinically

Preclinical and Predictive Algorithms in Monitoring

STAT4, IL23R and a number of other genes.

**15. Conclusion** 

**16. References** 

(July 2010) ISSN 644-53

Patients with Autoimmune Diseases and Their Relatives-at-Risks 215

Other loci in the MHC class III region associated with SLE include: the SKIV2L gene encoding the superkiller viralicidic activity of a 2-like protein, the PTPN22 gene, TNFAIP3 and TRAF1-C5 loci (TNF-associated signalling pathway genes), Integrin-α-M (ITGAM),

In-depth studies into pathogenesis and etiogenesis of autoimmune diseases and discovery of reliable biomarkers for diagnosing various pathological conditions provide a way for predicting, with a sufficiently high degree of probability, the risk of relapses and exacerbations and possible clinical manifestations of the disease. In its turn, considerable recent progress in medical science (in medical genetics, bionanomedicine and bioinformatics, in particular) provides a clue to the design of advanced protocols for preclinical screening of patients. The construction of individual genetic maps with special reference to familial predispositions and time-lapse monitoring of risk groups for pathomorphological markers have one common goal, viz., to collect information for early implementation of preventive and therapeutic intervention strategies. Moreover, dynamic control over functional activities of different body organs and tissues on the basis of well established and validated proteomic and metabolomic data enables early prediction of exacerbations and complications and implementation of preventive therapy. The latter is based on the use of state-of-art pharmacological protocols and, if surgical correction is

required, of the most recent advances in transplantation and regenerative medicine.

with the ultimate goal to improve current standards of public health care at large.

Considerable improvement and wide-scale application of preclinical diagnosis algorithms and preventive treatment protocols for routine clinical application are among the most topical problems in today's medical practice. More urgent strategies are aimed at compensating structural and functional deficiencies of damaged organs and fragments thereof. In genetic studies combined with early detection of minor lesion foci and analysis of immune, proteomic and metabolomic disturbances open up new vistas for social welfare

Achenbach, P.; Warncke, K.; Reiter, J.; Naserke, H.E.; Williams, A.J.; Bingley, P.J.; Bonifacio,

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important causes of AA established thus far can be presented as follows: (i) genetic predisposition and hereditary diseases affecting the molecular architectonics of connective tissue (e. g. Marfan's syndrome); (ii) atherosclerosis and arterial hypertension. Very often, AA is associated with atherosclerosis, especially, in patients of senior age groups. Male gender, smoking, carriage of specific infectious pathogens (herpes simplex virus, cytomegalovirus, *Chl. pneumonia*, syphilis and tuberculosis pathogens) also play a role in the pathogenesis of AA.

Long duration of the *preclinical* stage (aortal dilation to the critical level) in patients with AA provides the physician with a unique opportunity to break the pathogenetic linkage and thus to arrest the further progression of the disease on going from the preclinical to the clinical stage.

It is more expedient to perform preclinical screening in three steps in full conformity with prenosological diagnostic protocols. *(i)* identification of blood serum levels of biomarkers in the form of so-called serodiagnostic packages (matrix metalloproteinases (MMP), cystatin *С*, osteoprotegerin (OPG), soluble fractions of elastin (SFE) and heavy chains of myosin (HCM), antibodies against *Ch. pneumonia*, CMV and HSV). These biomarkers are used as diagnostic package components and allow maximally accurate diagnosis and, which is no less important, estimation of lesion size even at the *preclinical* stage; *(ii)* MRT or contrasting CT scanning angiography for identifying exact location of dilated vessels, viz., *topological sites* in the vascular network responsible for hypersecretion of specific biomarkers; *(iii)* biopsy of the dilated portion of the aorta containing a suspected aneurism followed by morphological, immunogenetic and molecular-biological testing of bioptats. This procedure is highly invasive and its implementation is not recommended in the absence of positive results in the first two steps. If the dilated portion of the aorta cannot be visualized directly and the first-step tests give positive results, screening for biomarkers must be repeated after a period of several months. If positive results are obtained from serological doublet tests, MRT or CT angiography must be conducted to the required extent.

Early (*preclinical*) diagnosis holds especially great promise being the most efficient step in prophylactic and preventive treatment of AA. The uniqueness and high therapeutic potentials of *preclinical* diagnosis combined with low invasiveness of the nonsurgical approach and design, on its basis, of more advanced diagnostic protocols opens up fresh opportunities for the development of rationalized and practicable innovative technologies as a breakthrough in cardio- and angiosurgery. Prospective analysis of clinical utility of *targeted* therapy as a tool for *preventive* (preoperative) treatment and/or postsurgical angiorehabilitation will also make the subject of future investigations.
