Physiologic Autoimmunity and Preventive Medicine

The immune system is a natural component of and direct participant in the physiological activity of healthy organisms. The main forms of physiological activity of the immune system are based on the intrinsic abilities of self-identification, selfmaintenance, self-regulation, and self-reparation – that is, on recognizing components of the “self”, i.e., natural autoimmunity. The most ancient and homeostatically important function of natural autoimmunity is autoclearance. A multitude of immune functions, including those related to antimicrobial defense, derived from the basic function of autoclearance. Pathological processes of any kind in any organ are usually accompanied by apoptosis/necrosis of the resident cells and, accordingly, by increased extracellular concentration of intracellular components. These events induce the secondary rise in production of autoantibodies with appropriate specificity (opsonines), which provides augmentation of clearance by facilitating the efficacy of macrophagedependent consumption of debris in the affected organ. This phenomenon is sanogenic in nature and adaptive in essence. Therefore, secondary changes in production and serum content of tissue-specific autoantibodies can be considered the universal and earliest detectable marker of any chronic disease.

The goals of preventive medicine from the immunologic perspective should continue to be aimed at increasing the number of vaccinations against dangerous infectious diseases and various types of virally-induced cancer. In the future, we can perhaps hope to find treatments that would prevent rejections of transplanted organs or even cure autoimmune diseases. These hopes are justified by well-documented research of immunosuppressive regulatory cells over the past decades. However, the missing link is the way how we can control them to do what we desire in each clinical setting. So far, all we therapeutically have is still an unsatisfactory crude “off-switch” for the immune system in terms of glucocorticoid hormones or other general immunosuppressants. We need better control at both, the intracellular and extracellular therapeutic levels. The help might come if we “think” before we try novel therapies. One way how we might improve planning research and clinical trials would be to see the function of the immune system from a different perspective. Here I try to help that by discussing various suggestions about how the immune system works. My suggestion is the Integrity hypothesis, which sees the role of the immune system in checking the normalcy of tissue architecture and communication. I propose that natural cooperation exists side by side with natural selection, so that the immune system represents a search engine for potential commensal microorganisms in addition to its defensive function.

Immune system plays a great physiological role in maintaining of heart tissue homeostasis. This concerns numerous proteins, expressed in myocardium in norm (heart proteomics) and, of course, their “fingerprints” in mirror of immunculus (heart immunomics of main immunogenic region B-epitopes). In this chapter we tried to reveal the problem of cardiac specific proteins, their impact in heart physiology and local autoimmunity, the mechanisms of their formation and approaches for highly specific immunotherapy, based on their profiles in dynamics of pharmacological treatment. Here we discuss implications of antibody therapy and antibody elimination, peptide therapy and immunomodulation under guidance of physiological immunity, partially based on recently received data.

Autoimmunity and its contradictory nature in autopathokinesis have drawn attention from the emergence of immunology as a science. The properties of antibodies towards nuclear antigens of endocrine cells are both theoretically and clinically hot topics as are their applications in the modulation of genetically determined cell functions. In this chapter we discuss the history of physiological autoimmunity concept, the difference and borders between physiological autoimmunity and pathological autoallergy, regulatory potential of the first and pathogenic implications of the last one. The review of our data on antibody production after immunization of animals with some nuclear antigens is given, characterizing their properties and the mechanisms of their intracellular penetration and association with nuclear targets. There are data on the presence of similar autoantigens and corresponding autoantibodies in the blood sera of intacts. The antibodies towards chromatin components appear to be able to penetrate into the nuclei of the endocrine cells and act there through mechanism(s) different from hormonal regulators, at least in adrenals. They stimulate or inhibit proliferation, translation and transcription, hormone biosynthesis in target cells. This suggests that autoimmunity is one of the mechanisms in the physiological regulation of cellular morphogenesis and genetically determined functions. Physiological autoimmunity thus contributes to the bringing-together and co-tuning of genetic information reading, adaptive immune system is regarded as a tool for self-construction of multicellular organism and for support of multicellularity. At the same time, however, the literature on autoimmunity has mostly been concentrated on eliciting a particular disease only. Special reconsideration of these statements is given, the concept of Immunacea is coined, immunoneuroendocrine regulatory meta-system is reviewed, penetration of antibodies into living cells is discussed, some aspects of fetal-maternal immune relations are considered, and link of human microbiome to autoimmunity is emphasized.

Type 1 diabetes (T1D) is a severe autoimmune disease characterized by the destruction of the pancreatic beta-cells. The genetic predisposition to T1D and a vast variety of triggering factors initiate autoimmune processes culminating in the appearance of autoantibodies (autoAbs). The destruction of β-cells of the islets of Langerhans occurs as a result of infiltration of immune system cells. The metabolic changes, the activity of autoantibodies and the protein and genetic markers are considered as the predictors of insulin dependent diabetes mellitus 1(IDDM 1). Multiple sclerosis (MS) is an autoimmune disease characterized by the progression of neurological disturbances which result from the interaction between the processes of inflammation and neurodegeneration. The estimated median incidence of MS worldwide is 2.5 per 100,000, and prevalence is estimated at approximately 1.5 million cases. The onset of MS usually falls at the age between 20 and 40. Women are affected approximately twice as often as men [1]. Preventive medicine and predictive medicine are understood as a complex of measures, aimed at prevention and prediction of diseases, as against the therapeutical and palliative medicine, which remedy disorders or treating their symptoms. The basic methods of the preventive medicine are subclinical diagnostics, using the molecular approaches. Such diagnostics are based on the detection of bioindicators of hidden pathology long before the actual manifestation of symptoms of the disease. Genomics, proteomics and cytomics are the basic methods of prediction, which help to estimate susceptibility to diseases and prevent them.

“…The initial paradigm “one autoantibody for one disease” does not appear to be useful any longer. An autoantibody profile does seem to offer more diagnostic and prognostic power than the determination of single autoantibody specificity” (P-L. Meroni). Why is it so? Fruitfulness of the idea for identification of autoantibody depends on reactivity patterns (autoantibody signatures or profiles) illustrated by analyses of few examples where clinical and laboratory symptoms corresponded to changes in profiles of serum auto-Abs and mismatched to single auto-Ab serum evaluation. Author proposes that future “mapping” repertoires of thousands of natural auto-Abs as the profiles will lead to the appearance of principally new technologies in clinical as well as pre-clinical diagnosis of different chronic diseases.

Hashimoto’s thyroiditis as most prevalent autoimmune endocrine disorder of nowadays is detailed, with data on its natural history, etiology, pathogenesis and comorbidity. A review of authors’ original papers is given, establishing the clinical pathophysiological hypothesis, initially coined in 2002, about regular transition of adolescent hypothalamic syndrome (obesity with rose striae) with age into early metabolic syndrome, complicated by autoimmune thyroiditis. Some evidences are obtained, that witness for marfanoid phenotype and chronic disequilibrium between local, autacoid-mediated and systemic, hormone-mediated regulation, typical for inherited connective tissue disorders, may promote this transition. Pathogenetic role of hyperprolactinemia and cytokine misbalance in transition of physiologic anti-thyroid autoimmunity into autoallergic disease is evaluated. Prevention, early recognition and prediction of autoimmune thyroiditis course, as well as preventive treatment of its complications are reviewed.