Currently, a major health concern is focused on many diseases caused by heterogeneous aberrations of the immune system, including autoimmune diseases, which account for one of the top leading causes of death worldwide. The molecular approach has provided an answer to several fundamental questions about the etiopathogenetic mechanisms of such diseases and has thus considerably provided the opportunity for researchers and clinicians to compare their own experiences and to bring their hypotheses closer together. It therefore appears appropriate to propose this collective work, which contains various and often specific subjects on autoimmune disorders.
2. Immune system: self- and non–self-discrimination
The essential functions of the immune system is to maintain the coherence of the cells and tissues and to ensure their integrity by rejecting foreign aggressive substances or infectious agents, that is, the “nonself,” and the immunogenic altered self, referred to as “modified self,” while respecting the normal components of the host, that is, the “unmodified self-antigens” [1, 2] (Figure 1).
Two strategies are adopted to preserve immune system integrity and coherence : the first strategy corresponds to the innate immunity, also known as nonadaptive immunity, which is triggered immediately after infiltration of microorganisms or upon danger signal integration; the second one involves adaptive immunity, which the activation takes place after pretreatment of the antigen by innate immune cells. Adaptive immunity develops more slowly than innate immunity. It is characterized by immunological memory, allowing it to generate faster and more intense responses in subsequent exposures to the same antigen, which has previously induced a primary immune response.
Cells of innate immunity can recognize, through membrane or intracellular genetically encoded receptors (pattern recognition receptors, PRRs), invariant motifs (pathogen-associated molecular patterns, PAMPs) that are displayed on a large number of pathogens, but absent in host cells. These receptors are preformed or very rapidly inducible in humans. They can also recognize and bind substances released from damaged host tissues and cells (damage-associated molecular patterns, DAMPs) .
The cells of the adaptive immune system—B cells and T cells—are derived from the same pluripotent hematopoietic stem cells . These cells carry on their surface highly diversified antigen-specific receptors, which are able of interacting with a quasi-unlimited number of antigens, thanks to their structure diversity. B cells specifically recognize and bind intact antigens, through highly variable domains of their cell-surface receptors (B cell receptors, BCR), whereas T cells specifically recognize and interact via the highly variable domains of their receptors (T cell receptors, TCR) with peptide fragments derived from antigens in association with major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs) . Two classes of such cells have been defined by their functions and their differentiation markers (cluster of differentiation, CD), but also by the class of MHC molecules they recognize: CD4+ helper T cells and CD8+ cytotoxic T cells that interact with peptide-class-II-MHC and peptide-class-I-MHC complexes, respectively . The subset of CD4+ T cells that express high levels of CD25 (CD4+ CD25high), so-called regulatory T cells (Tregs), is essential in maintaining immunological self-tolerance and prevention of autoimmunity. A deleterious autoimmune reaction may be generated as a result of decreased frequency and/or function of Treg cells in both organ-specific and systemic autoimmune diseases . Of note, regulatory cells are not limited to CD4+ T cells but can include various immune cell subsets, such as CD8+ Treg, Tr1 regulatory cells, Th3 cells, natural killer like T (NKT) cells, and Breg cells [8–10] that can prevent destructive immune responses and autoimmunity. Additionally, to establish a self-tolerance by the immune system, potentially dangerous autoreactive T cell and B cell clones must be deleted through negative selection or clonal deletion within mechanisms of central tolerance occurred in the thymus and bone marrow, respectively, before they develop into fully immunocompetent cells [11, 12]. Failure or breakdown of negative selection, which can also occur in the periphery, can lead to the development of autoimmunity and autoimmune diseases [11–15].
3. Reactions against self-antigens and autoimmunity
When the immune system is abnormally overactivated, as a result of defective regulation function, and triggers a strong reaction against its unmodified components, autoimmune pathological manifestations might develop. Autoimmune responses involve, as a classical immune response, T cells, B cells, APCs, inflammatory cells, antibodies, and many other mediators of immunity such as cytokines.
Numerous factors have been associated to pathological autoimmunity, including genetic predisposition and epigenetic change, environmental factors (nutrition, viral and bacterial infection, and ultraviolet radiation), drugs (beta-blockers, antipsychotics, and antibiotics), vaccination, sex hormone, etc. [16–22] (Figure 2).
4. Autoimmune diseases
Autoimmune diseases and autoimmune-related diseases are numerous (there are more than 130, AARDA). Some of them are more severe or more frequent than others. They are conventionally distinguished in organ-specific autoimmune diseases, in which the autoantigen target is localized in one organ or tissue, and systemic or nonorgan specific autoimmune diseases in which autoantigens are widely distributed in the body or spread throughout several organs (Figure 3). In addition, common autoimmune disorders can coexist in the same patient [27, 28], which further complicates diagnosis and medical management.
Although it is not easy to determine for each individual the exact cause of pathological autoimmunity, given the extensive heterogeneity of autoimmune disorders , relevant research strategies with advanced technologies are developed or are still under investigation to control or prevent these diseases in a wider context (Figure 4).
The essential function of the immune system is the eradication of aggressive elements, particularly infectious agents and tumor cells. In order to ensure normal immune functions, lymphocyte clones which are capable of strongly recognizing harmless or unmodified elements of the self are eliminated or suppressed so that under normal conditions no autoimmune reaction is observed.
The explosion of knowledge thanks to molecular biology over the past few decades has opened new perspectives in the search for risk factors that could be directly involved in the occurrence of autoimmune diseases. It is now well-established that these diseases may be caused by a combination of a genetic predisposition and a triggering factor.
More than 130 autoimmune diseases and autoimmune-related diseases have been identified. Most often, a distinction is made between organ-specific autoimmune diseases, for which specific organs are the target of an attack by the immune system, and nonorgan specific autoimmune diseases which are of a systemic manifestation.
Significant progress has been made in understanding the etiopathogenetic mechanisms of autoimmune diseases. They should undoubtedly lead to more effective therapeutic strategies. Currently, there are multiple potential treatments that often rely on immunosuppression. Nevertheless, the best strategy would be to act more selectively on the self-reactive cells that are abnormally overactives.