Cellular and Molecular Mechanisms of Autoimmune Disease

Abstract

Autoimmune disease (AIDx) results from failure to sustain tolerance to self molecules. Dozens of AIDx involving one or multiple organ systems afflict 3% or more of people worldwide (>75% women). Predisposing factors for AIDx include genetic background, hormonal status, pathogens, and xenobiotic exposures. The incidence of AIDx is higher in individuals living in developed nations, including recent immigrants. Patients may have several AIDx simultaneously. Certain AIDx can prevent other AIDx. A history of AIDx raises the risk for developing hematopoietic neoplasia. Some common mechanisms for losing self-tolerance include reduced deletion or enhanced activation of autoreactive CD4 þ T-helper (Th) lymphocytes, defective immunomodulation by CD4 þ regulatory (Treg) and CD8 þ suppressor (Ts) T-lymphocytes, dysregulated signaling (leading to a relative increase in pro-inflammatory cytokines), comparable structure between self-antigens and foreign molecules, or expression of new epitopes on previously hidden or xenobiotic-modified self proteins. Organ-specific AIDx is generally a cell-mediated (Th1 or Th17) process, while multi-organ AIDx also incorporates a robust autoantibody (Th2) component. Cytokine signatures of different AIDx overlap incompletely; for a given AIDx, different patients have divergent cytokine profiles. Newer anti-AIDx agents are based on our increasing knowledge of AIDx pathogenesis and usually attempt to reverse lymphocyte dysfunction, quell pro-inflammatory signaling, or restore self-tolerance.

Conformational inactivation induces immunogenicity of the receptor-binding pocket of a bacterial adhesin

“…Such an approach also can be used in obtaining functional ligand-like antibodies for therapeutic or research purposes. Also, exposure of new epitopes that previously were hidden on self-antigens is one of the mechanisms underlying autoimmune diseases (30), although the mechanisms for unmasking self-epitopes are not fully understood. Our observations suggest that even a partial loss of the protein's ability to interact with its ligand (as the result of physiological dysfunction or a somatic mutation) could contribute to the uncovering of previously ligand-shielded self-epitopes.…”

Autoimmunity in Primary Antibody Deficiencies

“…The main mechanisms of central tolerance which cooperate in the induction of tolerance in B and T cells in bone marrow and thymus, respectively, include the deletion of high-affinity autoreactive lymphocytes, while peripheral tolerance or the peripheral regulatory process includes anergy, deletion by apoptosis, antigen ignorance, inhibitory receptors, and inhibition by regulatory T cells (Tregs) [27,28]. However, defects in self-tolerance development are the main mechanisms of autoimmunity; other mechanisms that may lead to autoimmunity are the occurrence of breaks in tolerance [34]. The main reason for this breakdown is not yet well known but several mechanisms have been suggested which lead to self-tolerance failure and autoimmunity occurrence (Table 2).…”

Environmental factors and human health: fibrous and particulate substance-induced immunological disorders and construction of a health-promoting living environment

“…2f, the overall findings indicate that an unbalance (decrease of Treg and increase of Tresp) may be present in the peripheral blood of SIL, and this unbalance may be the cause of subsequent autoimmune diseases in SIL [37,38,[52][53][54][55][56]. In the future, the effects of silica particles on Th17 cells, which are considered to play an important role in the development of autoimmune disease [57][58][59], should be analyzed to better understand the comprehensive effects of silica particles on immune dysregulation, particularly impairment of autoimmunity.…”