By forming complexes with DS, these self-molecules are transformed from non-antigenic singular molecules to antigenic complexes. We found that, when cells are dying or under stress, they express certain self-molecules to which DS has peculiar affinity. It is possible that DS is upregulated to facilitate dead cell clearance and new cell growth for tissue regeneration. DS, a glycosaminoglycan polysaccharide, is expressed most abundantly in the skin and other connective tissues, and its expression has been reported to increase during high cellular turnaround, such as wound healing. While simple compositional or structural changes can certainly generate a huge random mix of altered molecules, it cannot explain how they may induce autoimmune responses, let alone similar ones.īased on our studies, we have proposed a uniform autoantigenicity mechanism by which autoAgs share a common biochemical property in their affinity to dermatan sulfate (DS), and by which autoAgs forming a molecular complex with DS to induce autoreactive B cell responses. A protein may change by mutation, glycosylation, phosphorylation, methylation, citrullination, or fusion with another protein. Theoretically, a molecule may change itself in many ways by alternating its chemical composition or biochemical properties. A key, missing mechanism is how non-antigenic self-molecules become autoantigenic non-self. Thus, it is mysterious how these different molecules can all trigger a similar cascade of autoimmune responses. Moreover, the autoAgs appear to be a random collection of molecules that are expressed in different parts of human body and exhibit various biological functions. From a molecular point of view, certain self-molecules are targeted, as if they are non-self, by autoreactive cells, autoantibodies (autoAbs), or other factors, which subsequently leads to damage of the tissue where the autoantigens (autoAgs) reside.Īmong the hundreds of thousands of human molecules, only a small portion have been reported to be autoAgs. Due to unclear circumstances, however, the immune response can sometimes go astray and mistakenly attack its own tissue. Normally, the immune system reserves immune responses to attack invading microorganisms and protect the body. The underlying mechanism of autoimmunity has been rather intriguing. Any tissue may become a target of autoimmune attacks, which is why autoimmune diseases constitute a wide spectrum of symptoms, with more than 100 autoimmune diseases having been classified thus far. Our data contribute to the molecular etiology of autoimmunity and may deepen our understanding of autoimmune diseases.Īutoimmune diseases occur when an immune system starts to attack its own body. This study provides a proteomic repertoire of confirmed and potential autoantigens for future studies, and the findings are consistent with a mechanism for autoantigenicity: how self-molecules may form molecular complexes with DS to elicit autoimmunity. Protein network analysis indicates that these proteins have significantly more interactions among themselves than would be expected of a random set, with the top 3 networks being mRNA metabolic process regulation, apoptosis, and DNA conformation change. There are also 32 proteins related to the cytoskeleton. There are 55 vesicle-associated proteins and 12 ribonucleoprotein granule proteins, which may contribute to the diverse speckled patterns in HEp-2 stains. Among the 107 proteins, 82 can be located to nucleus and 15 to the mitotic cell cycle, which may correspond to the dominance of nuclear and mitotic staining patterns in HEp-2 test. Of these, 78 are verified autoantigens with previous reports as targets of autoantibodies, whereas 29 might be potential autoantigens yet to be verified. This study identified 107 proteins from fractions with low to high DS-affinity. Protein interaction network and pathway analyses were performed on all identified proteins. Literature text mining was conducted to verify the autoantigenicity of each protein. Proteins were eluted with salt gradients, and fractions with low to high affinity were collected and sequenced by mass spectrometry. Total proteins were extracted from cell lysate and fractionated with DS-Sepharose resins. In this study, we attempted to identify as many autoantigens as possible from HEp-2 cells using a unique proteomic DS-affinity enrichment strategy. Differential diagnosis of autoimmune disorders is based on commonly recognizable nuclear and cytoplasmic staining patterns. Autoantibody screening by indirect immunofluorescence staining of HEp-2 cells with patient sera is a current standard in clinical practice. Autoantibodies are a hallmark of autoimmune diseases.
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