Autoimmunity to Protective Molecules: Is it the Perpetuum Mobile (Vicious Cycle) of Autoimmune Rheumatic Diseases?

Martine Szyper Kravitz; Yehuda Shoenfeld


Nat Clin Pract Rheumatol. 2006;2(9):481-490. 

In This Article

Summary and Introduction

Apoptotic defects and impaired clearance of cellular debris are considered key events in the development of autoimmunity, as they can contribute to autoantigen overload and might be involved in the initiation of an autoimmune response. The C1q protein and mannose-binding lectin are activators of the complement system. The pentraxins are a group of highly conserved proteins including the short pentraxins, C-reactive protein and serum amyloid P, and the long pentraxin family member, pentraxin 3, all of which are involved in innate immunity and in acute-phase responses. In addition to their role in innate immunity and inflammation, each of these proteins participates in the removal of damaged and apoptotic cells. In this article, we discuss the clinical significance of different levels of these proteins, their role in the induction of or protection against autoimmunity, and the presence of specific autoantibodies against them in various autoimmune diseases.

Autoimmunity is characterized by systemic inflammation and the production of a multiplicity of autoantibodies.[1] Although the mechanisms that lead to the induction of such autoantibodies have not been established, evidence suggests that apoptotic cells provide autoantigens that serve as targets for the adaptive immune response.[2] During apoptosis, caspase activity leads to fragmentation of the nucleus and the redistribution of nuclear fragments to blebs on the cell surface. Some of these blebs are shed as apoptotic bodies. Cellular autoantigens that normally reside on the inside of the cell flip to the outside of the cell membrane, thus becoming exposed to components of the immune system. An additional mechanism by which this exposure of intracellular antigens can occur is via the transport of intracellular nucleoproteins to the cell-surface blebs during apoptosis.[3] These nuclear events provide important steps for antigen selection[4] and, if disrupted, can lead to impaired clearance of cellular and nuclear debris, thus contributing to autoantigen overload; in susceptible individuals, this process might initiate and maintain an autoimmune response.[4,5]

Several pattern-recognition molecules belonging to the innate immune response participate in the clearance of apoptotic cells. These molecules recognize microbial pathogens, activate complement, bind to apoptotic blebs, and stimulate uptake by phagocytes.[6,7,8,9,10,11] Among them are the collectins C1q[7] and mannose-binding lectin,[8] the pentraxins C-reactive protein (CRP)[9] and serum amyloid P (SAP) component,[10] and the pentraxin-related protein pentraxin 3 (PTX3).[11] As these molecules have a central role in acute-phase reactions, inflammation and apoptosis, a deficiency of any of them could disrupt processes of immunity and autoimmunity. To understand the possible roles of these proteins in autoimmunity, we have reviewed their prevalence, actions and clinical significance in several autoimmune conditions.


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