Chau-Ching Liu

Biomarkers for systemic lupus erythematosus: a review and perspective.

Purpose of reviewDespite decades of extensive work in the understanding of the etiopathogenesis of systemic lupus erythematosus, few biomarkers have been validated and widely accepted for this disease. The lack of reliable, specific biomarkers not only hampers clinical management of systemic lupus erythematosus but also impedes development of new therapeutic agents. This paper reviews briefly the historical aspects of systemic lupus erythematosus biomarkers and summarizes recent studies on candidate biomarkers. Recent findingsRecognizing the urgent need for lupus biomarkers, a Lupus Biomarker Working Group has recently been initiated to facilitate collaborative efforts aimed at identifying and validating biomarkers for systemic lupus erythematosus. Based on available data, several laboratory markers have shown promise as biomarkers for susceptibility, diagnosis, and disease activity. These include Fc receptor genes (disease susceptibility), complement C4d-bound erythrocytes (diagnosis or disease activity), CD27high plasma cells (disease activity), ‘interferon signature’ (disease activity), and anti-C1q antibodies (disease activity and organ involvement). SummaryThere is a longstanding and recently rejuvenated enthusiasm for biomarkers that precisely and specifically reflect the pathophysiologic and clinical changes in systemic lupus erythematosus. Promising candidate biomarkers have been identified but must still be validated through rigorous, large-scale multicenter studies.

Apoptosis and autoimmunity.

Cell death by apoptosis plays a significant and seemingly contradictory role in the development and pathogenesis of autoimmune diseases. Apoptosis is integral to the assembly and maintenance of a healthy, self-tolerant immune system. However, many of the molecular and cellular events specific to apoptosis generate a reservoir of self-antigens with the potential to initiate and possibly perpetuate autoimmune conditions. Recent findings that support this latter, more sinister role for apoptosis have shed light on a mystery that is common to many systemic autoimmune diseases, namely, why the majority of autoantibodies produced in patients with these diseases target proteins that are normally found inside the cell, often within the nucleus. This review will discuss how autoantigens are specifically altered during the apoptotic process and how the complement system participates in recognizing and clearing these potentially immunogenic packages.

Cell-Bound Complement Activation Products (CB-CAPs) as a Source of Lupus Biomarkers

Measurement of serum C3 and C4 has been used for several decades to monitor disease activity in patients with SLE. Despite the limited utility and recognized weaknesses of these assays, they have remained the gold standard during an era of unprecedented discovery in the complement field. The current urgent need for lupus biomarkers warrants efforts to mine the complement system for assays superior to serum C3 and C4. Recent studies of soluble and cell-bound complement activation products hold promise for achieving this goal.

Chapter 10 – Acute-Phase Proteins and Inflammation: Immunological and Clinical Implications

This chapter discusses the pathophysiological sequences of acute-phase response (APR), the biochemical and functional characteristics of two major acute-phase proteins in humans, and methods commonly used to measure the acute-phase response. The chapter reviews recent data implicating a pivotal role of acute-phase proteins in cardiovascular disease. APR refers to a wide range of neuroendocrinal, physiological, and metabolic changes that are initiated immediately after a tissue is afflicted with an infection or injury. At times, intense physical exercise or psychological stress can also induce mild to moderate APR-like changes. Such changes may take place locally or systemically. While the APR may first be involved in initiating and amplifying tissue inflammation, this complex response can ultimately aid in attenuating and resolving inflammation. Normally, the APR is elicited within a few hours after the initial insult and the majority of the response subsides over a period of 24–72 h.

Potential Roles of Antiphospholipid Antibodies in Generating Platelet-C4d in Systemic Lupus Erythematosus

Premature, accelerated onset of atherothrombotic disease is prevalent in patients with systemic lupus erythematosus (SLE). Most, if not all, atherothrombotic diseases are likely to involve platelets and complement. Previously, we discovered that platelets bearing complement activation product C4d (P-C4d) are present in SLE patients, and are significantly associated with antiphospholipid (aPL) antibody positivity and stroke in SLE patients. The goal of the present study was to further elucidate the role of aPL and other platelet-reactive autoantibodies in the generation of P-C4d. To determine the association between P-C4d and aPL antibodies, the serum levels of aPL antibodies and P-C4d of 180 SLE patients were measured by enzyme-linked immunoassays and flow cytometry, respectively. To investigate the role of aPL antibodies, and possibly other autoantibodies as well, in mediating the generation of P-C4d, in vitro 2-step P-C4d induction experiments were performed. The results showed that the presence and levels of aPL antibodies in the serum were specifically elevated in SLE patients with positive P-C4d. The plasma and immunoglobulins purified from SLE patients who were positive for P-C4d and aPL were capable of inducing C4d deposition on normal platelets in vitro. The capacity of SLE plasma in inducing P-C4d appeared to correlate proportionately to the serum aPL levels. Collectively, the results demonstrate that both aPL and other platelet-reactive autoantibodies may participate in mediating the generation of P-C4d in SLE patients.

Complement and Tissue Injury in SLE

Publisher Summary The complement system is arguably linked more intimately to systemic lupus erythematosus (SLE) than to any other human disease. The role of complement in SLE is both complex and paradoxically intriguing. On the one hand, activation of the complement system is thought to play an important role in tissue inflammation/damage in SLE as a consequence of tissue deposition of immune complexes formed by autoantigens and autoantibodies. On the other hand, a hereditary deficiency of a component of the classical pathway (C1, C2, or C4) has been associated with the development of SLE. Thus, while the complement system plays a role in tissue-destructive inflammatory processes once SLE is established in a patient, it also participates in maintaining immune tolerance to prevent the development of SLE. In patients with SLE, autoantibodies against complement components have also been found to cause acquired complement deficiency. Furthermore, deficiency or functional abnormalities of complement regulatory proteins have also been associated with human diseases, in which the disease manifestations and pathogenesis appear attributable to dysregulated complement-mediated injury of target cells and tissues. During flares of SLE, complement proteins would presumably be consumed at a rate proportional to the activity of the disease. Measuring complement activation may be useful for diagnosing the disease, assessing its activity, and determining its response to therapy.