Biologic Treatments in Interstitial Lung Diseases

Interstitial lung diseases (ILD) represent a group of heterogeneous parenchymal lung disorders with complex pathophysiology, characterized by different clinical and radiological patterns, ultimately leading to pulmonary fibrosis. A considerable proportion of these disease entities present with no effective treatment, as current therapeutic regimens only slow down disease progression, thus leaving patients, at best case, with considerable functional disability. Biologic therapies have emerged and are being investigated in patients with different forms of ILD. Unfortunately, their safety profile has raised many concerns, as evidence shows that they might cause or exacerbate ILD status in a subgroup of patients. This review article aims to summarize the current state of knowledge on their role in patients with ILD and highlight future perspectives

Spleen Tyrosine Kinase (Syk) Regulates Systemic Lupus Erythematosus (SLE) T Cell Signaling

Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules. Protein along with gene expression modulation for select molecules was confirmed. Specifically, levels of cytokine IL-21, cell surface receptor CD44, and intracellular molecules PP2A and OAS2 increased following Syk overexpression in normal T cells and decreased after Syk silencing in SLE T cells. Our results demonstrate that levels of Syk affect the expression of a number of enzymes, cytokines and receptors that play a key role in the development of disease pathogenesis in SLE and provide support for therapeutic targeting in SLE patients

Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study

Objective. To assess the efficacy of rituximab (RTX) in SSc

Rituximab-induced B cell depletion in autoimmune diseases: Potential effects on T cells

Peripheral B cell depletion strategies have been employed recently in the treatment of systemic autoimmune diseases and the initial clinical results have been encouraging. Although the major target of rituximab-based treatments was to reduce the levels of circulating auto-antibodies, additional mechanisms of action may operate. Recent studies have addressed the question of potential effects of transient B cell depletion on other, non-B cell populations. The data, albeit uncontrolled, suggest that anti-CD20 monoclonal antibody treatment is associated with significant effects in the T cell pool, whereas individual clinical responses do not always correlate with changes in autoantibody titers. More specifically, it has been reported that rituximab administration may decrease the activated phenotype of peripheral and tissue-resident T cells by abolishing antigen presentation by B cells, and may enhance the numbers and function of regulatory T cells. In this review we analyze and discuss available data emerging from B cell depletion studies in patients with systemic Lupus erythematosus, rheumatoid arthritis and other autoimmune conditions. Further controlled studies are needed to confirm the role of B cell depletion in modifying T cell function in vivo. (c) 2008 Elsevier Inc. All rights reserved

The Pathophysiologic Role of Monocytes and Macrophages in Systemic Lupus Erythematosus: A Reappraisal

Objectives: To review current developments, regarding the pathophysiologic role of monocytes and macrophages in systemic lupus erythematosus (SLE). Methods: We searched Medline for articles written in the English language using the following terms: monocyte(s) or macrophage(s) and lupus. Although our search spanned the years 1971 to 2008, the majority of the short-listed articles belonged to the period 2000 to 2008. Published literature on phenotypic and functional properties of monocytes/macrophages (Mo/M phi) in SLE was reviewed. References from identified articles were also selected. Currently available experimental data and their relevance to the pathogenesis of SLE are critically discussed. Results: It has traditionally been held that impaired phagocytosis by monocytes and macrophages in SLE allows for the accumulation of apoptotic debris leading to a sequel of autoimmune phenomena. Recent paradigms derived from animal models of systemic autoimmunity, however, has broadened our understanding regarding the possible pathophysiologic roles of Mo/M phi in SLE. Data derived from studies in patients with SLE show multiple aberrations in activation status and secretory functions of circulating and tissue-infiltrating Mo/M phi. Such aberrations may be associated with dysregulation of T-cell function and autoantibody production in SLE. Moreover, emerging evidence suggests that phagocytic capacity and antigen-presenting properties of Mo/M phi are enhanced in some patients with SLE. Conclusions: While defective phagocytosis represents a distinctive feature of monocyte function in some patients with SLE, aberrant activation of the Mo/M phi system may be a more appropriate concept to encompass the broad spectrum of Mo/M phi disorders in SLE. Aberrant function of lupus Mo/M phi appears to play a dynamic role in the initiation and perpetuation of the systemic autoimmune response and organ damage. Delineation of the altered biology of lupus Mo/M phi could provide possible future therapeutic targets for patients with SLE. 2010 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 39:491-50

The Infectious Basis of ACPA-Positive Rheumatoid Arthritis

Rheumatoid arthritis (RA) is associated with HLA-DRB1 shared epitope (HLA-DRB1SE) and anti-citrullinated protein autoantibodies (ACPAs). ACPAs precedes the onset of clinical and subclinical RA. There are strong data for three infectious agents as autoimmunity triggers in RA, namely Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans causes of periodontal disease (PD), and Epstein-Barr virus (EBV). P. gingivalis expresses arginine gingipains, that cleave proteins at the arginine residues, and peptidyl arginine deiminase (PPAD), which citrullinates arginine residues of proteins, thus forming neoantigens that lead to ACPA production. Peripheral blood plasmablasts from ACPA+RA patients produce ACPAs the majority of which react against P. gingivalis. A. actinocycetemcomitans produces leukotoxin A, a toxin that forms pores in the neutrophil membranes and leads to citrullination and release of citrullinated autoantigens in the gums. EBV can infect B cells and epithelial cells and resides as latent infection in resting B cells. Abs against citrullinated peptides derived from EBV nuclear antigen appear years before RA and cross-react with human citrullinated fibrin. Citrullinated proteins are potential arthritogenic autoantigens in RA. The conversion of arginine to citrulline increases the peptide binding affinity to HLA-DRB1SE. Also, citrullinated fibrinogen induces arthritis in HLA-DRB1*0401 transgenic mice, and transfer of their splenic T cells causes arthritis to recipient mice