Recent research has led to a better but as yet incomplete understanding of the complex roles osteopontin plays in mammalian physiology. A soluble protein found in all body fluids, it stimulates signal transduction pathways (via integrins and CD44 variants) similar to those stimulated by components of the extracellular matrix. This appears to promote the survival of cells exposed to potentially lethal insults such as ischemia/reperfusion or physical/chemical trauma. OPN is chemotactic for many cell types including macrophages, dendritic cells, and T cells; it enhances B lymphocyte immunoglobulin production and proliferation. In inflammatory situations it stimulates both pro- and anti-inflammatory processes, which on balance can be either beneficial or harmful depending on what other inputs the cell is receiving. OPN influences cell-mediated immunity and has been shown to have Th1-cytokine functions. OPN deficiency is linked to a reduced Th1 immune response in infectious diseases, autoimmunity and delayed type hypersensitivity. OPN's role in the central nervous system and in stress responses has also emerged as an important aspect related to its cytoprotective and immune functions. Evidence suggests that either OPN or anti-OPN monoclonal antibodies (depending on the circumstances) might be clinically useful in modulating OPN function. Manipulation of plasma OPN levels may be useful in the treatment of autoimmune disease, cancer metastasis, osteoporosis and some forms of stress.

/pdf/osteopontin-role-in-immune-regulation-and-stress-responses-1tiq571alr.pdf

Osteopontin: Role in immune regulation and stress responses

Despite recent progress in the understanding of systemic lupus erythematosus (SLE), the striking 9:1 female to male ratio of disease incidence remains largely unexplained. In addition, peak SLE incidence rates occur during the early reproductive years in women. Studies which illuminate potential causes underlying this sex difference and characteristic onset during the reproductive years have the potential to fundamentally advance our understanding of disease pathogenesis in SLE. Similarly, progress in this area will likely inform human reproductive immunology. Studies of sex hormone function in the immune system are of obvious importance; however, it seems likely that many other types of sex-related genetic and immunological differences will contribute to SLE. In this review, we will focus on recent work in sex-related differences in cytokine pathways and genetics of these pathways as they relate to SLE pathogenesis. It seems quite possible that many of these sex-related differences could be important to reproductive fitness, which may explain the conservation of these immune system features and the observed female predominance of SLE.

/pdf/the-unexplained-female-predominance-of-systemic-lupus-dgu5z1zsdx.pdf

The Unexplained Female Predominance of Systemic Lupus Erythematosus: Clues from Genetic and Cytokine Studies

Osteopontin (Opn) is important for T helper type 1 (TH1) immunity and autoimmunity. However, the role of this cytokine in TH2-mediated allergic disease as well as its effects on primary versus secondary antigenic encounters remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and that Opn-s, the secreted form of Opn, exerts opposing effects on mouse TH2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge. These effects of Opn-s are mainly mediated by the regulation of TH2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and TH2-promoting conventional DCs during secondary antigenic challenge. Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established TH2 responses and protected mice from allergic disease. These effects on TH2 allergic responses suggest that Opn-s is an important therapeutic target and provide new insight into its role in immunity.

Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets.

Osteopontin (OPN) is a protein involved in various pathophysiological events. OPN has been studied as a secreted protein, but recent reports showed that OPN can be found in the cytoplasm and the nucleus. Therefore, some OPN molecules are not secreted and stay in cells. Such intracellular OPN (iOPN) has biological functions distinct from secreted OPN (sOPN). iOPN is involved in cytoskeletal rearrangement and in signal transduction pathways downstream of innate immune receptors, such as Toll-like receptors (TLRs), as an adaptor or scaffolding protein. Although sOPN and iOPN are generated from the same Opn mRNA species, biological outcomes mediated by two isoforms can be different. It would be necessary to delineate which isoform of OPN is responsible for pathophysiological events.

Intracellular osteopontin (iOPN) and immunity.

An overview on the genetic of rheumatoid arthritis: a never-ending story.

Objective

To test the association of osteopontin (OPN) polymorphisms with systemic lupus erythematosus (SLE).



Methods

The coding 5′ and 3′ flanking regions of the OPN gene were scanned for polymorphisms by denaturing high-performance liquid chromatography. A case–control association study was performed in 394 Italian SLE patients and 479 matched controls. OPN serum levels were determined by enzyme-linked immunosorbent assay in 40 patients and 124 controls, and the mean levels were compared between the different OPN genotypes.



Results

Among the 13 detected single-nucleotide polymorphisms (SNPs), alleles −156G (frequency 0.714 versus 0.651; P = 0.006, corrected P [Pcorr] = 0.036) and +1239C (0.377 versus 0.297; P = 0.00094, Pcorr = 0.0056) were significantly increased in the SLE patients compared with the controls. The presence of the associated allele in single or double dose conferred an odds ratio (OR) of 2.35 (95% confidence interval [95% CI] 1.38–4.02) for SNP −156 and an OR of 1.57 (95% CI 1.16–2.13) for SNP +1239. These effects were independent of each other, i.e., not a consequence of linkage disequilibrium between the 2 alleles. The risk associated with a double dose of susceptibility alleles at both SNPs was 3.8-fold higher (95% CI 2.0–7.4) relative to the complete absence of susceptibility alleles. With regard to individual clinical and immunologic features, a significant association was seen between lymphadenopathy and −156 genotypes (overall P = 0.0011, Pcorr = 0.046). A significantly increased OPN serum level was detected in healthy individuals carrying +1239C (P = 0.002), which is indicative of an association between the SLE susceptibility allele and OPN levels.



Conclusion

These data suggest the independent effect of a promoter (−156) and a 3′-untranslated region (+1239) SNP in SLE susceptibility. We can speculate that these sequence variants (or others in perfect linkage disequilibrium) create a predisposition to high production of OPN, and that this in turn may confer susceptibility to SLE.

B. Bigliardo

Papers

Two single-nucleotide polymorphisms in the 5' and 3' ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus.