An important step towards completing the rheumatoid arthritis cycle

In the previous issue of Arthritis Research & Therapy data are presented showing that circulating immune complexes containing citrullinated fibrin(ogen) are present in anti-citrullinated protein antibody-positive rheumatoid arthritis patients, and that such immune complexes co-localize with complement factor C3 in the rheumatoid synovium. These results corroborate the idea that citrullination is intimately involved in the pathophysiology of rheumatoid arthritis and complete our model (the rheumatoid arthritis cycle) for the development and chronic nature of this disease.     

The RNA interference pathway: a new target for autoimmunity

Many intracellular macromolecular complexes that are involved in the production or degradation of RNAs are targeted by autoantibodies in systemic autoimmune diseases. RNA interference (RNAi) is a recently characterized gene silencing pathway by which specific mRNAs are either degraded or translationally suppressed. In a recent issue of Arthritis Research and Therapy, Andrew Jakymiw and colleagues reported that the enigmatic Su autoantigen complex contains key components of the RNAi machinery. Anti-Su autoantibodies from both human patients with rheumatic diseases and a mouse model of autoimmunity recognize the endonucleolytic Argonaute and Dicer proteins, both crucial enzymes of the RNAi pathway. These data raise the question of how the anti-Su response is triggered. So far, it is unknown whether molecular modifications may be involved, as has been proposed for other intracellular autoantigens. The implication of RNAi in anti-viral defence may suggest a role for virus infection in this process.     

A mitochondrial mutator plasmid that causes senescence under dietary restricted conditions

Background

The definition of human MHC class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association.

Results

Here, we present HLA-E allele haplotype association and population linkage disequilibrium (LD) analysis within the ~1.3 Mb bounded by HLA-B/Cw and HLA-A to increase the resolution of identified class I haplotypes. Through local breakdown of LD, we inferred ancestral recombination points both upstream and downstream of HLA-E contributing to alternative block structures within previously identified haplotypes. Through single nucleotide polymorphism (SNP) analysis of the MHC region, we also confirmed the essential genetic fixity, previously inferred by MHC allele analysis, of three conserved extended haplotypes (CEHs), and we demonstrated that commercially-available SNP analysis can be used in the MHC to help define CEHs and CEH fragments.

Conclusion

We conclude that to generate high-resolution maps for relating MHC haplotypes to disease susceptibility, both SNP and MHC allele analysis must be conducted as complementary techniques.     

Conservation of protein phosphorylation sites within gene families and across species

Recent large scale phosphoproteomics studies have helped identify many phosphorylation sites of both membrane and soluble proteins. In most cases the relevance of specific sites has yet to be established whereas in a small number of cases their potency in modulating protein activity is evident. With the increasing amount of data it is becoming clear that phosphosites are often conserved within protein families, pointing to generic regulatory mechanisms. In addition, such mechanisms may be conserved across species. In this addendum evidence is presented for these phenomena occurring in rice and Arabidopsis.Key words: Arabidopsis, kinase, phosphoproteomics, rice     

Potential therapeutic implications of new insights into respiratory syncytial virus disease

Viral bronchiolitis is the most common cause of hospitalization in infants under 6 months of age, and 70% of all cases of bronchiolitis are caused by respiratory syncytial virus (RSV). Early RSV infection is associated with respiratory problems such as asthma and wheezing later in life. RSV infection is usually spread by contaminated secretions and infects the upper then lower respiratory tracts. Infected cells release proinflammatory cytokines and chemokines, including IL-1, tumor necrosis factor-α, IL-6, and IL-8. These activate other cells and recruit inflammatory cells, including macrophages, neutrophils, eosinophils, and T lymphocytes, into the airway wall and surrounding tissues. The pattern of cytokine production by T lymphocytes can be biased toward 'T-helper-1' or 'T-helper-2' cytokines, depending on the local immunologic environment, infection history, and host genetics. T-helper-1 responses are generally efficient in antiviral defense, but young infants have an inherent bias toward T-helper-2 responses. The ideal intervention for RSV infection would be preventive, but the options are currently limited. Vaccines based on protein subunits, live attenuated strains of RSV, DNA vaccines, and synthetic peptides are being developed; passive antibody therapy is at present impractical in otherwise healthy children. Effective vaccines for use in neonates continue to be elusive but simply delaying infection beyond the first 6 months of life might reduce the delayed morbidity associated with infantile disease.