Cure Arthritis Naturally

Cure Arthritis Naturally

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Some rheumatic diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome, have an autoimmune pathogenesis. Features such as the presence of autoantibodies and immune cell infiltration in tissues are hallmarks of these entities. The hypothesis that pathogenic mechanisms are in common appears to be reasonably justified. Supporting this is the fact that there is familial aggregation of autoimmune clinical manifestations in families of patients with any of these diseases, suggesting that even genetic factors (and environmental factors) are shared. A recent study following 1,177 lupus patients identified strong familial aggregation of rheumatoid arthritis cases in families of lupus probands [1]. The concept of shared autoimmunity was therefore recently put forward, and it has attained support by findings that there is association with variants of genes shared among the diseases. The two most recent examples are PDCD1 and the RUNX genes.


PDCD1 is the gene coding for the immunoreceptor PD-1. PD-1, a 55 kDa protein contains a tyrosine inhibitory motif (ITIM) and a tyrosine switch motif (ITSM) in its intracellular domain, and has been found to be an inhibitor of cellular activation [2-4]. It is thus postulated that PD-1 may regulate peripheral tolerance by attenuating TCR/BCR activation after encounter with suboptimal rather than optimal doses of antigen. Mice made deficient for pd1 develop a lupus like disease with mild glomerulonephritis and arthritis, and autoimmune dilated cardiomyopathy, depending on the genetic background of the strain [5, 6]. The gene for PD-1, PDCD1 has been mapped to 2q37.3 [7], a region identified linked to SLE in families of Nordic origin [8, 9]. The analysis of SNPs and haplotypes led to the identification of genetic association with the allele of one polymorphism (named PD1.3A) and SLE [10]. This allele was found to disrupt a binding site for a transcription factor RUNX1, as tested using electrophoretic mobility shift and supershift assays. A second study identified PD1.3A associated with type 1 diabetes in the Danish population [11], but failed to identify association with PD1.3A and SLE, although a tendency was observed [12]. In contrast, association with SLE nephritis was found with a second polymorphism shown to be also potentially disrupting the binding site of another regulator of transcription, ZEB, however this has not been experimentally shown [12]. A study also performed in Swedish RA patients identified association of PD1.3A with those patients being negative for the rheumatoid factor and the HLA shared epitope [13]. It should be noted that the patients with RA were of recent onset and it is highly feasible that many of these would develop SLE later. Follow up of these individuals would be required. Nevertheless, association has been found for a third polymorphism PD1.5T in Chinese patients with RA [14]. This study has not been replicated in a second set of Chinese RA patients; instead, association was found with a haplotype formed by the polymorphisms PD1.1 located in the promoter of PDCD1 and the synonymous polymorphism PD1.5 (T-C, Ala-Ala) [15] while PD1.3 was non-polymorphic in this population. It is now becoming clear from these studies that the genetic contribution to susceptibility to rheumatic diseases by PDCD1 results from various polymorphisms identified for this gene, although PD1.3 is the major polymorphism in Caucasians.

The functional polymorphism PD1.3 is located in the fourth intron of PDCD1 at a regulatory repeat with binding sites for several transcription factors. As said, the presence of the A allele disrupts the binding site for the transcription factor RUNX1 [10]. In a way a pathway evolves.

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