Diagnosis and Management of Autoinflammatory Diseases in Childhood

Systemic sclerosis (SSc), also termed “scleroderma,” is a progressive, systemic disease of unknown origin characterized by excessive fibrosis, vascular abnormalities and immune dysfunction. Nramp 1 gene has multiple pleiotropic effects on macrophage activation pathways, including up-regulation of the chemokine/cytokine genes KC, tumor necrosis factor α, interleukin-1 b, inducible nitric oxide syntase, and major histocompatibility complex class II expression, as well as tumoricial activity and antimicrobial activity. All of these pleiotropic effects are important for resistance to infection, but they may also be involved in the induction and maintenance of autoimmune diseases. We analyzed four natural resistance associated macrophage protein 1 (NRAMP1) gene polymorphisms including 5′ promoter (GT)n microsatellite, INT4 (469 + 14G/C), 3′UTR (1729 + 55del4), and D543N (codon 543, Asp to Asn) in 52 systemic sclerosis patients with interstitial lung involvement and 136 healthy controls. We found a significant association between INT4, (GT)n polymorphisms (p = 0.006 and 0.027, respectively), and SSc. Our findings suggest that NRAMP1 is a plausible candidate gene for SSc.     

The chloroplast trnP-trnW-petG gene cluster in the mitochondrial genomes of Beta vulgaris,B. trigyna and B. webbiana: evolutionary aspects

The chloroplast trnP-trnW-petG gene cluster has been identified in the mitochondrial DNA (mtDNA) of sugar beet (Beta vulgaris). The chloroplast-derived trnW gene is transcribed in the mitochondria; the other two genes, however, do not seem to be transcribed. This gene cluster is also present in the mitochondrial genomes of two wild Beta species, B. trigyna and B. webbiana. Sugar beet and the two wild relatives share 100% sequence identity in the coding regions of both the mitochondrial trnP and trnW genes. On the other hand, the petG genes from the wild Beta mtDNAs were found to be disrupted either by a 5-bp duplication (B. trigyna) or by a deletion of the 5 region (B. webbiana). A data-base search revealed that a conserved sequence of 60 bp is present in the trnP-trnW intergenic region of the mitochondrial genomes of the three Beta species as well as in other higher plants, including wheat and maize, and that the conserved sequence is absent from the chloroplast counterpart. Our results thus favour the hypothesis of a monophyletic origin of the trnP-trnW-petG cluster found in the plant mitochondrial genomes examined.     

Conservation of the organization of the streptokinase gene region among pathogenic streptococci

Using ten gene-specific probes from the cloned and sequenced streptokinase gene (skc) region (8 931 bp) of Streptococcus equisimilis H46A, a human serogroup C strain, the conservation of these genes and their linkage relationships were studied by Southern hybridization in pathogenic streptococci differing taxonomically, serologically, in regard to their host range, and in the class of plasminogen activator produced. The results indicate that in S. pyogenes (strains A374, NZ131 and SF130/13) and a human group G strain (G19 908) both gene content and gene order as determined for H46A (dexB-abc-lrp-skc-orf1-rel) are preserved. The same is true of an equine S, equisimilis isolate (87-542-W), the streptokinase gene of which has been shown to hybridize detectably with skc, a result at variance with that obtained previously by others. In contrast, the chromosomal DNA of three S. uberis strains (0140J, C198, C216) of bovine origin, two of which produced a plasminogen activator different from streptokinase, hybridized only with dexB-, abc- and rel-specific probes, and the homologues of these genes appeared to lie close to each other. The maintenance of the organization of the streptokinase gene region in strains differing in overall chromosomal character suggests that this gene arrangement is of selective advantage.     

NRAMP1 (SLC11A1) gene polymorphisms that correlate with autoimmune versus infectious disease susceptibility in tuberculosis and rheumatoid arthritis

NRAMP1 gene has multiple pleiotropic effects on macrophage activation pathways. These pleiotropic effects may increase resistance to infections such as tuberculosis (TB), but may also lead to susceptibility of autoimmune diseases such as rheumatoid arthritis (RA). It has been hypothesized that allele 3 would be associated with autoimmune diseases, whereas allele 2 would be associated with infectious diseases, and genetic factors that enhanced survival in the epidemics of TB might have led to susceptibility for the development of RA. We analysed four NRAMP1 gene polymorphisms including 5′ promoter (GT)_n (rs34448891), INT4 (469 + 14G/C) (rs3731865), 3′UTR (1729 + 55del4) (rs17235416) and D543N (codon 543, Asp to Asn) (rs17235409) in 112 patients with TB, 98 patients with RA, 80 healthy controls for TB and 122 healthy controls for RA using ARMS‐PCR and PCR‐RFLP. We found a significant association between INT4 and RA (P = 0.004, odds ratio: 2.06, 95% CI: 1.24–3.41), but no significant differences between 5′ promoter, D543N, 3′UTR polymorphisms and RA. There were no associations between NRAMP1 gene polymorphisms and TB. Similarly, no significant differences were observed between NRAMP1 polymorphisms and rheumatoid factor positivity and erosive disease in RA and localization of TB. INT4 polymorphism may be associated with RA in Turkish patients.