Toll-like receptor 9 polymorphisms in brazilian patients with systemic lupus erythematosus: a pilot study / Polimorfismos do receptor toll-like 9 em pacientes brasileiros com lúpus eritematoso sistêmico: um estudo piloto

Toll-like receptor 9 (TLR9) is an important component of the innate immune system and have been associated with several autoimmune diseases, such as Systemic Lupus Erythematosus (SLE). The aim of this study was to investigate polymorphisms in TLR9 gene in a Brazilian SLE patients group and their association with clinical manifestation, particularly Jaccoud’s arthropathy (JA). We analyzed DNA samples from 204 SLE patients, having a subgroup of them presenting JA (n=24). A control group (n=133) from the same city was also included. TLR9 single nucleotide polymorphisms (SNPs) (−1237 C>T and +2848 G>A) were identified by sequencing analysis. The TLR9 gene genotype frequency was similar both in SLE patients and the control group. In the whole SLE population, an association between the homozygosis of allele C at position −1237 with psychosis and anemia (p < 0.01) was found. Likewise, the homozygosis of allele G at position +2848 was associated with a discoid rash (p < 0.05). There was no association between JA and TLR9 polymorphisms. These data show that TLR9 polymorphisms do not seem to be a predisposing factor for SLE in the Brazilian population, and that SNPs are not associated with JA.

O receptor Toll-like 9 (TLR9) é um componente importante do sistema imunológico inato e tem sido associado a várias doenças autoimunes, como o Lúpus Eritematoso Sistêmico (LES). O objetivo deste estudo foi investigar polimorfismos no gene TLR9 em um grupo de pacientes brasileiros com LES e sua associação com a manifestação clínica, particularmente a artropatia de Jaccoud (JA). Foram analisadas amostras de DNA de 204 pacientes com LES, e um subgrupo com JA (n=24). Um grupo de controle (n=133) da mesma cidade também foi incluído. Os polimorfismos de nucleotídeos únicos TLR9 (SNPs) (−1237 C>T e +2848 G>A) foram identificados pela análise de sequenciamento. A frequência do genótipo genético TLR9 foi semelhante tanto em pacientes com LES quanto no grupo controle. Em toda a população de LES, foi encontrada associação entre a homozigose do alelo C na posição −1237 com psicose e anemia (p < 0,01). Da mesma forma, a homozigose do alelo G na posição +2848 foi associada a uma erupção cutânea discoide (p < 0,05). Não houve associação entre polimorfismos JA e TLR9. Esses dados mostram que os polimorfismos TLR9 não parecem ser um fator predisponível para o LES na população brasileira, e que os SNPs não estão associados ao JA.

Al-Aqeel Sewairi syndrome, a new autosomal recessive disorder with multicentric osteolysis, nodulosis and arthropathy. the first genetic defect of matrix metalloproteinase 2 gene

We report a distinctive autosomal recessive multicentric osteolysis in Saudi Arabian families with distal arthropathy of the metacarpal, metatarsal and interphalangeal joints, with ultimate progression to the proximal joints with decreased range of movements and deformities with ankylosis and generalized osteopenia. In addition, they had large, painful to touch palmar and plantar pads. Hirsutism and mild dysmorphic facial features including proptosis, a narrow nasal bridge, bulbous nose and micrognathia. Using a genome-wide search for microsatellite markers from 11 members of the family from the Armed Forces Hospital and King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia, localized the disease gene to chromosome 16q12-21. Haplotype analysis with additional markers narrowed the critical region to 1.2cM and identified the matrix metalloproteinase 2 [MMP-2], [gelatinase A, collagenase type IV, EC 3.4, 24,24] gene as a disease candidate at Mount Sinai School of Medicine, New York, United States of America in April 2000. Some affected individuals were homoallelic for a nonsense mutation [TCA>TAA] in codon 244 of exon 5, predicting the replacement of a tyrosine residue by a stop codon in the first fibronectin type II domain [Y244X]. Other affected members had a missense mutation in exon 2 arginine 101-histidine [R101H] leading to no MMP-2 enzyme activity in serum or fibroblast or both of affected individuals. In other affected members, a non-pathogenic homoallelic GT transversion resulted in the substitution of an aspartate with a tyrosine residue in codon 210 of exon 4 [D210Y]. The MMP-2-null mouse has no developmental defects, but are small, which may reflect genetic redundancy. The discovery that deficiency of this well-characterized gelatinase/collagenase results in an inherited form of an osteolytic and arthritic disorder provides an invaluable insights for the understanding of osteolysis and arthritis and is the first genetic evidence that MMP2 deficiency is important in growth and development

Terapia génica y sus perspectivas clínicas en ortopedia / Gene therapy and its clinical perspectives in orthopaedics

La terapia génica se refiere a la transferencia de genes a individuos con fines terapéuticos. Esta técnica se ha desarrollado durante los últimos 10 años y tiene aplicaciones en todas las áreas de la medicina. Originalmente dirigida al tratamiento de padecimientos congénitos, actualmente también se estudian sus posibles aplicaciones en el tratamiento de padecimientos adquiridos. Presentamos los conceptos generales de la terapia génica y sus posibles aplicaciones en ortopedia como futuras opciones terapéuticas

Evidence to show MHC-linked factors other than HLA-B27 governing susceptibility to spondylo-arthropathies in Asian Indians.

The HLA antigen profile of 129 North Indian patients with ankylosing spondylitis, 66 patients with Reiter's syndrome and 57 patients with 'unclassifiable' arthritis was compared with 380 normal, healthy controls. Besides B27 which appeared with a significantly increased frequency in the three patient groups, other HLA antigens, viz. A2 and B35, showed deviated frequencies. The HLA supratype A2, B27 was found to be at an elevated frequency in patients with ankylosing spondylitis and unclassifiable arthritis whereas the B35, B27 combination showed a decreased frequency in our Reiter's syndrome sample. These data suggest that besides B27, other HLA-linked factors influence susceptibility to spondylitic disorders and might act as 'modifier' genes for the type and severity of spondylo-arthropathy in a B27-positive individual.