Chemokines are critical for the inflammatory process in autoimmune diseases such as rheumatoid arthritis (RA). The chemokine receptor-5 (CCR5) mediates chemotaxis by CC-chemokines and is expressed by lymphocytes with the Th1 phenotype and monocyte/macrophages. A 32 bp deletion in the CCR5 (CCR5-⌬32 allele) abolishes receptor expression in homozygotes, while CCR5-⌬32 carriers would express less receptor than wild-type homozygotes. This polymorphism is related to the resistance to HIV-1 infection and progression towards AIDS. We hypothesized that the CCR5-⌬32 allele may modulate the severity of disease in RA. A total of 160 RA-patients (71 and 89 with severe and non-severe phenotypes, respectively) and 500 healthy individuals from the same Caucasian population (Asturias, northern Spain) were genotyped. Carriers of the CCR5-⌬32 allele were at a significantly higher frequency (P = 0.012) in non-severe compared to severe patients (17% vs 4%). Our results suggest that the CCR5-⌬32 polymorphism is a genetic marker related to the severity of RA. Genes and Immunity (2000) 1, 288-289.Keywords: chemokines; CCR5-⌬32 allele; rheumatoid arthritis; disease severity Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease of the joints characterized by the infiltration of the synovial membrane with T lymphocytes and macrophages, and pannus formation over the underlying cartilage and bone. The inflammatory process observed in RA is mediated by chemotactic factors released by the inflamed tissues. Chemokines display a potent chemotactic activity for cells of the immune system, playing an important role in both the destructive and the fibrovasculoproliferative phases of RA.1 The chemokine receptor-5 (CCR5) mediates chemotaxis by the CC-chemokines RANTES, MIP-1␣ and MIP-1. This receptor is expressed by lymphocytes exhibiting the Th1-phenotype and by monocytes/macrophages.
2In addition to its role in inflammation, CCR5 also acts as an HIV-1 coreceptor to mediate the first step in cell entry:fusion of the viral envelope with the membrane in the the target CD4 + cell. A 32 bp deletion at the coding region of the CCR5 gene, the CCR5-⌬32 mutation, leads to the expression of reduced amounts of the CCR5 protein in heterozygous individuals.3 CCR5-⌬32 homozygotes do not express the receptor and have nearly complete resistence to HIV-1 infection despite repeated exposure, while heterozygotes progress slowly towards AIDS compared to wild-type homozygotes. 4 The CCR5-
The folate availability seems to be critical for the DNA integrity since it is required for the transfer of methyl groups in the biosynthesis of thymidilate. Although the excessive incorporation of uracils to the DNA can be efficiently removed, this mechanism of reparation produces many double-strand breaks from two opposing nicks. Several chromosomal abnormalities (mainly translocations and deletions perhaps not well understood) are involved in the origin of lymphoproliferative disorders. The TT homozygosity at nucleotide 677 in the gene of methylene tetrahydrofolatereductase (MTHFR), a key enzyme in folate metabolism, was recently linked to a significant protection against colon carcinoma and acute lymphoblastic leukaemia in adults. We analysed the genotype frequencies of C677T-MTHFR in a group of 143 patients with lymphoproliferative disorders (REAL classification) and 200 controls. Overally, the frequencies of the polymorphic allele were similar (35.3% and 32.0% respectively)(P=0.6). We did not find differences between patients and controls except for myeloma/plasmacytoma group (n=26) which showed a CC genotype less than expected (19% vs 46%) (p=0.01) with a frequency ratio of 0.28 (0.10-0.77). Even among the IgG myeloma cases only one patient showed a common genotype (CC) (1/15, 7%) (P=0.003). If these preliminary data are validated with prospective studies, the 677C allele of MTHFR gene could be confirmed as an effective multiple myeloma protective factor (specially for the IgG cases).
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