Inflammatory Disease Associated Gene Polymorphisms Detected in Patients with Chronic Graft-vs-Host Disease.

Chronic graft-vs-host disease (cGVHD) is the most serious and common long-term complication of allogeneic hematopoietic stem cell transplantation(HSCT). Incidence of cGVHD is 20% to 70% of recipient surviving more than 100days after HSCT. cGVHD most commonly affects the skin, liver, eyes, lung, or the mouth, while multiple other sites may also be affected. Similarities of clinical features of cGVHD and several inflammatory diseases and auto-immune diseases have been commonly observed. Autoantibody formation has also been noted in experimental models of cGVHD, although the pathogenetic role of antibodies in cGVHD is still poorly defined. Both donor and host factors contribute to the pathogenesis of GVHD. While the most important determinant is the compatibility of HLA, non HLA genetic associations with cGVHD have not been extensively studied. Therefore we investigated a relationship between cGVHD and well known inflammatory disease associated gene polymorphisms. We analyzed 100 pairs of Japanese HLA-matched sibling recipients and donors who underwent HSCT in Japanese Red-cross Nagoya First hospital(1990–2001). We examined SNPs, Fc receptor-like3 (FCRL3), programmed cell death 1(PDCD1), peptidyl arginine deiminase(PADI4), solute carrier family 22 memberA4(Slc22A4), and DLG5 by PCR-SSO methods or TaqMan assays, and analyzed correlation between these gene polymorphisms and clinical feature of cGVHD. Statistical analysis were done by using Fisher’s exact probability test.

So far FCRL3-169T allele has been correlated with high incidence of cGVHD(p=0.017). Especially, 18 patients out of 37 who has been occurred extensive cGVHD have -169T/T genotype. On the other hand, there is no relationship between cGVHD and FCRL3 SNP in donors. Our result is FCRL3 -169T allele has been correlated with incidence of cGVHD. FCRL3 is one of a new family genes of FCγ receptor II/III, and is located at chromosome 1q21-23 which is the regions implicated in susceptibility to multiple autoimmune disease. FCRL3 has high structural homology with classical FCγreceptor, although it’s ligands and function are not yet known. Contrary to our result, FCRL3 -169C allele is disease-susceptible allele to inflammatory disease. Since the expression of FCRL3 are detected in the germinal center in spleen and tonsils, residual host B cells or other types of cells expressing the gene might be involved in pathogenesis of cGVHD. This study is the first to report the relationship between cGVHD and inflammatory disease associated gene polymorphisms in hosts.