RESUMO
BACKGROUND: In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection. METHODS: We performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor-recipient pairs. We defined genomic collision as a specific donor-recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses. RESULTS: In the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P = 9.8×10-5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P = 6.5×10-5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P = 4.7×10-8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses. CONCLUSIONS: We found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.).
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Variações do Número de Cópias de DNA , Rejeição de Enxerto/genética , Transplante de Rim , Proteínas com Domínio LIM/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Estudos de Coortes , Estudos de Associação Genética , Genótipo , Antígenos HLA/genética , Teste de Histocompatibilidade , Humanos , Imunoglobulina G/sangue , Proteínas com Domínio LIM/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Polimorfismo de Nucleotídeo Único , Doadores de TecidosRESUMO
The herpes zoster infection occurs in the United States, particularly targeting those who are immunocompromised, and can present with many manifestations including encephalitis. Instances of varicella zoster virus (VZV) encephalitis in immunocompetent patients have been rarely reported, but such diagnoses are becoming more frequent as detection of VZV has improved with the adoption of molecular diagnostic panels such as the BioFire Film Array meningitis panel (Salt Lake City, USA). Here, we present an interesting case of acute meningoencephalitis in an immunocompetent adult female without dermatomal neuralgia or cutaneous lesions attributable to VZV. Given many inconsistencies between the patient's presentation and the positive polymerase chain reaction (PCR) result for VZV, we suspected our patient was infected with an undetected organism while possibly simultaneously shedding previously acquired VZV. As molecular diagnostic panels are increasingly used and have greatly improved detection of rarer etiologies of disease, we encourage clinicians to interpret results with caution.