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.)

BackgroundCD157/Bst1 glycoprotein is expressed in >85% of malignant pleural mesotheliomas and is a marker of enhanced tumor aggressiveness.ResultsIn vitro, mesothelial cells (malignant and non-malignant) released CD157 in soluble form or as an exosomal protein. In vivo, sCD157 is released and can be measured in pleural effusions by ELISA. Significantly higher levels of effusion sCD157 were detected in patients with malignant pleural mesothelioma than in patients with non-mesothelioma tumors or with non-malignant conditions. In our patient cohort, the area under the receiver-operating characteristic curve for sCD157 that discriminated malignant pleural mesothelioma from all other causes of pleural effusion was 0.685, cut-off (determined by the Youden Index) = 23.66 ng/ml (62.3% sensitivity; 73.93% specificity). Using a cut-off that yielded 95.58% specificity, measurement of sCD157 in cytology-negative effusions increased sensitivity of malignant pleural mesothelioma diagnosis from 34.42% to 49.18%.ConclusionsEvaluation of soluble CD157 in pleural effusions provides a diagnostic aid in malignant mesothelioma.MethodsSoluble CD157 (sCD157) was detected biochemically in culture supernatants of malignant and non-malignant mesothelial cells, and in pleural effusions from various pathological conditions. An ELISA system was established to measure the concentration of sCD157 in fluids, and extended to analyze sCD157 in pleural effusions from a cohort of 295 patients.

For most patients with established MS we found intrathecal humoral response, type two, and the number and arrangement of IgG bands generally does not change during the disease, because they reflect long-term non-specific immune stimulation rather than a specific immune response that during infectious disease changes (quantitatively and qualitatively).

Background: Polyglandular autoimmune syndrome type III (PAS III) is combination two most common autoimmune disease: Diabetes mellytus type 1 (DM1) and autoimmune thyroid disease (AITD). Objectives: The aims of the study were a) to define conection between polymorphism of CTLA-4 gene, rs 231775 with PAS III; b) to establish the conection of inherited genotype with severity of clinical features; and c) to estimate the rate of risk for severe clinical presentation among subgroups in study population. Metods: This research included 50 subjects with diagnosed PAS III syndrome, wich are on treatment in clinic for Nuclear medicine and andocrinology KCUS. As methods of research has used: hystory of disesase AND clinical examination. As material is used blood sample. From blood sample DNA was isolated withn Qiamp- DNA- mini kit, with accopanied protocol. Results: In our study, 50 patients with polyglandular autoimmune syndrome type III (PAS III) were examined, and in the study population had 26 female subjects and 24 male subjects. The average age of the participants was 31.64 years, and in the subgroups: group GWT (G-wild type) the average age was 30.20 years, group GM (G-mutated) 32.40 years and group GH (G-heterozygote) 30 , 60 years. Using the Chi-square test, the association between the polymorphism rs231775 and PAS-III was demonstrated, χ2 (2.100) = 18.258, where p < 0.0001. Using the Chi-square test, the association between the rs231775 polymorphism and the severity of the clinical picture, χ2 (2.50) = 8.531, where p< 0.0140 was proved. The CTLA-4 rs231775 genotypes were also assessed for disease severity. Conclusion: This study suggests that CTLA-4 expression plays a key role in balancing the immune system as well as the response against one’s own tissues, and thus in the regulation of autoimmune diseases.

Introduction and Aims: Indoleamine 2,3 dioxygenase (IDO) is an intracellular enzyme involved in systemic immune tolerance and control of infections. IDO acts through degradation of essential amino acid Tryptophan (Trp), necessary for pathogens proliferation, suppressing the replication of bacteria and preventing viral spread. On the other hand with the attempt to terminate inflammatory response, IDO activates immunesuppressive mechanisms via Tregs facilitating further development of infection. Aim of the study was to detect IDO activity and immunological related markers in the first year after kidney transplantation focusing on correlations with infection development. Methods: IDO activity (Kyn/Trp) and IDO mRNA were investigated in 26 patients receiving cadaveric kidney transplant in parallel with Foxp3, IL17, Ror-C, TGFbeta, IL6 mRNAa. Sampling was at 0, 15, 30, 60, 180, 360 days after transplant. IDO activity was assessed in sera as Kyn/Trp ratio, simultaneously determined by isocratic RP-HPLC method with UV detection. Real time PCR (Taqman) was used to measure mRNAs normalized on Abelson housekeeping gene mRNA and expressed as fold increase. Results: IDO activity (Kyn/Trp ratio) decreases from T0 (19.1;) to T30 (7.4;IQR 6.3-8.6) then increases again at T60 (8.8; IQR 7.2-11.) followed by stabilization until T360. A significant correlation between IDO activity and IDO mRNA was observed at T60 ( p=0.05) and T180 ( p=0.02). At T60 a significant increase of IDO activity vs T15 ( p0.001) and T30( p=0.01)and IDO mRNA expression was observed ( p=0.02). 9/26 patients developed viral infections during follow-up (5 CMV after a median of 2 months, 3 BKV after 5 months, 1 HZV after 1 month). Patients with infections (INF) had induction regimen (basiliximab and steroids) and tacrolimus through levels superimposable to those without infections (NONINF). At time of infection 6/9 pts were under MMF. No rejection episodes occurred before infections. 1/26 had CNI toxicity and subsequent BKV infection. At T60 IDO activity was significantly different among INF versus NONINF (INF Kyn/ Trp median 11,40;IQR 8, vs NONINF 7.85;. IL-17 was significantly reduced in INF (IL-17 INF 0,3;IQR 0.04-1,27 vs NONINF 4.89;IQR 1.2-7.7 p=0.006) while Ror-C was significantly increased (Ror-C INF 1.23;IQR 0.7-1.7 vs NONINF 0.44;IQR 0.15-0.9, p=0.03). Foxp3, TGF beta and IL6 mRNA expression did not differ at T60 between the two groups. Conclusions: IDO activity 60 days after transplant was significantly higher in patients who later developed viral infections, not correlated to other parameters of infection or of overimmunesuppression. Increased IDO activity and decreased IL-17 can be expression of an environment permissive to infections in transplanted patients and could represent a useful biomarker for infection prevention.