Impact of alloimmune T cell responses on hepatitis C virus replication in liver transplant recipients

We investigated the influence of alloimmune T cell responses on hepatitis C virus (HCV) replication in HCV-infected patients after liver transplantation (LT). To monitor the immune-status in 27 HCV-infected LT recipients, we routinely performed mixed lymphocyte reaction (MLR) assays within 4 weeks after LT. HCV RNA titers in most patients fluctuated in inverse proportion to the stimulation index (SI) of anti-donor reactive T cells early after LT. Two weeks after LT, recipients with high HCV RNA titers (>1000 KIU/mL) displayed a significantly lower SI for anti-donor reactive T cells than recipients with low HCV RNA titers did (<1000 KIU/mL). An in vitro transwell assay mimicking the anatomical features of the interaction between HCV-infected hepatocytes and alloreactive T cells in allograft livers demonstrated that interferon (IFN)-γ was necessary to suppress HCV replication. This study proves the significant impact of alloimmune T cell responses on HCV replication in HCV-infected LT recipients.     

Loss of HIV-specific memory B-cells as a potential mechanism for the dysfunction of the humoral immune response against HIV

A central, yet unresolved issue in the pathogenesis of HIV disease is the mechanism of antibody perturbation. In this study, HIV-specific memory B-cells were quantified in groups of infected subjects and compared with memory responses to other antigens and antibody titers. HIV-specific memory B-cell responses were vigorous in individuals with CD4⁺ T-cell counts > 350/μl and weak or undetectable in subjects with CD4⁺ T-cell numbers < 200/μl. Memory B-cell loss was permanent, because antiretroviral therapy failed to restore HIV-specific memory responses while influenza- and tetanus toxoid-specific memory B-cells remained unaffected or recovered. Antibody titers to Gag strongly correlated with memory B-cell frequencies. In contrast, Env-specific antibodies were maintained in advanced disease despite low or undetectable levels of memory B-cells. These results provide a potential mechanism by which destruction of HIV-specific CD4⁺ T-cells affects the humoral immune response against HIV and compromises the ability to maintain an effective antibody response.     

Epstein-Barr virus DNA load kinetics analysis in allogeneic hematopoietic stem cell transplant recipients: Is it of any clinical usefulness?

BackgroundThere is a lack of clinical information regarding the usefulness of plasma Epstein-Barr virus (EBV) DNA load kinetics analyses in the management of EBV infections in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Namely, it remains unknown whether this type of analysis can help physicians to anticipate the development of high-level EBV DNAemia episodes requiring rituximab treatment or predict the risk of recurrent EBV DNAemia or post-transplant lymphoproliferative disorders (PTLDs).Study designUnicentric, retrospective, observational study including 142 consecutive patients undergoing T-cell replete allo-HSCT. The plasma EBV DNA load was monitored on a weekly basis using the artus^® EBV PCR kit.ResultsFifty-five of the 142 patients (38.7%) developed at least one episode of EBV DNAemia; 13 of the 55 initial EBV DNAemia episodes (23.6%) were preemptively treated with rituximab, 7 patients had a recurrent episode of EBV DNAemia, and biopsy-proven PTLDs were diagnosed in 4 patients. The initial plasma EBV DNA load was not significantly different (P = 0.269) in episodes of self-resolving EBV DNAemia, those requiring rituximab treatment, or those leading to PTLDs. The plasma EBV DNA load doubling times were similar across all the groups (P = 0.799), and the EBV DNA-load half-life was not associated with the occurrence of recurrent EBV DNAemia (P = 0.550).ConclusionPlasma EBV DNA-load kinetics analyses are unlikely to be useful in predicting the occurrence of high-level EBV DNAemia, PTLD, or recurrent EBV DNAemia.     

Considerable decrease in antibodies against hepatitis B surface antigen following kidney transplantation

BackgroundImmunization against hepatitis B virus (HBV) in kidney transplantation (KT) candidates and recipients is recommended. If anti-HBV surface antigen antibody (anti-HBsAb) titer of 10 IU/L is admitted to be protective, the optimal threshold, at and after KT, is unknown. In addition, the natural evolution of anti-HBsAb titers after KT is not reported.ObjectivesTo describe rates of protective immunity to HBV at time of KT (baseline) and evolution of anti-HBsAb titers during the following year.Study designWe retrospectively analyzed HBV serology at baseline, 15 days, and 4 and 12 months post-KT. No patient received vaccination during the study period, but information about previous vaccination was unavailable.ResultsAt baseline 80% of 141 recipients had anti-HBsAb titer ≥10 IU/L. Among these 113 patients, 84 had subsequent HBV serologies at day 15 and month 4, and 67 had also serology at month 12. At month 12, 25% of patients had lost protective anti-HBsAb titers (p < 0.001). The duration of protective anti-HBsAb titers was significantly longer when the initial titer was ≥ 100 IU/L versus <100 IU/L (log-rank test p < 0.0001). Protective titers at month 12 persisted in 93% of patients with initial titer ≥100 IU/L compared to 33% with 10–100 IU/L titer (p < 0.0001). In contrast, duration of protective titers did not differ according to the anti-HBV core antigen antibody status at baseline.ConclusionsDespite a high prevalence of protective anti-HBsAb titer at KT, the loss of protective immunity during the following year was considerable, particularly when initial anti-HBsAb titer was <100 IU/L.     

Role of the Fyn −93A>G polymorphism (rs706895) in acute rejection after liver transplantation

The tyrosine kinase Fyn phosphorylates tyrosine residues on key targets involved in early T-cell signal transduction. T-cell signal transduction is one essential step for acute transplant rejection. The aim of this study was to evaluate the association of Fyn −93A>G single nucleotide polymorphism (SNP) (rs706895) with the susceptibility to acute rejection episodes in liver transplantation. In total, 72 liver transplant recipients with one biopsy proven acute rejection (S-BPAR), 56 with multiple BPAR (M-BPAR), 105 without BPAR (No-BPAR), and 145 healthy controls were enrolled in this case-control study. The SNP was genotyped by polymerase chain reaction–allele specific restriction enzyme analysis (PCR–ASRA) and was analyzed for a recessive and a dominant model. The Fyn −93G allele exhibits in healthy controls a statistically significant lower frequency than in liver recipients (18% vs. 24%; p = 0.046) or in liver recipients with BPAR (18% vs. 27%; p = 0.017). However, the genotype and allele frequencies of the Fyn −93A>G SNP demonstrate no significant differences between recipients with acute rejection episodes (S-BPAR and M-BPAR) and No-BPAR recipients. Thus our results provide no evidence that the Fyn −93A>G SNP contributes to the susceptibility to acute liver transplant rejection in a Caucasian population.     

Maraviroc in addition to cART during primary HIV infection: Results from MAIN randomized clinical trial and 96-weeks follow-up

BackgroundMulti-targeted treatment strategies including maraviroc (MVC) during Primary HIV Infection (PHI) may benefit from the immune-modulatory properties of this CCR5-inhibitor.ObjectivesWe conducted a proof-of-concept clinical trial aimed at assessing whether maraviroc in addition of a combination antiretroviral therapy (cART) initiated during PHI would improve immunological and virological parameters.Study designThe MAIN (Maraviroc in HIV Acute INfection) study was a randomized open-label clinical trial (EUDRACT number: 2008-007004-29) which enrolled 29 patients with PHI. Subjects were randomly assigned to receive cART-only (cART), cART + 8 weeks of MVC (ST-MVC) or cART + 48 weeks of MVC (LT-MVC), regardless of predicted co-receptor usage. After 48 weeks patients in ST-MVC and LT-MVC groups discontinued MVC. Patients were evaluated at week 48 and at week 96 of follow-up to assess differences in CD4 T-cell gain and plasma HIV-RNA.ResultsTwenty-nine patients were enrolled. Seven patients (24%) had a predicted CXCR4 co-receptor usage. At week 48, 27 patients (93.1%) reached HIV-RNA <50cps/mL. Median CD4 T-cell count increase was 313 cells/μL (p < 0.001, Wilcoxon signed-rank test). At multivariate linear regression analysis, LT-MVC arm had the greatest CD4 T-cell increase, while patients in ST-MVC arm had the least gain in CD4 T-cells (p = 0.007). At week 96, multivariate analysis showed no associations between former treatment arm and CD4 T-cell gain.ConclusionsThe MAIN study showed that MVC for 48 weeks in addition to cART during PHI was able to enhance CD4 T-cell gain, regardless of co-receptor usage. After MVC discontinuation, the difference between treatment arms was lost.     

Reconstitution of Th17, Tc17 and Treg cells after paediatric haematopoietic stem cell transplantation: Impact of interleukin-7

Successful reconstitution of T lymphocytes after allogeneic haematopoietic stem cell transplantation (HSCT) is needed to establish the graft-versus-leukaemia effect and an effective anti-microbial defense, but the ratio between functionally different T-cell subsets needs to be balanced to avoid graft-versus-host disease (GVHD).IL-7 is essential for T-cell generation in the thymus and peripheral T-cell homeostasis. High IL-7 levels have been associated with impaired T-cell reconstitution, increased risk of acute GVHD and treatment-related mortality, but the underlying cellular mechanisms behind these associations have not been investigated previously. We hypothesized that increased levels of IL-7 post-transplant alters the balance between immune-regulatory T cell subsets during the post-transplant lymphocyte recovery towards a more pro-inflammatory profile.We quantified Th17 cells, Tc17 cells and Tregs in 29 children following HSCT. Th17 cell and Treg counts rose significantly from day +90 to +180 post-HSCT, and prior acute GVHD was associated with significant changes in the concentration of Tregs (9.4 × 10⁶/L vs. 1.3 × 10⁶/L, P = 0.0052) and the Th17/Treg ratio (1.5 vs. 4.2, P = 0.025). The plasma level of IL-7 at day +90 correlated inversely with Th17 cell counts (r_s = ?0.65, P = 0.0002) and the proportion of Tc17 cells (r_s = 0.64, P = 0.0005) at day +90, but not with Tregs. Furthermore, high IL-7 levels at day +7 were predictive of a less naïve T-cell phenotype at day +90.These findings add further evidence that IL-7 is a key regulatory factor that may tune the balance between functionally different T-cell subsets following HSCT.     

CCR2-64I and CXCL12 3′A alleles confer a favorable prognosis to AIDS patients undergoing HAART therapy

BackgroundThe chemokine receptor polymorphisms CCR5Δ32, CXCL12 3′A, CCR2-64I and CCR5-59029 G/A have been demonstrated to affect HIV-1 infection and progression.ObjectiveWe studied the impact of the above polymorphisms on the effectiveness of a 30-month treatment with highly active antiretroviral therapy (HAART) in 149 HIV-1 patients.Study designWe stratified the patients according to CD4 CDC criteria and applied Kaplan–Meier analysis using the following end-point criteria: (a) the time from HAART initiation to undetectable viral load (VL) counts (VL < 50 copies/ml), (b) the duration of undetectable VL status and (c) the time required for CD4+ T-cell counts to pass over the 500 cells/ml threshold.ResultsOur results in the second group (CD4 201–500) revealed that patients with the CCR2-64I allele achieved undetectable VL counts at 3.5 ± 0.48 months as compared to 10.26 ± 1.42 months in the control group (p = 0.018). The VL remained undetectable for 28 ± 2 months, in contrast to 20 ± 2 months in the control group (p = 0.048). Patients carrying CXCL12 3′A restored the CD4 population faster than the control group (9 ± 2 and 14 ± 2 months, respectively, p = 0.023). The CCR5Δ32 and CCR5-59029 G/A alleles did not appear to affect the parameters studied.ConclusionsOur results suggest that patients carrying either CCR2-64I or CXCL12 3′A have a more favorable prognosis during HAART treatment.     

Optimized light therapy for non-seasonal major depressive disorder: effects of timing and season

BackgroundLight Therapy (LT) when combined with standard antidepressant treatment for unipolar depression hastens recovery. We studied the influence of LT timing on the antidepressant efficacy of LT and the influence of the season of treatment and recurrence on the response to treatment.MethodsWe studied 70 inpatients affected by Unipolar Depression, treated for three weeks with combined LT and venlafaxine. Two-third of the patients received LT following a predictive algorithm based on MEQ scores; the others received LT at 11:00 a.m. Severity of depression was rated on the Hamilton Depression Rating Scale (HDRS). A subgroup of patients wore activity monitors.ResultsHDRS scores significantly decreased during treatment (Friedman's ANOVA: χ2 = 186.82, p < 0.00001). LT administered in the early morning showed a better relative efficacy than late morning (F = 4.576; p = 0.012) with the clinical improvement correlating with an advance in rest–activity rhythm acrophase (r = ? 0.336; p = 0.017). Season of hospitalization interacted with LT timing and time in influencing response to treatment (F = 3.101; p = 0.049) and season of episode recurrence significantly interacted with LT timing, season of hospitalization and time (F = 5.925; p = 0.0035).LimitationsThe major limitation of the study is the small sample size when considering simultaneously LT schedules, season of treatment and recurrence. Moreover, even if none of the patients fulfilled DSM-IV criteria for seasonal pattern of recurrence, they were not administered any questionnaire about seasonality.ConclusionsWe confirmed the usefulness of LT as a non-pharmacological antidepressant therapy for non-seasonal depression. Season and timing of administration and timing of the rest–activity cycle affected response to treatment.     

Early post-operative acute phase response in patients with early graft dysfunction is predictive of 6-month and 12-month mortality in liver transplant recipients

Early allograft dysfunction (EAD) after liver transplantation is mostly a reversible event caused by factors related to ischemia/reperfusion (I/R) injury. EAD represents a hepatic injury associated with pre- and early post-transplant inflammatory cytokine responses. Aim of the present study was to evaluate the prognostic and diagnostic value of CRP in liver transplant recipients with EAD.Materials and methodsForty-seven patients with EAD were compared with 115 non-EAD patients. Pre- and post-transplant parameters were analyzed. EAD was defined based on postoperative liver function tests such as INR, bilirubin and liver enzymes. Statistical analysis was performed using SPSS version 18.0.ResultsPre-transplant liver enzyme were not significantly different in the two groups. At day 3, 5 and 10 post-transplant CRP was significantly higher in patients with EAD than in non-EAD patients (p ⩽ 0.001 for all investigations) and remained consistently high in patients with EAD and low in non-EAD patients. EAD patients with high CRP at post-transplant days 3 and 5 showed lower survival at 6-month and 12-month post-transplant than patients with low CRP.ConclusionOur results indicate a prognostic and diagnostic value of CRP in patients with early graft dysfunction and predict 6-month and 12-month mortality in liver transplant recipients.     

No direct effect of an elective caesarean section on the phenotypic and functional characteristics of maternal peripheral blood T lymphocytes

ProblemThe short term effect of the caesarean delivery on the phenotypic and functional characteristics of the peripheral blood leukocytes of the mother is unknown.Method of studyWe determined the composition and activation status of the maternal peripheral blood leukocytes isolated within 4 h before and within 24 h after elective caesarean delivery with neuraxial anaesthesia. Furthermore, we determined the proliferative and cytotoxic response of these leukocytes to several stimulators.ResultsNo significant differences in the percentage of CD4+CD25bright and CD8+CD28− T cells or the expression of activation markers FoxP3, CD69 and HLA-DR were observed in peripheral blood drawn before caesarean delivery compared to after caesarean delivery. Also the alloreactive immune responses in samples taken before and after the caesarean delivery were similar.ConclusionOur results show that the phenotype and immune response of maternal peripheral blood T cells obtained before elective caesarean delivery are not different from those obtained after caesarean delivery. This knowledge will facilitate sample collection for future studies on the immune response in term pregnancies.     

Inhibitor kinazy Brutona u chorych z nawrotowym lub opornym na leczenie chłoniakiem z komórek płaszcza – wyniki międzynarodowego,wieloośrodkowego,badania II fazy z ibrutynibem (PCI-32765) – EHA Encore

Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling essential for normal B-cell development. Ibrutinib is an oral BTK inhibitor that induces apoptosis and inhibits migration and adhesion of malignant B-cells. Updated results of this international, multicenter, phase 2 study of single agent ibrutinib in relapsed or refractory MCL will be presented.Ibrutinib 560 mg PO QD was administered continuously until disease progression. Tumor response was assessed every 2 cycles (one cycle = 28 days). The study enrolled 115 patients (65 bortezomib-naïve, 50 bortezomib-exposed); 111 patients were treated; 110 were evaluable for response. Baseline characteristics included: median age 68 years, time since diagnosis 42 months, number of prior treatments 3; bulky disease (>10 cm) 13%, prior stem cell transplant 10%, high risk MIPI 49%.Median time on treatment was 9.2 months; 53% of patients remain on therapy. Median PFS was 13.9 months and DOR has not yet been reached. Responses increased with longer treatment: comparing to previous data described at ASH 2011, the CR rate increased from 16% to 39%, and the ORR increased from 69% to 75%.     

Clinical and microbiological characteristics of the infections in patients treated with rituximab for autoimmune and/or malignant hematological disorders

Introduction

Rituximab is commonly used for the treatment of hematological malignancies and autoimmune diseases. Despite a reputation for good tolerance, case-series and registries reported rituximab-related infections of variable severity including opportunistic infections. We aimed at describing the natural history of infectious events (IE) after treatment by rituximab providing clinical and microbiological features and outcome.

Efficacy and safety of rituximab in systemic sclerosis: French retrospective study and literature review

Objective

To describe safety and efficacy of rituximab in patients with systemic sclerosis.

14-bp ins/del polymorphism and +3142C>G SNP of the HLA-G gene have a significant impact on acute rejection after liver transplantation

Expression of human leukocyte antigen G (HLA-G) has been associated with increased graft survival and decreased rejection episodes. It has been described that the HLA-G 14-base pair (bp) insertion/deletion (ins/del) (rs66554220) and +3142C>G (rs1063320) gene polymorphisms modify the expression level of HLA-G. The aim of the study was to investigate whether these HLA-G polymorphisms have an impact on acute rejection after liver transplantation. In total, 146 liver transplant recipients (57 with acute rejection and 89 without acute rejection) and 99 corresponding liver donors were genotyped for both polymorphisms. In liver transplantation the 14-bp ins/ins and the +3142GG genotypes are more frequent in recipients without rejection compared to recipients with rejection (3.5% vs. 31.5%, p = <0.001; 12.3% vs. 41.6%, p = <0.001) demonstrating an association with protection from acute rejection. In contrast, in liver donors we could not reveal an association. We conclude that 14-bp ins/ins and +3142GG genotypes of HLA-G in liver transplant recipients are of importance for prediction of acute rejection after liver transplantation. Thus genotyping of liver recipients for both polymorphisms might be useful to stratify liver transplant recipients according to the risk of acute liver transplant rejection.     

Development of data-driven models for the flow cytometric crossmatch

HLA laboratories use virtual crossmatching (VXM) to predict recipient and donor compatibility using HLA antibody data and donor HLA type. Increasingly, transplant centers are utilizing VXM as the final compatibility determination prior to transplant. However, the VXM interpretation is based on HLA experience of individual transplant centers. This study developed data-driven algorithms that predicted flow cytometric crossmatch (FCXM) outcomes using HLA antibody mean fluorescent intensity (MFI) data and donor HLA typing without the need for human interpretation. Two algorithms were evaluated; an MFI Optimal-Threshold model and a Least-Squares-Fitting model. The Optimal-Threshold model correctly determined between 81.5% and 85.5% of T or B-cell responses. A class I antibody MFI threshold of 4670 was optimal for predicting T-cell response while an antibody MFI threshold of 6180 was optimal for predicting B-cell responses. HLA class I antibodies had a 1.47-fold greater influence on FCXM outcomes than class II antibodies. HLA-B antibodies influenced T and B-cell responses more than HLA-A or -C (-B > -A > -C). The Least-Squares-Fitting model increased accuracy to 94.1% and 88.8% for T and B-cell responses, respectively. The algorithms described here provide enhanced FCXM prediction and novel insights into the influence of specific HLA antibodies on the crossmatch outcome.     

In vitro methotrexate as a practical approach to selective allodepletion.

Graft-versus-host disease (GVHD) is a major cause of transplant-related morbidity and mortality in recipients of allogeneic hematopoietic stem cell transplantation. As GVHD is mediated predominantly by alloreactive donor T cells, selective allodepletion from the graft may alleviate GVHD, whereas potentially maintaining other advantages conferred by donor T cells, such as graft survival, antiviral immunity, and graft-versus-leukemia effect. In this study, we evaluated the ability of methotrexate, a clinically approved antimetabolite drug, to deplete alloreactive T cells in HLA-mismatched mixed lymphocyte reactions (MLR). We observed that methotrexate could inhibit the proliferation of alloreactive T cells in primary in vitro MLR. On reexposure of methotrexate-treated cells to the same allostimulus, a significant reduction in the alloreactive immune response was observed, whereas responses to third-party allostimuli and viral antigens were preserved. Thus, our results provide preclinical evidence that in vitro methotrexate treatment results in specific allodepletion and may be used as an effective agent for preventing GVHD.     

Diagnostic usefulness of dynamic changes of CMV-specific T-cell responses in predicting CMV infections in HCT recipients

BackgroundCMV-specific cell mediated immune responses before and after hematopoietic stem cell transplantation (HCT) can categorize patients as at high or low risk of CMV development.ObjectivesWe evaluated the usefulness of the CMV-specific T-cell ELISPOT assay for predicting the development of CMV infections after HCT in recipients with donor-positive and recipient-positive CMV serology (D+/R+ ).Study designCMV pp65 and IE1-specific ELISPOT assays were performed before HCT (D0), and at 30 (D30) and 90 (D90) days after HCT.ResultsOf the 84 HCT recipients with D+/R+, 42 (50%) developed ≥ 1 episode of CMV infection. Thirty-nine (64%) of 61 patients with Δ(D30-D0) pp65 < 42 developed CMV infections compared with 3 (14%) of 21 patients with Δ(D30-D0) pp65 ≥ 42 (P < 0.001). Twenty-three (74%) of 31 patients with Δ(D30-D0) IE1 < −4 developed CMV infections compared with 19 (37%) of 51 patients with Δ(D30-D0) IE1 ≥ −4 (P = 0.001). pp65 Δ(D30-D0) ≥ 42 had 93% sensitivity for ruling out subsequent CMV infection, and pp65 Δ(D30-D0) < 42 followed by Δ(D30-D0) IE1 < −4 had 100% specificity for ruling in the subsequent CMV infection. In addition, 10 (53%) of 19 patients with Δ(D90-D30) pp65 < 23 had relapsing CMV infections, compared with 3 (15%) of 20 patients with Δ(D90-D30) pp65 ≥ 23 (P = 0.02). The sensitivity and specificity of Δ(D90-D30) pp65 were 77% (95% CI 50–92) and 65% (95% CI, 46–81).ConclusionDynamic change in the CMV-specific ELISPOT assay before versus after HCT appears to predict the subsequent development of CMV infection and relapsing CMV infection.     

Limited impact of cytomegalovirus infection in the long-term outcome of renal and liver transplant

BackgroundThe strength of the assumed association of CMV and long term deleterious events in solid organ transplant recipients (SOT) is controversial.ObjectivesThe aim of the present study was to evaluate whether viral replication dynamics during CMV infection or CMV disease may correlate not only with graft dysfunction and survival, but also with other potentially related late events in a long-term followed cohort of kidney (KT) and liver (LT) transplant recipients.Study design162 SOT (104 kidney, 58 liver) at our institution (2003–2005) with survival over 180 days and a median follow-up of 71 months (9–86) were analyzed. Using a Cox proportional hazard model, CMV infection (including area under the curve of DNAemia[AUC]) and CMV disease in the first 180 days were evaluated as potential predictors of the following late events (>180 days): mortality, graft dysfunction (GD), graft loss (GL), cardiovascular events (CVE), malignant tumors (MT).ResultsCMV infection occurred in 59% and CMV disease in 8%. Late death occurred in 17%, GD in 45.6%, GL in 14.2%, CVE in 10.5% and MT in 9.9%. We found no significant association between the intensity or duration of CMV viremia (AUC, persistent viremia or untreated CMV viremia) or CMV disease and the development of evaluated late events. According multivariate analysis neither CMV infection (hazard ratio [HR] 2.18 95% CI 0.949–5 p = 0.066) nor CMV disease (HR: 1.72; 95% CI 0.59–5 p = 0.31) were significantly correlated with late mortality.ConclusionsOur data do not support that CMV infection or CMV disease contribute significantly to long-term deleterious events in SOT.     

Impact of TNF-α and LTα gene polymorphisms on genetic susceptibility in Indian SLE patients

The promoter polymorphisms of tumour necrosis factor-α (TNF-α) and intronic Lymphotoxin-α (LTα) have been implicated as genetic risk factors for systemic lupus erythematosus (SLE) in various ethnic groups. The aim of this study was to investigate an impact of TNF-α (?308G/A; 238G/A) and LTα (+252A/G) gene polymorphisms in disease susceptibility among Indian 200 SLE patients along with 201 healthy controls. The gene polymorphisms were studied by using direct DNA sequencing and Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) methods. Serum levels were measured by multiplex assay. Allelic frequencies of TNF-α ?308A (OR = 2.3, p = 0.0001, Pc = 0.0003) and LTα +252G (OR = 2.1, p < 0.0001, Pc < 0.001) were significantly higher in SLE patients. Frequency of haplotype-AGG was found to be higher in patients than controls (OR = 12.2, p = 0.0050). Serum levels of TNF-α and LTα also were found to be significantly higher in patients showing variant alleles. TNF-α ?308G/A + A/A genotypes (p < 0.01) and LTα +252 A/G + G/G genotypes (p < 0.02) were significantly associated with renal disorders and haematological manifestations. SLE patients with ?308G/A + A/A genotypes showed higher prevalence of anti-dsDNA antibodies (OR = 3.9, p = 0.0014, Pc = 0.0098) and anti-Sm antibodies (OR = 4.1, p = 0.0002, Pc = 0.0014). The present study suggests TNF-α ?308A and LTα +252G as risk alleles for disease susceptibility associated with higher serum levels of TNF-α and LTα and concomitant discrete clinical features among Indian SLE patients.