Influence of infection on malaria-specific antibody dynamics in a cohort exposed to intense malaria transmission in northern Uganda.

The role of submicroscopic infections in modulating malaria antibody responses is poorly understood and requires longitudinal studies. A cohort of 249 children ≤5 years of age, 126 children between 6 and 10 years and 134 adults ≥20 years was recruited in an area of intense malaria transmission in Apac, Uganda and treated with artemether/lumefantrine at enrolment. Parasite carriage was determined at enrolment and after 6 and 16 weeks using microscopy and PCR. Antibody prevalence and titres to circumsporozoite protein, apical membrane antigen-1 (AMA-1), merozoite surface protein-1 (MSP-119 ), merozoite surface protein-2 (MSP-2) and Anopheles gambiae salivary gland protein 6 (gSG6) were determined by ELISA. Plasmodium falciparum infections were detected in 38·1% (194/509) of the individuals by microscopy and in 57·1% (284/493) of the individuals by PCR at enrolment. Antibody prevalence and titre against AMA-1, MSP-119 , MSP-2 and gSG6 were related to concurrent (sub-)microscopic parasitaemia. Responses were stable in children who were continuously infected with malaria parasites but declined in children who were never parasitaemic during the study or were not re-infected after treatment. These findings indicate that continued malaria infections are required to maintain antibody titres in an area of intense malaria transmission

Effects of psychological interventions and patients' affect on short-term quality of life in patients undergoing colorectal surgery

Psychological interventions can improve Quality of Life (QoL). Object of interest was if different psychological interventions influence short-term QoL after colonic resection for carcinoma. Furthermore, we wanted to see if there is a correlation between patients` preoperative affect and postoperative QoL. Sixty patients that underwent colorectal surgery were divided into three groups. Group one (n = 20) received Guided Imagery and group 2 (n = 22) Progressive Muscle Relaxation. The third group (Control, n = 18) had no intervention. Quality of Life (QoL) was measured using the EORTC QLQ-C30 and the Gastrointestinal Quality of life Index (GIQLI). Patients' affect was measured by the PANAS questionnaire. The higher the preoperative Negative Affect was, the lower were the scores for QoL on the 30th postoperative day. Patients' QoL was highest preoperatively and lowest on the third postoperative day. On the 30th postoperative day scores for QoL were almost as high as preoperative without difference between the three groups. Neither Guided Imagery nor Progressive Relaxation was influencing short-term QoL measured by the EORTC QLQ-C30 and the GIQLI questionnaire after colorectal surgery for cancer. Screening patients' with the PANAS questionnaire might help to identify individuals that are more likely to have a worse QoL postoperatively

Kinetics of Humoral and Memory B Cell Response Induced by the Plasmodium Falciparum 19-kilodalton Merozoite Surface Protein 1 in mice.

The 19-kDa carboxyl-terminal fragment of the merozoite surface protein-1 (MSP-1(19)) has been shown to regulate antibody (Ab)-mediated protective immunity to blood-stage malaria infection. But the serological memory to this antigen tends to be short-lived, and little is known of the mechanisms that regulate the formation of B cell memory to MSP-1(19) antigen. We studied the formation of B cell memory response after immunization with the recombinant 19-kDa Plasmodium falciparum merozoite surface protein 1 (PfMSP-1(19)). Immunization with PfMSP-1(19) resulted in delayed increase in germinal center (GC) B cell numbers. This poor GC reaction correlated with short-lived PfMSP-1(19)-specific antibodies in serum and the short life of PfMSP-1(19)-specific plasma cells and memory B cells (MBCs) in spleen and bone marrow. PfMSP-1(19)-specific MBCs were capable of producing antigen (Ag)-specific Ab-secreting cell (ASC) responses that were short-lived following challenge immunization of the immune mice with antigen or transgenic Plasmodium berghei parasite expressing PfMSP-1(19) in place of native P. berghei MSP-1(19) at 8 weeks after the last immunization or following adoptive transfer into naive hosts. However, no protection was achieved in PfMSP-1(19) immune mice or recipient mice with PfMSP-1(19)-specific MBCs following challenge with transgenic P. berghei. Our findings suggest that PfMSP-1(19)-specific IgG production by short-lived plasma cells combined with the poor ability of the PfMSP-1(19)-induced MBCs to maintain the anamnestic IgG responses failed to contribute to protection against infection

Evidence for gene–gene epistatic interactions among susceptibility loci for systemic lupus erythematosus

Objective Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to test for gene–gene interactions in a number of known lupus susceptibility loci. Methods Eighteen single‐nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2‐step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing. Results We detected and confirmed gene–gene interactions between the HLA region and CTLA4 , IRF5 , and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 × 10 −5 [FDR ≤0.05], P for multifactor dimensionality reduction = 5.9 × 10 −45 ). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively ( P = 0.0028 and P = 0.0047, respectively). Conclusion We provide evidence for gene–gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90353/1/33354_ftp.pd

Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity

Objectives. B cells drive the production of autoreactive antibodysecreting cells, ASCs, in autoimmune diseases such as Systemic Lupus Erythematosus, SLE, and Sjogren, s syndrome, causing long-, term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI-, could deplete ASCs in autoimmune conditions in vivo and in vitro. Methods. Use of a BMI-, inhibitor in both mouse and human autoimmune settings was investigated. Lyn, mice, a model of SLE, were treated with the BMI-, small molecule inhibitor PTC-, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast-based assay was established, and the impact of PTC-, on ASCs derived from Sjogren, s syndrome, patients was evaluated. Results. BMI-, inhibition significantly decreased splenic and bone marrow ASCs in Lyn, mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG, immune complexes and anti-DNA IgG. PTC-, was also efficacious in reducing ex vivo plasma cell survival from both Sjogren, s syndrome, patients and age-matched healthy donors. Conclusion. These data provide evidence that inhibiting BMI-, can deplete ASC in a variety of contexts and thus BMI-, is a viable therapeutic target for antibody-mediated autoimmune diseases.Jack Polmear, Lauren Hailes, Moshe Olshansky, Maureen Rischmueller, Elan L'Estrange-Stranieri, Anne L Fletcher, Margaret L Hibbs, Vanessa L Bryant, Kim L Good-Jacobso

Recent advances in cortical visual impairment

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66022/1/j.1469-8749.2001.tb00387.x.pd

Homeostatic apoptosis prevents competition-induced atrophy in follicular B cells

While the intrinsic apoptosis pathway is thought to play a central role in shaping the B cell lineage, its precise role in mature B cell homeostasis remains elusive. Using mice in which mature B cells are unable to undergo apoptotic cell death, we show that apoptosis constrains follicular B (FoB) cell lifespan but plays no role in marginal zone B (MZB) cell homeostasis. In these mice, FoB cells accumulate abnormally. This intensifies intercellular competition for BAFF, resulting in a contraction of the MZB cell compartment, and reducing the growth, trafficking, and fitness of FoB cells. Diminished BAFF signaling dampens the non-canonical NF-κB pathway, undermining FoB cell growth despite the concurrent triggering of a protective p53 response. Thus, MZB and FoB cells exhibit a differential requirement for the intrinsic apoptosis pathway. Homeostatic apoptosis constrains the size of the FoB cell compartment, thereby preventing competition-induced FoB cell atrophy.Stéphane Chappaz, Kate McArthur, Liam Kealy, Charity W. Law, Maximilien Tailler, Rachael M. Lane ... et al

Type I interferon induces CXCL13 to support ectopic germinal center formation.

Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection-induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation