Circulating B Cells Display Differential Immune Regulatory Molecule Expression in Granulomatosis with Polyangiitis.

Granulomatosis with polyangiitis (GPA) is a B cell-mediated, relapsing, autoimmune disease. There is a need for novel therapeutic approaches and relapse markers to achieve durable remission. B cells express immune regulatory molecules that modulate their activation and maintain tolerance. While recent studies show dysregulation of these molecules in other autoimmune diseases, data on their expression in GPA are limited. This study aimed to map the expression of surface immune regulatory molecules on circulating B cell subsets in GPA and correlate their expression with clinical parameters. Immune regulatory molecule expression on circulating B cell subsets was comprehensively examined in active GPA (n=16), GPA in remission (n=16), and healthy controls (HCs, n=16) cross-sectionally using a 35-color B cell-specific spectral flow cytometry panel. Our supervised and unsupervised in-depth analysis revealed differential expression of inhibitory and stimulatory immune molecules on distinct B cell populations in GPA, with the most notable differences observed in active GPA. These differences include the upregulation of FcγRIIB on non-mature B cells, downregulation of CD21 and upregulation of CD86 on antigen-experienced B cells, and elevated CD22 expression on various populations. Additionally, we found a strong association between FcγRIIB, BTLA, and CD21 expression on specific B cell populations and disease activity in GPA. Together, these findings provide novel insights into the immune regulatory molecule expression profile of B cells in GPA, and could potentially form the foundation for new therapeutic approaches and disease monitoring markers.

Student engagement and learning outcomes: an empirical study applying a four-dimensional framework.

INTRODUCTION: This study applies Reeve's four-dimensional student engagement framework to a medical education context to elucidate the relationship between behavioral, emotional, cognitive, and agentic engagement and learning outcomes. Meanwhile, we categorize learning outcomes in knowledge and skills, and added taxonomies to the cognitive education objectives for the knowledge part, including memorization, comprehension, and application. METHODS: We used the China Medical Student Survey to investigate student engagement, and combined it with the Clinical Medicine Proficiency Test for Medical Schools results as a standardized measurement of learning outcomes. We performed multivariate regression analyses to delve into the effectiveness of different types of student engagement. Moreover, we evaluated the moderating roles of gender and the National College Entrance Examination (NCEE) within the relationships between student engagement and learning outcomes. RESULTS: We observed that emotional engagement is most effective in promoting learning outcomes in basic medical knowledge and basic clinical skills. Emotional engagement and cognitive engagement could effectively contribute to learning outcomes in all three aspects of basic medical knowledge. In contrast, behavioral and agentic engagement showed negative effects on learning outcomes. Besides, we found that the results of the NCEE played a positive moderating role. CONCLUSION: This study provides robust evidence for the effectiveness of emotional engagement and cognitive engagement in promoting learning outcomes. Whereas behavioral and agentic engagement may not be good predictors of learning outcomes in macro-level general competence tests. We suggest a combined effort by students and institutions to promote student engagement and bridge the distance between general competency tests and daily learning activities.

Development and evaluation of the Measure of the International Learning Environment Status (MILES) in international higher education.

The aim of this study was to develop and evaluate an instrument to assess international students' perceptions of the international learning environment called 'Measure of the International Learning Environment Status' (MILES). We based the development of the MILES on a solid theoretical framework from Moos by addressing three domains to measure the quality of the international learning environment, namely goal direction, relationships, and system change and system maintenance. We have designed and constructed the instrument in three steps. Firstly, we have collected items from relevant existing instruments and grouped them into the three domains via content analysis. Secondly, we applied a Delphi procedure involving international higher education experts from different stakeholder groups and from different cultural backgrounds to identify and reach consensus on the items comprehensively covering important elements of the international learning environment. Thirdly, we carried out an initial questionnaire evaluation. The final MILES consisted of 47 items with 13 in the first domain, 17 in the second and 17 in the third domain. The content of the domains was clearly in line with Moos theoretical framework and we interpreted the sets of items as goal direction, relationships, and supporting services, respectively. This study provides a comprehensive and systematically developed instrument for future research to better understand international students' perspectives towards the international learning environment that are supported by stakeholders from a range of cultures.

Influence of online collaborative learning on social network and academic performance of medical students: lessons learned from the COVID-19 pandemic.

Introduction: The social distancing restrictions due to the COVID-19 pandemic have changed students' learning environment and limited their social interactions. Therefore, the objective of this study was to investigate the influence of the social distancing restrictions on students' social networks, wellbeing, and academic performance. Methods: We performed a questionnaire study in which 102 students participated before and 167 students during the pandemic. They completed an online questionnaire about how they formed their five peer social networks (study-related support, collaboration, friendship, share information, and learn-from) out-of-class. We performed social network analysis to compare the sizes, structures, and compositions of students' five social networks before and during the pandemic, between first- and second-year students, and between international and domestic students. Additionally, we performed Kruskal-Wallis H test to compare students' academic performance before and during the pandemic. We performed thematic analysis to answers for two open-end questions in the online questionnaire to explore what difficulties students encountered during the COVID-19 pandemic and what support they needed. Results: The results showed that the size of students' social networks during the pandemic was significantly smaller than before the pandemic. Besides, the formation of social networks differed between first- and second-year students, and between domestic and international students. However, academic performance did not decline during the COVID-19 pandemic. Furthermore, we identified three key areas in which students experienced difficulties and needed support by thematic analysis: social connections and interactions, learning and studying, and physical and mental wellbeing. Conclusion: When institutions implement learning with social distancing, such as online learning, they need to consider changes in students' social networks and provide appropriate support.

Challenges to acquire similar learning outcomes across four parallel thematic learning communities in a medical undergraduate curriculum.

BACKGROUND: To train physicians who are able to meet the evolving requirements from health care, the University of Groningen Medical Center adopted in 2014 a new curriculum named G2020. This curriculum combines thematic learning communities with competency-based medical education and Problem-based learning. In the learning community program, different learning tasks were used to train general competencies. The challenge of this program was whether students acquire similar levels of learning outcomes within the different variations of the program. METHOD: We used the assessment results of three cohorts for the first two bachelor years. We used progress tests and written tests to analyze knowledge development, and the assessment results of seven competencies to analyze competence development. Concerning knowledge, we used the cumulative deviation method to compare progress tests and used the Kruskal-Wallis H test to compare written test scores between programs. Descriptive statistics are used to present all assessments of the students' competencies. RESULTS: We observed similarly high passing rates both for competency and knowledge assessments in all programs. However, we did observe some differences. The two programs that focused more on competencies development underperformed the other two programs on knowledge assessment but outperformed on competencies assessment. CONCLUSION: This study indicates that it is possible to train students in different learning programs within one curriculum while having similar learning outcomes. There are however some differences in obtained levels between the different programs. The new curriculum still needs to improve by balancing variations in the programs and comparability of assessments across the programs.

A social network perspective on peer relationship formation of medical undergraduates within large-scale learning communities.

INTRODUCTION: Students' formal networks, which are formed by a formal curriculum design, such as formally organized study groups within learning communities (LCs), may benefit students' interactions and learning. It is unclear how large-scale LCs contribute to the formation of different informal peer relationships, which refers to student self-organized out-of-class relationships. Two mechanisms can explain relationship formation in LCs. Propinquity within formal networks and homophily of students' characteristics (nationality, sex, academic performance) may promote students' peer relationships. This study explores to what extent the formation of students' informal networks was determined by their formal networks (LCs) while controlling for students' characteristics and which mechanisms play an important role. METHODS: With online surveys, data were collected about five informal networks (help-seeking, collaboration, information sharing, friendship, and learn-from) from 69 first- and 51 second- bachelor year medical students (2890 relationships). Students were divided into four LCs in the formal curriculum. We compared students' five informal network structures between first- and second-year students, domestic and international students, within and between formal networks. Besides, we used Quadratic Assignment Procedure (QAP) Regression Analysis in Ucinet to investigate the associations between students' informal and formal networks (LCs) and students' characteristics. RESULTS: Propinquity (in the same LC) plays a role since students have more informal connections within LCs than between LCs. Furthermore, it seems to play a greater role for second-year students than for first-year students. Homophily of nationality is important in informal networking since students are more likely to connect with others of similar nationalities. CONCLUSION: Students become more connected within the LC when they remain in the same LC for a longer period. Formal networks enhance the students' informal interactions within LCs but seem to restrict the interactions among students from other LCs. International students need support in order to integrate with domestic students in LCs.

Differences in IgG autoantibody Fab glycosylation across autoimmune diseases.

BACKGROUND: Increased prevalence of autoantibody Fab glycosylation has been demonstrated for several autoimmune diseases. OBJECTIVES: To study whether elevated Fab glycosylation is a common feature of autoimmunity, this study investigated Fab glycosylation levels on serum IgG and its subclasses for autoantibodies associated with a range of different B cell-mediated autoimmune diseases, including rheumatoid arthritis, myasthenia gravis subtypes, pemphigus vulgaris, antineutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, anti-glomerular basement membrane glomerulonephritis, thrombotic thrombocytopenic purpura, and Guillain-Barré syndrome. METHODS: The level of Fab glycosylated IgG antibodies was assessed by lectin affinity chromatography and autoantigen-specific immunoassays. RESULTS: In 6 of 10 autoantibody responses, in 5 of 8 diseases, the investigators found increased levels of Fab glycosylation on IgG autoantibodies that varied from 86% in rheumatoid arthritis to 26% in systemic lupus erythematosus. Elevated autoantibody Fab glycosylation was not restricted to IgG4, which is known to be prone to Fab glycosylation, but was also present in IgG1. When autoimmune diseases with a chronic disease course were compared with more acute autoimmune illnesses, increased Fab glycosylation was restricted to the chronic diseases. As a proxy for chronic autoantigen exposure, the investigators determined Fab glycosylation levels on antibodies to common latent herpes viruses, as well as to glycoprotein 120 in individuals who are chronically HIV-1-infected. Immunity to these viral antigens was not associated with increased Fab glycosylation levels, indicating that chronic antigen-stimulation as such does not lead to increased Fab glycosylation levels. CONCLUSIONS: These data indicate that in chronic but not acute B cell-mediated autoimmune diseases, disease-specific autoantibodies are enriched for Fab glycans.

Biological Characteristics of HLA-G and Its Role in Solid Organ Transplantation.

Organ transplantation is a lifesaving option for patients with advanced diseases. Rejection is regarded as one of the most severe risk factors post-transplantation. A molecule that contributes to immune tolerance and resisting rejection is human leukocyte antigen (HLA)-G, which belongs to the non-classical major histocompatibility complex class (MHC) I family. HLA-G was originally found to play a role during pregnancy to maintain immune tolerance between mother and child. It is expressed in the placenta and detected in several body fluids as soluble factor as well as different membrane isoforms on cells. Recent findings on HLA-G show that it can also play multifaceted roles during transplantation. This review will explain the general characteristics and biological function of HLA-G and summarize the views supporting the tolerogenic and other roles of HLA-G to better understand its role in solid organ transplantation (SOT) and its complications. Finally, we will discuss potential future research on the role of HLA-G in prevention, diagnosis, and treatment in SOT.

Changes in T and B cell subsets in end stage renal disease patients before and after kidney transplantation.

BACKGROUND: The incidence of kidney transplantation performed in elderly patients has increased steadily recently. Higher risk of infection and mortality, but lower rate of rejection, are reported in older kidney transplant patients. This study aims to analyze the effect of transplantation on aging of T and B cells in kidney transplant patients, with the emphasis on age and Cytomegalovirus (CMV) latency. RESULTS: We included 36 patients before and after (median 2.7 years) kidney transplantation and 27 age- and sex-matched healthy controls (HC). T and B cell subsets were measured by flow cytometry, with a focus on aged T cells (CD28-), and age associated B cells (ABCs, CD19 + CD21-CD11c+). Three years after transplantation a significant increase of total T cells among the lymphocytes was found compared to pre-transplantation and HC. Among the T cells CD4+ cells were decreased, especially naïve CD4+ cells and regulatory T cells. Total CD8+ cell proportions were increased, and proportions of naïve CD8+ cells were significantly decreased after transplantation, while CD8+ effector memory T cells re-expressing CD45RA were increased. CD28- T cells were significantly higher compared to HC after transplantation, especially in CMV seropositive patients. B cells were significantly decreased, while among B cells memory B cells and especially ABCs were increased after transplantation. CONCLUSIONS: After transplantation T and B cell subsets change towards more terminally differentiated memory cells compared to age-matched HC. Proportions of aged T cells and ABCs were associated with CMV serostatus.

B Cell Activation and Escape of Tolerance Checkpoints: Recent Insights from Studying Autoreactive B Cells.

Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of autoantigens to T cells. However, the mechanisms that underlie the development of autoreactive B cells are not well understood. Here, we review recent studies leveraging novel techniques to identify and characterize (auto)antigen-specific B cells. The insights gained from such studies pertaining to the mechanisms involved in the escape of tolerance checkpoints and the activation of autoreactive B cells are discussed. In addition, we briefly highlight potential therapeutic strategies to target and eliminate autoreactive B cells in autoimmune diseases.

Ageing of Immune System and Response to a Live-Attenuated Herpes Zoster Vaccine in Lung Transplant Candidates.

The mean age of lung transplant recipients has significantly increased in recent decades. Elderly recipients have a higher risk of developing herpes zoster (HZ), and they have in general a worse response to vaccination than younger persons do. We investigated the relationship between the humoral and cellular immune response to a live-attenuated HZ vaccine (Zostavax®, Merck Sharp and Dohme) and the frequencies of T and B cell subsets, especially aged cell subsets (CD28-T cells and age associated B cells, ABCs). In total, 37 patients awaiting lung transplantation received one dose of Zostavax®, and peripheral blood was collected before and within 6 months after vaccination. We observed a robust immune response after vaccination. The frequencies of CD28-T cells before vaccination had no impact on the subsequent immune response to HZ vaccination. However, a higher frequency of ABCs before vaccination correlated with a lower immune response especially regarding the cellular immune response. Cytomegalovirus seropositivity was associated with increased frequencies of CD28-T cells but not with frequencies of ABCs in the patients. In conclusion, increased levels of ABCs might disturb the cellular immune response to HZ vaccination, which could lower the efficacy of such vaccination in elderly transplant recipients.

Prophylactic vaccination with a live-attenuated herpes zoster vaccine in lung transplant candidates.

BACKGROUND: Herpes zoster (HZ) is caused by the reactivation of varicella-zoster virus (VZV). Patients with lung transplants are at high risk for HZ owing to their immunocompromised status and the need for lifelong immunosuppression. In this study, patients on the waiting list for lung transplantation were vaccinated by a live-attenuated HZ vaccine (Zostavax, Merck Sharp & Dohme), and the safety and immunogenicity of this vaccine were studied. METHODS: In total, 105 patients with end-stage pulmonary disease (ESPD) were enrolled (68 participants received 1 dose of Zostavax and 37 participants were enrolled as unvaccinated controls). Among them, 43 patients underwent lung transplantation and were followed up for further analysis. VZV immunoglobulin G antibody titers and VZV-specific cell-mediated immunity (CMI) on multiple time points before and after vaccination and before and after transplantation were measured. RESULTS: Immune response to Zostavax was higher in younger patients, highest within 3 months after vaccination, and not influenced by gender or type of ESPD. Age, cytomegalovirus serostatus, and immunity to VZV at baseline impacted the subsequent immune response to the vaccine. Short-term immunosuppressant treatment had strong effects on VZV CMI levels, which returned to a high level at 6 months after transplantation in vaccinated patients. Zostavax did not impact infection or rejection rate after transplantation. CONCLUSIONS: Zostavax was safe and induced a robust humoral and cellular response for patients awaiting lung transplantation regardless of the type of ESPD. Patients younger than the recommended vaccination age of over 50 years showed a strong response and could also benefit from pre-transplant immunization.

The influence of mixing international and domestic students on competency learning in small groups in undergraduate medical education.

BACKGROUND: Medical curricula are increasingly internationalized, with international students being mixed with domestic students in small group learning. Small group learning is known to foster competency learning in undergraduate medical education, specifically Communication, Collaboration, Leadership, and Professionalism. However, it is unclear what happens with the learning of competencies when international students are introduced in small groups. This study explores if students in international small groups master the competencies Collaboration, Leadership and Professionalism at the same level as students in domestic groups in an undergraduate medical curriculum. METHOD: In total, 1215 Students of three academic year cohorts participated in the study. They were divided into four learning communities (LCs), per year cohort, in which tutor groups were the main instructional format. The tutorials of two learning communities were taught in English, with a mix of international and Dutch students. The tutorials of the other two learning communities were taught in Dutch with almost all domestic students. Trained tutors assessed three competencies (Collaboration, Leadership, Professionalism) twice per semester, as 'Not-on-track', 'On-track', or 'Fast-on-track'. By using Chi-square tests, we compared students' competencies performance twice per semester between the four LCs in the first two undergraduate years. RESULTS: The passing rate ('On-track' plus 'Fast-on-track') for the minimum level of competencies did not differ between the mixed and domestic groups. However, students in the mixed groups received more excellent performance evaluations ('Fast-on-track') than the students in the homogenous groups of Dutch students. This higher performance was true for both international and Dutch students of the mixed groups. Prior knowledge, age, gender, and nationality did not explain this phenomenon. The effect could also not be explained by a bias of the tutors. CONCLUSION: When students are educated in mixed groups of international and Dutch students, they can obtain the same basic competency levels, no matter what mix of students is made. However, students in the mixed international groups outperformed the students in the homogenous Dutch groups in achieving excellent performance scores. Future research should explore if these findings can be explained from differences in motivation, perceived grading or social network interactions.

Immune response to varicella-zoster virus before and after renal transplantation.

BACKGROUND: Herpes zoster (HZ) risk is high in renal transplant recipients. Vaccination prior to transplantation may provide a useful strategy for the prevention of HZ in the posttranplantation period. However, it is not known whether immunity to varicella-zoster virus (VZV) is affected due to treatment surrounding transplantation. METHODS: Both humoral and cellular immunity to VZV were determined prior to and 2-3 years after renal transplantation in 60 adult patients, and 62 matched healthy controls. VZV-specific cellular immunity was measured by an interferon gamma (IFNγ) enzyme-linked immunospot (ELISpot) assay and by analyzing T-cell functionality using flowcytometry. VZV-IgG levels were measured using an in-house glycoprotein enzyme-linked immunosorbent assay (gpELISA). RESULTS: Using paired analysis, it was determined that numbers of IFNγ-producing cells did not change after transplantation, but were significantly lower in transplant recipients after transplantation than in controls (p = 0.028). Patients in whom the post-transplant period was complicated by rejection or any acute infection (excluding HZ) had a lower number of IFNγ-producing cells than patients who did not. VZV IgG levels did not differ from controls, but a significant decrease was observed after transplantation (p < 0.0001). CONCLUSIONS: VZV-specific cellular immunity, which is essential in the prevention of HZ, did not markedly change in patients following renal transplantation. This suggests that preventive vaccination before transplantation may be beneficial. Our results extend knowledge on VZV immunity after transplantation, vital when considering strategies for the prevention of HZ in these patients.

Repertoire Analysis of B-Cells Located in Striated Ducts of Salivary Glands of Patients With Sjögren's Syndrome.

A major complication of primary Sjögren's syndrome (pSS) is development of mucosa associated lymphoid tissue (MALT) B-cell lymphoma, particularly in salivary glands. These lymphomas express FcRL4 and are characteristically associated with lymphoepithelial lesions. Neoplastic B-cells may be derived from non-neoplastic glandular intraductal B-cells, also virtually all expressing FcRL4. A characteristic feature of MALT lymphomas is the production of rheumatoid factors (RFs), which are largely encoded by stereotypic immunoglobulin variable heavy chain (IGHV) sequences. The aim of this study was to examine whether there is a relationship between the intraductal and periductal B-cells and whether the intraductal B-cells are selected for RF. RNA was extracted from laser-microdissected infiltrated ductal areas and periductal infiltrates from frozen parotid gland tissue sections of 5 pSS patients. PCR amplified IGHV transcripts were cloned into pCR™4-TOPO vector and subsequently sequenced. Microdissected ducts yielded 96 unique IGHV sequences derived from intraductal B-cells, while 119 unique IGHV sequences were obtained from periductal infiltrates. No major difference in VH-gene usage was observed between intraductal and periductal B-cells. Nearly all (>90%) IGHV sequences derived from both intraductal and periductal B-cells were mutated. Clonal expansions as defined by shared VDJ rearrangements were also present among both intraductal and periductal B-cells: in total 32 clones were found, from which 12 were located within ducts, 15 in periductal areas, and five clones shared members in both areas. We observed 12 IGHV rearrangements encoding for RF sequences from which two were derived from intraductal B-cells and 10 from periductal B-cells. Nine RF sequences were part of a clone. Together these findings indicate that intraductal and periductal B-cells are closely related to each other. Intraductal B-cells are most likely derived from periductal B-cells. We did not obtain evidence that RF-specific B-cells are enriched within the striated ducts. We speculate that in principle any activated B-cell can enter the striated ducts from the periductal infiltrate, irrespective of its antigenic specificity. Within the ducts, these B-cells may receive additional activation and proliferation signals, to further expand at these sites and by acquisition of driver-mutations develop toward lymphoma.

The formation of mutated IgM memory B cells in rat splenic marginal zones is an antigen dependent process.

Previous studies in rodents have indicated that only a minor fraction of the immunoglobulin heavy chain variable region (IGHV-Cµ) transcripts carry somatic mutations and are considered memory B cells. This is in marked contrast to humans where nearly all marginal zone B (MZ-B) cells are mutated. Here we show in rats that the proportion of mutated IgM+ MZ-B cells varies significantly between the various IGHV genes analyzed, ranging from 27% mutated IGHV5 transcripts to 65% mutated IGHV4 transcripts. The observed data on mutated sequences in clonally-related B cells with a MZ-B cell or follicular B (FO-B) cell phenotype indicates that mutated IgM+ MZ-B and FO-B cells have a common origin. To further investigate the origin of mutated IgM+ MZ-B cells we determined whether mutations occurred in rearranged IGHV-Cµ transcripts using IGHV4 and IGHV5 genes from neonatal rat MZ-B cells and FO-B cells. We were not able to detect mutations in any of the IGHV4 and IGHV5 genes expressed by MZ-B cells or FO-B cells obtained from neonatal rat spleens. Germinal centres (GCs) are absent from neonatal rat spleen in the first few weeks of their life, and no mutations were found in any of the neonatal sequences, not even in the IGHV4 gene family which accumulates the highest number of mutated sequences (66%) in the adult rat. Therefore, these data do not support the notion that MZ-B cells in rats mutate their IGHV genes as part of their developmental program, but are consistent with the notion that mutated rat MZ-B cells require GCs for their generation. Our findings support that the splenic MZ of rats harbors a significant number of memory type IgM+ MZ-B cells with mutated IGHV genes and propose that these memory MZ-B cells are probably generated as a result of an antigen driven immune response in GCs, which still remains to be proven.

Herpes Zoster and Immunogenicity and Safety of Zoster Vaccines in Transplant Patients: A Narrative Review of the Literature.

This narrative review focuses on the herpes zoster (HZ) and its prevention in transplant patients. Varicella zoster virus (VZV) is highly contagious and distributed worldwide in humans. Primary VZV infection usually causes varicella and then establishes a lifelong latency in dorsal root ganglia. Reactivation of VZV leads to HZ and related complications such as postherpetic neuralgia. Age and decreased immunity against VZV are important risk factors for developing HZ. Transplant patients are at increased risk for developing HZ and related complications due to their immunocompromised status and the need for lifetime immunosuppression. Diagnosis of HZ in transplant patients is often clinically difficult, and VZV-specific antibodies should be determined by serologic testing to document prior exposure to VZV during their pre-transplant evaluation process. Although antiviral agents are available, vaccination should be recommended for preventing HZ in transplant patients considering their complicated condition and weak organ function. Currently, there are two licensed HZ vaccines, of which one is a live-attenuated vaccine and the other is a HZ subunit vaccine. Both vaccines have shown promising safety and efficacy in transplants patients and especially the subunit vaccine could be administered post-transplant since this vaccine does not contain any live virus. Larger studies are needed about safety and immunogenicity of HZ vaccines in transplant populations, and extra efforts are needed to increase vaccine usage according to guidelines.

Increased incidence of herpes zoster in patients on renal replacement therapy cannot be explained by intrinsic defects of cellular or humoral immunity to varicella-zoster virus.

BACKGROUND: Patients in need of long-term renal replacement therapy (RRT) are known to be at increased risk of herpes zoster, occurring when the latently present varicella-zoster virus (VZV) reactivates. In this study we investigated immunity to VZV in patients receiving RRT, with the aim of better understanding the mechanism behind the increased risk. METHODS: Patients treated for at least three months with hemodialysis or peritoneal dialysis, and matched healthy controls (HC) were included. Cellular immunity to varicella-zoster virus (VZV) was studied using an interferon-γ (IFNγ) enzyme-linked immunospot (ELISpot) assay, flow-cytometric analysis of cytokine production and a proliferation assay. Humoral immunity was determined by measuring immunoglobulin (Ig)G antibody levels to VZV using an in-house glycoprotein enzyme-linked immunosorbent assay (ELISA). Multiple regression was used to assess variables of influence on measures of cellular and humoral immunity to VZV in patients receiving RRT. RESULTS: Similar numbers of IFNγ spot-forming cells and levels of VZV-IgG were found in 97 patients and 89 HC. Age and transplantation history were negatively associated with cellular immunity (p = 0.001 and p = 0.012, respectively) while treatment modality, gender and urea levels were not. No variables were found to be associated with VZV-IgG levels. CONCLUSIONS: Increased incidence of herpes zoster in patients receiving RRT cannot be explained by intrinsic defects of cellular or humoral immunity to VZV as measured by the methods used in this study, although older age and previous transplantation were associated with decreased cellular immunity to VZV. Herpes zoster susceptibility might be caused by a diminished function of otherwise capable T cells in a uremic environment.

Heterogeneity of Memory Marginal Zone B Cells.

The marginal zone (MZ) is largely composed of a unique subpopulation of B cells, the so-called MZ-B cells. At a molecular level, memory B cells are characterized by the presence of somatically mutated IGV genes. The earliest studies in the rat have documented the presence of hapten-specific MZ-B cells after immunization in the MZ. This work later received experimental support demonstrating that the IGHV-Cµ transcripts expressed by phenotypically defined splenic MZ-B cells (defined as CD90negIgMhighIgDlow B cells) can carry somatic hypermutation. However, only a minor fraction (< 10%-20%) of these MZ-B cells is mutated and is considered to represent memory B cells. Memory B cells can either be class-switched (IgG, IgA, IgE), or non-class-switched (IgM) B cells. B cells in the MZ are a heterogeneous population of cells and both naïve MZ-B cells; class switched and unswitched memory MZ-B cells are present at this unique site in the spleen. Naïve MZ-B cells carry unmutated Ig genes, produce low-affinity IgM molecules and constitute a first line of defense against invading pathogens. Memory MZ-B cells express high-affinity Ig molecules, directed to (microbial) antigens that have been encountered. In this review, we report on the memory compartment of splenic MZ-B cells in the rat to provide insights into the origin and function of these memory MZ-B cells.

Review: What Is the Current Evidence for Disease Subsets in Giant Cell Arteritis?

Giant cell arteritis (GCA) is an autoimmune vasculitis affecting large and medium-sized arteries. Ample evidence indicates that GCA is a heterogeneous disease in terms of symptoms, immune pathology, and response to treatment. In the current review, we discuss the evidence for disease subsets in GCA. We describe clinical and immunologic characteristics that may impact the risk of cranial ischemic symptoms, relapse rates, and long-term glucocorticoid requirements in patients with GCA. In addition, we discuss both proven and putative immunologic targets for therapy in patients with GCA who have an unfavorable prognosis. Finally, we provide recommendations for further research on disease subsets in GCA.