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Summary: The occurrence of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) has been reported since the coronavirus disease 2019 (COVID-19) vaccination, but whether there is a causal relationship or coincidence remains to be verified. We combined the term COVID-19 vaccination with each word of AAV to search for case reports and case series published in PubMed, EMBASE, and Web of Science databases before 13 March 2023. A total of 56 patients who developed AAV after COVID-19 vaccination were identified from 44 research centers. Of the 56 subjects, 43 (76.7%) were vaccinated with the mRNA vaccine, followed by the adenovirus vaccine (14.3%) and inactivated vaccine (9.0%) (P = 0.015). Compared with relapsed AAV, new-onset AAV patients had at least two other diseases previously (P < 0.001). Twenty-five (44.6%) patients presented symptoms after the first injection, and the medium onset time was 12 (1–77) days, while Twenty-eight (50.0%) patients developed symptoms after the second dose, and their medium period was 14 (1–60) days. Forty-four (78.5%) patients achieved remission after immunosuppressive agents, plasma exchange, and hemodialysis. One (1.8%) patient died from progressive respiratory failure and nine (16.1%) did not recover, leaving five patients permanently dependent on hemodialysis. Pathogenic ANCA may be activated by enhanced immune response and epitope spreading after COVID-19 vaccination and induced the occurrence of AAV, especially in genetically susceptible populations. The occurrence of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) has been reported since the coronavirus disease 2019 (COVID-19) vaccination, but whether there is a causal relationship or coincidence remains to be verified. This paper explores the occurrence of AAV, especially in genetically susceptible populations. [ABSTRACT FROM AUTHOR]

Summary: Adjuvants, as the name indicates, are adjoined material aimed to assist in functioning as when added to vaccines they are meant to boost the effect and strongly stimulate the immune system. The response of the immune system can be unpredictable, and the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was developed to address possible adverse reactions of an autoimmune and inflammatory type that may be caused by adjuvants. While ASIA, as a syndrome, was coined and defined in 2011; reports describing patients with vague and nonspecific clinical symptoms following vaccinations appeared much earlier. In other words, ASIA came to define, arrange, and unite the variety of symptoms, related to autoimmunity, caused not by the vaccine itself, rather by the adjuvant part of the vaccine such as aluminum, among others. Accordingly, the introduction of ASIA enabled better understanding, proper diagnosis, and early treatment of the disorder. Furthermore, ASIA was shown to be associated with almost all body systems and various rheumatic and autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, and systemic sclerosis. In addition, the correlation between COVID-19 and ASIA was noticed during the pandemic. In this review, we summarized the reported effects of adjuvants and medical literature before and after ASIA was defined, the several ways ASIA can manifest and impact different systems of the body, and the incidences of ASIA during the COVID-19 pandemic. It is important to clarify, that vaccines are among, if not the, most effective means of fighting infectious diseases however, we believe that vaccines manufacturing is not above criticism, particularly when it comes to added substances possessing a risk of side effects. Adjuvants such as aluminum, mineral oils, and silicone are added to vaccines in order to trigger a stronger immune response. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was introduced in 2011 to address nonspecific symptoms and disorders appearing following vaccinations, which in fact were reported by many papers before the introduction of the syndrome. During the pandemic of COVID-19, a correlation between ASIA, COVID-19, and COVID-19 vaccines has been reported. [ABSTRACT FROM AUTHOR]

Summary: The immune system plays a critical role in protecting the host against infection but is subject to numerous levels of control that are necessary to prevent pathological, tissue-damaging responses. Inappropriate inflammatory immune responses to self-antigens, innocuous commensal microorganisms, or environmental antigens can lead to chronic, debilitating, and degenerative diseases. Regulatory T cells have an essential, non-redundant, and dominant function in preventing pathological immune responses, as shown by the development of systemic fatal autoimmunity in humans and animals with a genetic deficiency in regulatory T cells. In addition to controlling immune responses, there is a growing understanding that regulatory T cells also contribute directly to tissue homeostasis by promoting tissue regeneration and repair. For these reasons, the prospect of enhancing regulatory T-cell numbers and/or function in patients represents an appealing therapeutic opportunity with potential applications in many diseases, including some where the pathological role of the immune system has only recently been recognized. Approaches to enhance regulatory T cells are now starting to be explored in clinical studies in humans. This review series brings together papers highlighting the Treg-enhancing approaches that are most advanced clinically and examples of therapeutic opportunities based on our growing understanding of regulatory T-cell functions. [ABSTRACT FROM AUTHOR]

Healthy pregnancy is accompanied by various immunological and metabolic adaptations. Maternal obesity has been implicated in adverse pregnancy outcomes such as miscarriage, preeclampsia, and gestational diabetes mellitus (GDM), while posing a risk to the neonate. There is a lack of knowledge surrounding obesity and the maternal immune system. The objective of this study was to consider if immunological changes in pregnancy are influenced by maternal obesity. Peripheral blood was collected from fasted GDM-negative pregnant women at 26–28 weeks of gestation. Analysis was done using immunoassay, flow cytometry, bioenergetics analysis, and cell culture. The plasma profile was significantly altered with increasing BMI, specifically leptin (r = 0.7635), MCP-1 (r = 0.3024), and IL-6 (r = 0.4985). Circulating leukocyte populations were also affected with changes in the relative abundance of intermediate monocytes (r = –0.2394), CD4:CD8 T-cell ratios (r = 0.2789), and NKT cells (r = –0.2842). Monocytes analysed in more detail revealed elevated CCR2 expression and decreased mitochondrial content with increased BMI. However, LPS-stimulated cytokine production and bioenergetic profile of PBMCs were not affected by maternal BMI. The Th profile skews towards Th17 with increasing BMI; Th2 (r = –0.3202) and Th9 (r = –0.3205) cells were diminished in maternal obesity, and CytoStim™-stimulation exacerbates IL-6 (r = 0.4166), IL-17A (r = 0.2753), IL-17F (r = 0.2973), and IL-22 (r = 0.2257) production with BMI, while decreasing IL-4 (r = –0.2806). Maternal obesity during pregnancy creates an inflammatory microenvironment. Successful pregnancy requires Th2-biased responses yet increasing maternal BMI favours a Th17 response that could be detrimental to pregnancy. Further research should investigate key populations of cells identified here to further understand the immunological challenges that beset pregnant women with obesity. This paper describes the effect of pre-pregnancy body mass index (BMI) on the immune profile of peripheral blood from GDM-negative, pregnant women at 28 weeks of gestation. It reveals a phenotype of systemic inflammation, monocyte activation and altered Th1/Th2/Th17 balance [ABSTRACT FROM AUTHOR]

Understanding the T-cell response to SARS-CoV-2 is key in patients who lack antibody production. We demonstrate the applicability of a functional assay to measure the T-cell response in a cohort of patients with immunodeficiency. T-cell responses to COVID are now linked to improved outcomes. This paper demonstrates a method to robustly test responses for routine diagnostic use in healthy controls and those unable to make a detectable antibody response due to underlying immune deficiency (primary or acquired). [ABSTRACT FROM AUTHOR]

Summary: Ageing dramatically affects number and function of both innate and adaptive arms of immune system, particularly T cell subsets, contributing to reduced vaccination efficacy, decreased resistance to infections and increased prevalence of cancer in older people. In the present paper, we analysed the age‐related changes in the absolute number of lymphocytes in 214 Sicilian subjects, and in the percentages of T and natural killer (NK) cells in a subcohort of donors. We compared these results with the immunophenotype of the oldest living Italian supercentenarian (aged 111 years). The results were also sorted by gender. The correlation between number/percentage of cells and age in all individuals. and separately in males and females, was examined using a simple linear regression analysis. We did not record the increase in the rate of inversion of the CD4/CD8 ratio, frequently reported as being associated with ageing in literature. Our observation was the direct consequence of a flat average trend of CD4+ and CD8+ T cell percentages in ageing donors, even when gender differences were included. Our results also suggest that CD4+ and CD8+ subsets are not affected equally by age comparing females with males, and we speculated that gender may affect the response to cytomegalovirus (CMV) infection. The supercentenarian showed a unique immunophenotypic signature regarding the relative percentages of her T cell subsets, with CD4+ and CD8+ T cell percentages and CD4+ naive T cell values in line with those recorded for the octogenarian subjects. This suggests that the supercentenarian has a naive 'younger' T cell profile comparable to that of a >80‐year‐old female. [ABSTRACT FROM AUTHOR]

Summary: The factors responsible for the spectrum of coronavirus 19 (COVID‐19) disease severity and the genesis and nature of protective immunity against COVID‐19 remain elusive. Multiple studies have investigated the immune responses to COVID‐19 in various populations, including those without evidence of COVID‐19 infection. Information regarding innate and adaptive immune responses to the novel severe respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has evolved rapidly. Data are accumulating defining disease phenotypes that aid in rational and informed development of new therapeutic approaches for the treatment of patients infected with SARS‐CoV‐2 and the development of novel vaccines. In this paper, data on important innate immune responses are summarized, including cytokines, specifically interleukin (IL)‐6 and complement, and potential treatments are explored. Adaptive immune responses and derivative therapeutics such as monoclonal antibodies directed at spike proteins are also examined. Finally, data on real‐time assessments of adaptive immune responses are explored, which include CD4+/CD8+ T cells, natural killer (NK) T cells, memory B cells and T follicular cells with specificities for COVID‐19 peptides in infected and normal individuals. Data of two novel vaccines have been released, both showing > 95% efficacy in preventing SARS‐CoV‐2 infection. Analysis of humoral and cellular responses to the vaccines will determine the robustness and durability of protection. In addition, long‐term assessment of SARS‐CoV‐2 memory B and T cell‐mediated immune responses in patients recovering from an infection or those with cross‐reactive immunological memory will help to define risk for future SARS‐CoV infections. Finally, patients recovering from SARS‐CoV‐2 infection may experience prolonged immune activation probably due to T cell exhaustion. This will be an important new frontier for study. This review summarizes published data on the relevant innate and adaptive immune responses to SARS‐CoV‐2. Data characterizing innate and adaptive immune responses have rapidly led to informed therapeutic interventions, including vaccine development and recognition of dysfunctional immune responses that are likely responsible for post‐COVID‐19 autoimmunity. [ABSTRACT FROM AUTHOR]

Summary: Allergic sensitization is commonly assessed in patients by performing the skin prick test (SPT) or determining specific immunoglobulin (IgE) levels in blood samples with the ImmunoCAP™ assay, which measures each allergen and sample separately. This paper explores the possibility to investigate respiratory allergies with a high throughput method, the Meso Scale Discovery (MSD) multiplex immunoassay, measuring IgE levels in low volumes of blood. The MSD multiplex immunoassay, developed and optimized with standards and allergens from Radim Diagnostics, was validated against the SPT and the ImmunoCAP assay. For 18 adults (15 respiratory allergy patients and three controls), blood collection and the SPT were performed within the same hour. Pearson correlations and Bland–Altman analysis showed high comparability of the MSD multiplex immunoassay with the SPT and the ImmunoCAP assay, except for house dust mite. The sensitivity of the MSD multiplexed assay was ≥78% for most allergens compared to the SPT and ImmunoCAP assay. Additionally, the specificity of the MSD multiplex immunoassay was ≥ 87% – the majority showing 100% specificity. Only the rye allergen had a low specificity when compared to the SPT, probably due to cross‐reactivity. The reproducibility of the MSD multiplex immunoassay, assessed as intra‐ and interassay reproducibility and biological variability between different sampling moments, showed significantly high correlations (r = 0·943–1) for all tested subjects (apart from subject 13; r = 0·65–0·99). The MSD multiplex immunoassay is a reliable method to detect specific IgE levels against respiratory allergens in a multiplexed and high‐throughput manner, using blood samples as small as from a finger prick. [ABSTRACT FROM AUTHOR]

Summary: Isolated decreased serum‐immunoglobulin (Ig)M has been associated with severe and/or recurrent infections, atopy and autoimmunity. However, the reported high prevalence of clinical problems in IgM‐deficient patients may reflect the skewed tertiary centre population studied so far. Also, many papers on IgM deficiency have included patients with more abnormalities than simply IgM‐deficiency. We studied truly selective primary IgM deficiency according to the diagnostic criteria of the European Society for Immunodeficiencies (ESID) (true sIgMdef) by reviewing the literature (261 patients with primary decreased serum‐IgM in 46 papers) and analysing retrospectively all patients with decreased serum‐IgM in a large teaching hospital in 's‐Hertogenbosch, the Netherlands [1 July 2005–23 March 2016; n = 8049 IgM < 0·4 g/l; n = 2064 solitary (IgG+IgA normal/IgM < age‐matched reference)]. A total of 359 of 2064 (17%) cases from our cohort had primary isolated decreased serum‐IgM, proven persistent in 45 of 359 (13%) cases; their medical charts were reviewed. Our main finding is that true sIgMdef is probably very rare. Only six of 261 (2%) literature cases and three of 45 (7%) cases from our cohort fulfilled the ESID criteria completely; 63 of 261 (24%) literature cases also had other immunological abnormalities and fulfilled the criteria for unclassified antibody deficiencies (unPAD) instead. The diagnosis was often uncertain (possible sIgMdef): data on IgG subclasses and/or vaccination responses were lacking in 192 of 261 (74%) literature cases and 42 of 45 (93%) cases from our cohort. Our results also illustrate the clinical challenge of determining the relevance of a serum sample with decreased IgM; a larger cohort of true sIgMdef patients is needed to explore fully its clinical consequences. The ESID online Registry would be a useful tool for this. [ABSTRACT FROM AUTHOR]

Summary: Neuroimmunology as a separate discipline has its roots in the fields of neurology, neuroscience and immunology. Early studies of the brain by Golgi and Cajal, the detailed clinical and neuropathology studies of Charcot and Thompson's seminal paper on graft acceptance in the central nervous system, kindled a now rapidly expanding research area, with the aim of understanding pathological mechanisms of inflammatory components of neurological disorders. While neuroimmunologists originally focused on classical neuroinflammatory disorders, such as multiple sclerosis and infections, there is strong evidence to suggest that the immune response contributes to genetic white matter disorders, epilepsy, neurodegenerative diseases, neuropsychiatric disorders, peripheral nervous system and neuro‐oncological conditions, as well as ageing. Technological advances have greatly aided our knowledge of how the immune system influences the nervous system during development and ageing, and how such responses contribute to disease as well as regeneration and repair. Here, we highlight historical aspects and milestones in the field of neuroimmunology and discuss the paradigm shifts that have helped provide novel insights into disease mechanisms. We propose future perspectives including molecular biological studies and experimental models that may have the potential to push many areas of neuroimmunology. Such an understanding of neuroimmunology will open up new avenues for therapeutic approaches to manipulate neuroinflammation. [ABSTRACT FROM AUTHOR]

The importance of B cells and their critical role in the maintenance of health through generation of antibody-mediated immune protection is undoubted. However, the differences between the responses of B cells with different surface phenotypes in different microanatomical sites as well as diversity in B-cell function outside antibody production are just starting to be acknowledged and resolved. This series of reviews and papers that focus on human B cells will be divided across two issues. The first part of the review series in this issue captures practical information on identifying B-cell subtypes in blood in health and inflammatory diseases as well as describing aspects of B-cell diversity depending on immunoglobulin isotype and microanatomical context. It also explores our current understanding of cytokine production by human B cells and the effect of obesity on the B-cell response. The last review in this issue will reflect on the important lessons learned from the SARS-CoV-2 pandemic; in particular the role of antigen availability and its effect on B-cell memory and antibody production. [ABSTRACT FROM AUTHOR]

Summary: Lung disease due to nontuberculous mycobacteria (NTM) occurs with disproportionate frequency in postmenopausal women with a unique phenotype and without clinically apparent predisposing factors. Dubbed 'Lady Windermere syndrome', the phenotype includes low body mass index (BMI), tall stature and higher than normal prevalence of scoliosis, pectus excavatum and mitral valve prolapse. Although the pathomechanism for susceptibility to NTM lung disease in these patients remains uncertain, it is likely to be multi‐factorial. A role for the immunomodulatory consequences of oestrogen deficiency and altered adipokine production has been postulated. Altered levels of adipokines and dehydroepiandrosterone have been demonstrated in patients with NTM lung disease. Case reports of NTM lung disease in patients with hypopituitarism support the possibility that altered endocrine function influences disease susceptibility. This paper catalogues the evidence for immunomodulatory consequences of predicted endocrine changes in Lady Windermere syndrome, with emphasis on the immune response to NTM. Collectively, the data warrant further exploration of an endocrine link to disease susceptibility in Lady Windermere syndrome. Lady Windermere syndrome is a phenotype of nontuberculous mycobacterial lung disease characterized by female sex, postmenopausal status and slender body habitus. This review article explores potential modulation of anti‐mycobacterial immunity by hormone changes as a mediator of disease susceptibility in this syndrome. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) early secreted protein antigen 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) are among candidate vaccines against tuberculosis (TB). Results of experimental animal models show that these antigens are associated with induction of strong T cell immunity [interferon (IFN)-γ production], while others report that these proteins as virulent factors involved in pathogenicity of Mtb infection. However, the role of ESAT-6/CFP-10 during natural Mtb infections in humans has not been established. In this paper we present results of a longitudinal study from an Mtb-infected human population from an endemic setting. Whole blood assay was used to determine levels of IFN-γ, tumour necrosis factor (TNF)-α and interleukin (IL)-10 against rESAT-6/CFP-10 in TB patients, household contacts and community controls. The levels of IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 at baseline were significantly higher in patients and community controls than in household contacts. In patients, no significant difference was observed in the level of these cytokines before and after chemotherapy whereas, in contacts, the level of these cytokines increased significantly and progressively over time. The study shows that the levels of IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 are depressed during Mtb infection or exposure but are elevated during clinical TB. Our findings from a study of naturally infected human population suggest that IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 are markers for clinical TB but not for protective immunity. [ABSTRACT FROM AUTHOR]

It is just over 5 years since Clinical and Experimental Immunology came under the direction of a new team of Editors and made a concerted effort to refresh its approach to promoting clinical and applied immunology through its pages. There were two major objectives: to foster papers in a field which, at the time, we loosely termed 'translational immunology'; and to create a forum for the presentation and discussion of immunology that is relevant to clinicians operating in this space. So, how are we doing with these endeavours? This brief paper aims to summarize some of the key learning points and successes and highlight areas in which translational gaps remain. [ABSTRACT FROM AUTHOR]

Primary infection with varicella zoster virus (VZV), an exclusively human neurotrophic alphaherpsesvirus, results in varicella, known more commonly as chickenpox. Like other alphaherpesviruses, VZV establishes latency in the sensory ganglia and can reactivate to cause herpes zoster (also known as shingles), a painful and debilitating disease, especially in elderly and immunocompromised individuals. The overall incidence of herpes zoster in Europe and the United States is three per 1000 people, but increases sharply after 60 years of age to 10 per 1000 people. Zostavax® is a vaccine approved by the Federal Drug Administration for the prevention of herpes zoster. Unfortunately, this vaccine reduces the incidence of disease by only 51% and the incidence of post-herpetic neuralgia by 66·5% when administered to those aged 60 and older. Moreover, it is contraindicated for individuals who are immunocompromised or receiving immunosuppressant treatments, although they are at higher risk for herpes zoster compared to immune-competent older individuals. This paper reviews VZV pathogenesis, host responses and current vaccines available to prevent herpes zoster. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a hepatic presentation of obesity and metabolic syndrome. MicroRNA 26a (Mir-26a) has been reported to play functions in cellular differentiation, cell growth, cell apoptosis and metastasis. A recent paper indicated that Mir-26a regulated insulin sensitivity and metabolism of glucose and lipids. However, the role of Mir-26a in NAFLD still needs to be investigated further. In our current study, vectors encoding pre-Mir-26a (LV-26a) and an empty lentiviral vector (LV-Con) delivered approximately 2 × 107 transforming units of recombinant lentivirus were injected into mice through the tail vein. LV-26a-infected mice were protected from glucose dysmetabolism and showed markedly decreased total liver weight, hepatic triglyceride deposition and serum alanine transaminase (ALT) concentration when compared with LV-Con-treated mice. LV-26a-treated mice also exhibited decreased infiltration of immune cells in the liver - something attributed to reduce infiltration of T cell receptor (TCR)-γδ+, granulocyte-differentiation antigen-1 (Gr-1)+ cells and CD11b+ cells. Next, we found that Mir-26a inhibited the expression of interleukin (IL)−17 and IL-6 in vivo and in vitro. Furthermore, the decreased expression of IL-17 in the liver tissue induced by Mir-26a was abrogated completely by IL-6 overexpression. The decreased total liver weight, hepatic triglyceride deposition and serum ALT concentration induced by Mir-26a was also abrogated completely by IL-6 over-expression. In conclusion, the Mir-26a-IL-6-IL-17 axis regulates the development of NAFLD in a murine model. [ABSTRACT FROM AUTHOR]

Antibodies recognizing infliximab (IFX) may develop in a proportion of treated patients, leading to loss of response or hypersensitivity reactions (HRs). T cell response to IFX has been poorly investigated. This paper was addressed to detect IFX-specific T cells in treated patients with inflammatory diseases developing, or not, anti-drug antibodies (ADA) and to correlate the presence of specific T cells with the clinical outcomes of the treatment. A co-culture system of IFX-loaded dendritic cells and purified autologous CD4+ T cells was used to detect memory T cells in 32 ADA+ and 39 ADA- IFX-treated patients and control groups. The cytokine profile of IFX-specific T cells was also studied in culture supernatants. IFX-specific cell proliferation was detected mainly in cells from ADA+ patients, irrespective of their different diseases. HR patients displayed higher T cell proliferation than non-responder and tolerant patients. A mixed [interferon (IFN)-γ, interleukin (IL)-13, IL-10] cytokine profile was shown in cells from ADA+ patients, while IL-10 was the most frequently detected cytokine in the supernatants of cultures from ADA- patients. Immunoglobulin (Ig)E+ADA+ patients with previous HRs exhibited a more pronounced type 2 profile than IgE-ADA+ patients. This work provides evidence that IFX-specific circulating T cells are detectable mainly in ADA+ patients with HRs, regardless of their disease. The IFX-induced cytokine pattern partially correlates with the ADA isotype. [ABSTRACT FROM AUTHOR]

In this paper we have extended our earlier studies of the action of increasing Factor I concentration on complement activation by using a soluble activator, lipopolysaccharide (LPS) endotoxin, and using human erythrocytes as a source of CR1 - the co-factor needed for the final clip of iC3b to C3dg by Factor I. Using this more physiological system, the results show that we can predict that a quite modest increase in Factor I concentration - 22 μg/ml of extra Factor I - will convert the activity of the highest risk sera to those of the lowest risk. Preliminary experiments have been performed with erythrocytes allotyped for CR1 number. While we have not been able to perform an adequate study of their co-factor activities in our assays, preliminary experiments suggest that when Factor I levels are increased the difference produced by different allotypes of red cells is largely overcome. This suggests that in patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with eculizumab, additional treatment with Factor I may be very useful in reducing the need for blood transfusion. We have also explored the age-related allele frequency for the two polymorphisms of Factor H and the polymorphism of C3. In our population, unlike the 1975 study, we found no age variation in the allele frequency in these polymorphisms. This may, however, reflect that the Cambridge BioResource volunteers do not include many very young or very elderly patients, and in general comprise a population not greatly at risk of death from infectious disease. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) develops when there are insufficient insulinproducing beta cells to maintain glucose homeostasis. The prevailing view has been that T1D is caused by immune-mediated destruction of the pancreatic beta cells. However, several recent papers have challenged the long-standing paradigm describing T1D as a tissue-specific autoimmune disease. These authors have highlighted the gaps in our knowledge and understanding of the aetiology of T1D in humans. Here we review the evidence and argue the case for the autoimmune basis of human T1D. In particular, recent analysis of human islet-infiltrating T cells brings important new evidence to this question. Further data in support of the autoimmune basis of T1D from many fields, including genetics, experimental therapies and immunology, is discussed. Finally, we highlight some of the persistent questions relating to the pathogenesis of human type 1 diabetes that remain to be answered. [ABSTRACT FROM AUTHOR]

There is an increasing range of therapeutic options for primary antibody-deficient patients who require replacement immunoglobulin. These include intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), rapid push SCIg and most recently recombinant human hyaluronidase-facilitated SCIg (fSCIg). Advantages of fSCIg include fewer needle punctures, longer infusion intervals and an improved adverse effect profile relative to IVIg. Limited real-life experience exists concerning the practical aspects of switching or starting patients on fSCIg. We describe the first 14 patients who have been treated with fSCIg at the Immunodeficiency Centre for Wales (ICW), representing more than 6 patient-years of experience. The regimen was well tolerated, with high levels of satisfaction and no increase in training requirement, including for a treatment-naive patient. Two patients discontinued fSCIg due to pain and swelling at the infusion site, and one paused therapy following post-infusion migraines. Ultrasound imaging of paired conventional and facilitated SCIg demonstrated clear differences in subcutaneous space distribution associated with a 10-fold increase in rate and volume delivery with fSCIg. Patient profiles for those choosing fSCIg fell into two main categories: those experiencing clinical problems with their current treatment and those seeking greater convenience and flexibility. When introducing fSCIg, consideration of the type and programming of infusion pump, needle gauge and length, infusion site, up-dosing schedule, home training and patient information are important, as these may differ from conventional SCIg. This paper provides guidance on practical aspects of the administration, training and outcomes to help inform decision-making for this new treatment modality. [ABSTRACT FROM AUTHOR]

A better understanding about the mechanisms involved in the pathogenesis of type 2 diabetes mellitus (T2D) showed that inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin (IL)-1β play a pivotal role, mirroring data largely reported in rheumatoid arthritis (RA). IL-1β is produced mainly by monocytes (MO), and hyperglycaemia may be able to modulate, in the cytoplasm of these cells, the assembly of a nucleotide-binding domain and leucine-rich repeat containing family pyrin (NLRP3)-inflammosome, a cytosolic multi-protein platform where the inactive pro-IL-1β is cleaved into active form, via caspase-1 activity. In this paper, we evaluated the production of IL-1 β and TNF, in peripheral blood MO of patients affected by RA or T2D or both diseases, in order to understand if an alteration of the glucose metabolism may influence their proinflammatory status. Our data showed, after 24 h of incubation with different glucose concentrations, a significantly increased production of IL-1β and TNF in all evaluated groups when compared with healthy controls. However, a significant increase of IL-1β secretion by T2D/RA was observed when compared with other groups. The analysis of relative mRNA expression confirmed these data. After 24 h of incubation with different concentrations of glucose, our results showed a significant increase in NLRP3 expression. In this work, an increased production of IL-1β by MO obtained from patients affected by both RA and T2D via NLRP3-inflammasome activation may suggest a potential IL-1β targeted therapy in these patients. [ABSTRACT FROM AUTHOR]

The article presents information on the papers discussed in the 5th International Antineutrophil Cytoplasmic Antibodies (ANCA) Workshop. One of the papers discusses the involvement of ANCA-activated neutrophils in the pathogenesis of inflammation and endothelial injury in systemic vasculitis. The researchers devised a system to examine the effects of ANCA and neutrophils on the permeability of cultured endothelial cell monolayers. Human umbilical vein endothelial cell monolayers were established on tissue culture well inserts coated with FITC, Monolayers were incubated with control or ANCA-containing sera alone, unstimulated neutrophils alone, or various sera together with neutrophils.

In a previous paper (Gleichmann, van Elven & van der Veen, 1982), it had been reported that, in contrast to lupus like autoantibodies such as anti-DNA, autoantibodies to mouse thyroglobulin (MTg) were not detectable in serum of F1 mice suffering from a lupus like graft versus host disease (GVHD) (GVH F1). In the present paper, possible explanations for this restricted autoantibody formation during the potent allogeneic stimulation were investigated. The main question was whether the natural level of circulating MTg was too low to induce the formation of anti-MTg antibodies in GVH F1 mice. Existence, in the F1 mice studied, of B cells capable of producing anti-MTg antibodies was demonstrated by injection of lipopolysaccharide (LPS) and exogeneous MTg. However, MTg injected into various F1 mice at the onset of the GVH reaction (GVHR) failed to overcome the lack of antibody formation to MTg even though the GVHR led to a severe lupus like disease. Furthermore, adult thymectomy (ATx) of either the recipients, the donors, or both also did not break tolerance to MTg during the GVHR, irrespective of administration of exogeneous MTg. Thus, neither intravenous injection of MTg nor ATx, designed to remove T suppressor (Ts) cells, is adequate to enable an autoantibody response to MTg during lupus like GVHD. Hence, the non-specific T cell help that causes lupus like GVHD seems to be intrinsically insufficient to trigger the Tg reactive B cells. We suggest that globular proteins, such as Tg, require specific T cell help. In the presence of only non-specific T help, self-antigens such as DNA seem to be more apt than globular proteins to provide an effective signal 1 to the corresponding autoreactive B cells. [ABSTRACT FROM AUTHOR]

Studies have been conducted to characterize M. leprae antigens from purified Ieprae bacilli derived from infected armadillos. First, the proteins of the mycobacterial extracts were fractionated by SDS-PAGE. Subsequently, the proteins in the gel were electrophoretically transferred on a strip of nitrocellulose paper by the technique of 'electrophoretic blotting'. The separated bacterial protein bands, thus immobilized on the nitrocellulose paper were made to react immunologically with sera from the lepromatous patients, infected armadillo sera and other experimental mycobacterial antisera. It was observed that a majority of M. leprae proteins contained antigenic determinants also present on proteins of BCG. In addition, only two specific antigen bands of 33KD and 12KD were conspicuously detected by the patients' sera and the infected armadillo sera. These substances were further identified as polysaccharides or glycoproteins since they could only be stained by Schiff's reagent or alcian blue. Only 12KD glycoprotein band reacted with concanavalin A, whereas wheat germ agglutinin (WGA) did not show any reaction with them. These 33KD and 12KD glycoprotein antigens were found to lose their antigenicity after pepsin treatment and can be considered as glycoproteins. Further, radiolabelling experiments showed that 12KD antigen underwent radioiodination under usual conditions, but 33KD glycoprotein Failed to be similarly radiolabelled. It is suggested that these protein antigens have M. Ieprae specific determinants on a cross-reacting component. [ABSTRACT FROM AUTHOR]

Different studies over the last decade have linked the B cell-attracting chemokine CXC ligand 13 ( CXCL13) to the autoimmune disease systemic lupus erythematosus ( SLE). A pathogenetic role of this chemokine for disease manifestation in SLE was described initially in mouse models for SLE. Mechanisms of CXCL13 actions were also identified in SLE patients. Moreover, various clinical studies have identified CXCL13 serum levels as a useful biomarker in patients with SLE of different ethnicities for disease activity. In addition, CXCL13 seems to be a promising marker for the diagnosis of lupus nephritis, one of the most severe complications of SLE. However, its exact place within the mechanisms that lead to SLE remains to be defined. Further research is needed to resolve more details of the pathomechanism and the signalling pathway of CXCL13 in SLE. Blocking CXCL13 or the signal pathways of CXCL13 is seen as a promising therapeutic approach for SLE and will be addressed in the near future. This review summarizes all papers that linked CXCL13 to SLE and highlights its importance in the pathogenesis and diagnosis of SLE [ABSTRACT FROM AUTHOR]

This paper provides a thorough overview of the current advances in diagnosis and therapy of myasthenia gravis ( MG). Nowadays the term 'myasthenia gravis' includes heterogeneous autoimmune diseases, with a postsynaptic defect of neuromuscular transmission as the common feature. Myasthenia gravis should be classified according to the antibody specificity [acetylcholine, muscle-specific receptor tyrosine kinase ( MuSK), low-density lipoprotein receptor-related protein 4 ( LRP4), seronegative], thymus histology (thymitis, thymoma, atrophy), age at onset (in children; aged less than or more than 50 years) and type of course (ocular or generalized). With optimal treatment, the prognosis is good in terms of daily functions, quality of life and survival. Symptomatic treatment with acetylcholine esterase inhibition is usually combined with immunosuppression. Azathioprine still remains the first choice for long-term immunosuppressive therapy. Alternative immunosuppressive options to azathioprine include cyclosporin, cyclophosphamide, methotrexate, mycophenolate mofetil and tacrolimus. Rituximab is a promising new drug for severe generalized MG. Emerging therapy options include belimumab, eculizumab and the granulocyte- macrophage colony-stimulating factor. One pilot study on etanercept has given disappointing results. For decades, thymectomy has been performed in younger adults to improve non-paraneoplastic MG. However, controlled prospective studies on the suspected benefit of this surgical procedure are still lacking. In acute exacerbations, including myasthenic crisis, intravenous immunoglobulin, plasmapheresis and immunoadsorption are similarly effective. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes are immune-mediated erroneous attacks on the central or peripheral nervous systems, or both, directed originally against the tumour itself. They have been known for more than 40 years, but recently the discovery of new subgroups of paraneoplastic encephalitis syndromes with a remarkably good response to immune therapy has ignited new clinical and scientific interest. Knowledge of these subgroups and their associated autoantibodies is important in therapeutic decision-making. However, the abundance of new autoantibodies and syndromes can be confusing. This review paper summarizes current knowledge and new developments in the field of paraneoplastic neurological syndromes, their classification, pathophysiology and treatment. [ABSTRACT FROM AUTHOR]

Common variable immune deficiency ( CVID) is the most frequent symptomatic primary immune deficiency in adults. The standard of care is intravenous immunoglobulin ( IVIG) or subcutaneous immunoglobulin (sc IG) therapy. The cause of CVID is currently unknown, and there is no universally accepted definition of CVID. This creates problems in determining which patients will benefit from IVIG/sc IG treatment. In this paper, we review the difficulties with the commonly used European Society of Immune Deficiencies ( ESID) and the Pan American Group for Immune Deficiency ( PAGID) definition of CVID. We propose new criteria for the diagnosis of CVID, which are based on recent scientific discoveries. Improved diagnostic precision will assist with treatment decisions including IVIG/sc IG replacement. We suggest that asymptomatic patients with mild hypogammaglobulinaemia are termed hypogammaglobulinaemia of uncertain significance ( HGUS). These patients require long-term follow-up, as some will evolve into CVID. [ABSTRACT FROM AUTHOR]

A previous paper has reported that blockade of NKG2 D was effective in protecting allograft in murine models of cardiac transplantation, but the mechanism of NKG2 D blockade on attenuated cardiac allograft vasculopathy ( CAV) was still unknown. In our current study, we found that wild-type recipients treated with anti- NKG2 D monoclonal antibody (m Ab) plus cytotoxic T lymphocyte antigen ( CTLA)-4-immunoglobulin ( I)g showed prolonged allograft survivals (>90 days, P < 0·001) significantly and attenuated CAV. These in-vivo results correlated with reduced alloantibody production, low expression of interleukin ( IL)-17 and IL-6, while infiltration of regulatory T cells increased. IL-6 administration induced shorter allograft survival and higher CAV grade in CTLA-4- Ig plus anti- NKG2 D m Ab-treated recipients, whereas IL-17 had no significant effect on allograft survival and CAV grade in CTLA-4- Ig plus anti- NKG2 D m Ab-treated recipients. Furthermore, the prolonged allograft survival induced by NKG2 D blockade was abrogated partially with depletion of regulatory T cells. In conclusion, blockade of NKG2 D combined with CTLA-4- Ig attenuated CAV and this effect was associated with lower alloantibody production, inhibited IL-6 expression and enhanced expansion of regulatory T cells. [ABSTRACT FROM AUTHOR]

In this paper we provide a detailed description of an experimental method for investigating the induction and resolution of recall immune response to antigen in humans in vivo. This involves the injection of tuberculin purified protein derivative ( PPD) into the skin, followed by inducing suction blisters at the site of injection, from which leucocytes and cytokines that are involved in the response can be isolated and characterized. Using this technique we found that although the majority of CD4+ T cells in the skin that are present early in the response express cutaneous lymphocyte antigen ( CLA), the expression of this marker is reduced significantly in later phases. This may enable these cells to leave the skin during immune resolution. Furthermore, interleukin ( IL)-2 production can be detected both in CD4+ T cells and also in the blister fluid at the peak of the response at day 7, indicating that mediators found in the blister fluid are representative of the cytokine microenvironment in vivo. Finally, we found that older humans have defective ability to respond to cutaneous PPD challenge, but this does not reflect a global immune deficit as they have similar numbers of circulating functional PPD-specific CD4+ T cells as young subjects. The use of the blister technology enables further characterization of the skin specific defect in older humans and also general mechanisms that govern immune regulation in vivo. [ABSTRACT FROM AUTHOR]

We have shown previously that donor-derived splenocytes can replace recipients' bone marrow and induce donor-specific tolerance ( DST). We have also shown the usefulness of the chimeric state for the induction of DST. Further analysis of mixed splenocytes chimera, especially the role of each T cells in mixed splenocytes chimera, is indispensable issue for its clinical use. A chimeric state has been shown to achieve long-term survival in major histocompatibility complex ( MHC)-mismatched grafts. The donor-derived splenocytes can replace recipients' bone marrow and induce DST. The long-term survival of allogeneic skin grafts was achieved without immunosuppressants. In this study we show the role of each T cell type in a splenocyte mixed chimera. This review provides a short summary of our original work, adding some supplemental interpretations. Mixed chimerism is thus considered an attractive approach for the induction of DST without the use of immunosuppressants. In this paper, we summarize some of the findings on mixed splenocyte chimeras and review mixed chimerism in recent organ transplantation. [ABSTRACT FROM AUTHOR]

In Argentina, more than 3 million people suffer from asthma, with numbers rising. When asthma patients acquire viral infections which, in turn, trigger the asthmatic response, they may develop subsequent bacterial infections, mainly by Streptococcus (S.) pneumoniae. This encapsulated Gram+ bacterium has been considered historically a T cell-independent antigen. Nevertheless, several papers describe the role of T cells in the immune response to S. pneumoniae. We evaluated the response to S. pneumoniae and compared it to the response to Mycobacterium (M.) tuberculosis, a different type of bacterium that requires a T helper type 1 ( Th1) response, in cells from atopic asthmatic children, to compare parameters for the same individual under exacerbation and in a stable situation whenever possible. We studied asthma patients and a control group of age-matched children, evaluating cell populations, activation markers and cytokine production by flow cytometry, and cytokine concentration in serum and cell culture supernatants by enzyme-linked immunosorbent assay ( ELISA). No differences were observed in γδ T cells for the same patient in either situation, and a tendency to lower percentages of CD4+ CD25hi T cells was observed under stability. A significantly lower production of tumour necrosis factor ( TNF)-α and a significantly higher production of interleukin ( IL)-5 was observed in asthma patients compared to healthy individuals, but no differences could be observed for IL-4, IL-13 or IL-10. A greater early activation response against M. tuberculosis, compared to S. pneumoniae, was observed in the asthmatic patients' cells. This may contribute to explaining why these patients frequently acquire infections caused by the latter bacterium and not the former. [ABSTRACT FROM AUTHOR]

In a recent workshop organized by the JDRF focused on the 'Identification and Utilization of Robust Biomarkers in Type1 Diabetes', leaders in the field of type 1 diabetes ( T1D)/autoimmunity and assay technology came together from academia, government and industry to assess the current state of the field, evaluate available resources/technologies and identify gaps that need to be filled for moving the field of T1D research forward. The highlights of this workshop are discussed in this paper, as well as the proposal for a larger, planned consortium effort, incorporating a JDRF Biomarker Core, to foster collaboration and accelerate progress in this critically needed area of T1D research. [ABSTRACT FROM AUTHOR]

The dendritic cell ( DC) lineage is remarkably heterogeneous. It has been postulated that specialized DC subsets have evolved in order to select and support the multitude of possible T cell differentiation pathways. However, defining the function of individual DC subsets has proven remarkably difficult, and DC subset control of key T cell fates such as tolerance, T helper cell commitment and regulatory T cell induction is still not well understood. While the difficulty in assigning unique functions to particular DC subsets may be due to sharing of functions, it may also reflect a lack of appropriate physiological in-vivo models for studying DC function. In this paper we review the limitations associated with many of the current DC models and highlight some of the underlying difficulties involved in studying the function of murine DC subsets. [ABSTRACT FROM AUTHOR]

Bacille Calmette-Guérin (BCG), developed a century ago, is the only licensed tuberculosis (TB) vaccine in use to date. The protective efficacy of BCG against TB varies with no apparent protection in some population, and mechanisms of its immune protection is poorly known, and yet BCG is the most widely used vaccine, with more than 4 billion BCG-vaccinated children globally. BCG is probably the only licensed vaccine currently in use believed to mediate immune protection through the production of interferon (IFN)-γ by CD4 T cells, which in turn activates macrophages to kill Mycobacterium tuberculosis ( Mtb). Currently, a number of new TB candidate vaccines are in different phases of clinical trial. The majority of these new vaccines are either recombinant forms of BCG or prime boosters of BCG (rBCG) and their immunogenicity is tested using BCG as a benchmark by measuring specific IFN-γ produced by CD4+ T cells as a protective immune marker. However, some recent studies that examined mechanisms of immune protection of BCG in animals and humans have reported a lack of correlation between IFN-γ production by CD4 cells and BCG-induced immune protection. These studies point to the fact that there is a missing link in our understanding of TB immunology. Conversely, there is emerging evidence that other T cell subsets (gammadelta, γδ), CD8+ T cells and natural killer (NK) cells may play a vital role in immune protection against Mtb infection and BCG-induced immune protection. γδ T cells and NK cells, which were considered to be part of the innate immunity in the past, have been shown to develop immunological memory upon re-encounter with the same pathogen. In this paper, the controversy over the role of IFN-γ as a marker for protective immunity against TB, and emerging data on the role of γδ T cells, CD8+ and NK cells in TB immunology, will be presented. [ABSTRACT FROM AUTHOR]

Summary For many years, tonsillectomy has been used routinely in children to treat chronic or recurrent acute tonsillitis. Palatine tonsils are secondary lymphoid organs and the major barrier protecting the digestive and respiratory tracts from potential invasive microorganisms. They have been used as sources of lymphoid tissue; however, despite the hundreds of papers published on tonsillectomy, no studies addressing the functionality of the CD4+ and CD8+ T cells from chronically infected tonsils have yet been published. The aim of this study was to analyse the functionality of the CD4+ and CD8+ T cells with respect to tonsillar tissue. We used an affordable approach to measure the frequency of antigen-specific CD4+ T cells, the direct ex-vivo cytotoxicity of CD8+ T cells, memory T cell phenotype, cytokine profile and DC phenotype. Our results demonstrate that CD4+ and CD8+ T cells from tonsillar tissue are totally functional, as shown by their ability to produce cytokines, to degranulate and to differentiate into effector-memory T cells. [ABSTRACT FROM AUTHOR]

Summary Death rules our lives. In this short paper, we summarize new insights into molecular mechanisms of neurodegeneration. Here we review the most important processes of cell death: apoptosis and oncosis. We focus on autophagy, which is pivotal for neuronal homeostasis, in the context of neurodegeneration, infection and immunity. Its dysfunction has been linked to several neurodegenerative diseases such as Parkinson's, Huntington's and Alzheimer's diseases. Our understanding is still incomplete, but may highlight attractive new avenues for the development of treatment strategies to combat neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Summary It has long been known that tumour necrosis factor (TNF) /TNFRSF1A signalling is involved in the pathophysiology of multiple sclerosis (MS). Different genetic and clinical findings over the last few years have generated renewed interest in this relationship. This paper provides an update on these recent findings. Genome-wide association studies have identified the R92Q mutation in the TNFRSF1A gene as a genetic risk factor for MS (odds ratio 1·6). This allele, which is also common in the general population and in other inflammatory conditions, therefore only implies a modest risk for MS and provides yet another piece of the puzzle that defines the multiple genetic risk factors for this disease. TNFRSF1A mutations have been associated with an autoinflammatory disease known as TNF receptor-associated periodic syndrome (TRAPS). Clinical observations have identified a group of MS patients carrying the R92Q mutation who have additional TRAPS symptoms. Hypothetically, the co-existence of MS and TRAPS or a co-morbidity relationship between the two could be mediated by this mutation. The TNFRSF1A R92Q mutation behaves as a genetic risk factor for MS and other inflammatory diseases, including TRAPS. Nevertheless, this mutation does not appear to be a severity marker of the disease, neither modifying the clinical progression of MS nor its therapeutic response. An alteration in TNF/ TNFRS1A signalling may increase proinflammatory signals; the final clinical phenotype may possibly be determined by other genetic or environmental modifying factors that have not yet been identified. [ABSTRACT FROM AUTHOR]

Anti-citrullinated protein/peptide antibodies (ACPA) are a hallmark of rheumatoid arthritis (RA) and can be measured using different citrullinated substrates. In this paper we describe a new viral citrullinated peptide - VCP2 - derived from the Epstein-Barr virus-encoded protein EBNA-2 and analyse its potential as substrate for ACPA detection. Analysing sera from 100 RA patients and 306 controls, anti-VCP2 immunoglobulin (Ig)G were found in 66% of RA sera, IgM in 46% and IgA in 39%, compared with less than 3% of control sera. Anti-VCP2 IgG was associated with erosive arthritis, the presence of rheumatoid factor and anti-VCP1 and anti-cyclic citrullinated peptide (CCP) antibodies. Anti-VCP2 antibodies were detected in 1% and anti-VCP1 antibodies in 4% of CCP-negative RA sera; conversely, 3% of the VCP-negative sera were CCP-positive. Taken together, these data suggest that VCP2 could offer a valuable tool for ACPA detection. Inhibition assays showed that two non-overlapping epitopes - a citrulline-glycine stretch shared between VCP1 and VCP2 and the N-terminal portion of the VCP2 sequence - were targeted by anti-VCP2 antibodies. Moreover, in some RA sera that tested positive in CCP and VCP2 assays, preincubation with VCP2 inhibited binding to CCP, whereas in other sera the binding was unaffected. Thus, the reactivity with more than one ACPA substrate might be due in some RA patients to antibody populations with different specificities, and in others to cross-reactive antibody populations. Finally, affinity-purified anti-VCP2 antibodies immunoprecipitated deiminated Epstein-Barr virus nuclear antigen (EBNA-2) from an EBNA-2-transfected cell line, suggesting that viral sequences may be involved in the generation of the ACPA response. [ABSTRACT FROM AUTHOR]

The introduction of cyclophosphamide (CyP) as a treatment for Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) has been among the most significant contributions in vasculitis. Prior to the introduction of CyP, WG was a uniformly fatal disease, with mortality occurring within 5-12 months from pulmonary or renal failure or from infection due to glucocorticoids. In 1973 Fauci and Wolff, at the National Institutes of Health, published their experience with a regimen that combined CyP and prednisone in which disease remission was seen in 12 of 14 patients. Long-term experience with CyP provided even greater evidence for its efficacy in which an 80% survival rate was seen, with 91% of patients having significant improvement and 75% achieving complete remission. However, extended follow-up also demonstrated that disease relapse occurred in at least 50% of patients and that 42% experienced morbidity solely as a result of treatment. These observations showed that while CyP was life-saving, it did not prevent relapse and was associated with significant toxicity such that safer means to induce remission needed to be pursued. Strategies aimed at reducing exposure to CyP have included intermittent administration, induction-maintenance regimens and avoidance of CyP for non-severe disease. Recently, the introduction of rituximab has raised important questions regarding the place of CyP in the treatment of WG/MPA. This paper examines the past, present and future of CyP through a review of its efficacy and safety. [ABSTRACT FROM AUTHOR]

For treatment of several malignancies, transplantation of allogeneic haematopoietic stem cells (HSCT) derived from bone marrow or peripheral blood has been used as a therapeutic procedure for decades. In the past, HSCT has been suggested as a treatment option for infection with the human immunodeficiency virus type 1 (HIV-1), but these attempts were mostly unsuccessful. Today, after the introduction of an active anti-retroviral therapy, the lifetime expectancy of HIV-infected patients has improved substantially, but nevertheless the incidence rate of malignancies in these patients has increased considerably. Therefore, it can be assumed that there will be a rising necessity for HIV-1-infected patients with malignancies for allogeneic HSCT. At the same time, there is increasing interest in treatment methods which might target the HIV-1 reservoir more effectively, and the question has been raised as to whether allogeneic HSCT could be linked to such strategies. In this paper the data of more than 25 years experience with allogeneic HSCT in patients with HIV-1 are reviewed and analysed. [ABSTRACT FROM AUTHOR]

T cell lines with defined cytokine profiles are an invaluable tool for assessing the control of immune responses both in vitro and in vivo. Production of such cell lines can be complex and time-consuming. Here we present a powerful technique to assay the cytokines produced by T cells activated polyclonally or with specific antigens. This paper presents a detailed methodology for the identification and isolation of cytokine-producing T cells activated with the artificial superantigen, CytoStim, or viral and fungal antigens. These cells can be analysed for different cytokines simultaneously, or cultured further to rapidly establish T cell lines making known cytokine types. We highlight the enumeration, isolation and phenotype of interleukin-17-producing T cells, and the rapid generation of virus-specific Th1 T cell lines. [ABSTRACT FROM AUTHOR]

The considerable clinical heterogeneity of patients with common variable immunodeficiency disorders (CVID) shares some similarity with bone-marrow failure disorders such as Diamond-Blackfan anaemia (DBA) and Shwachman-Diamond syndrome (SDS), now recognized as defects in ribosome biogenesis or ribosomopathies. The recognition of a patient with DBA who subsequently developed CVID lends support to our previous finding of a heterozygous mutation in the SBDS gene of SBDS in another CVID patient, suggesting that ribosome biogenesis defects are responsible for a subset of CVID. Genetic defects in the ribosomal translational machinery responsible for various bone marrow failure syndromes are recognized readily when they manifest in children, but diagnosing these in adults presenting with complex phenotypes and hypogammaglobulinaemia can be a challenge. In this perspective paper, we discuss our clinical experience in CVID patients with ribosomopathies, and review the immunological abnormalities in other conditions associated with ribosomal dysfunction. With genetic testing available for various bone marrow failure syndromes, our hypothesis that ribosomal abnormalities may be present in patients with CVID could be proved in future studies by testing for mutations in specific ribosomal genes. New knowledge might then be translated into novel therapeutic strategies for patients in this group of immunodeficiency disorders. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4+ T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8+ and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes. [ABSTRACT FROM AUTHOR]

The cellular changes during ageing are incompletely understood yet immune system dysfunction is implicated in the age-related decline in health. The acquired immune system shows a functional decline in ability to respond to new pathogens whereas serum levels of cytokines are elevated with age. Despite these age-associated increases in circulating cytokines, the function of aged macrophages is decreased. Pathogen-associated molecular pattern receptors such as Toll-like receptors (TLRs) are vital in the response of macrophages to pathological stimuli. Here we review the evidence for defective TLR signalling in normal ageing. Gene transcription, protein expression and cell surface expression of members of the TLR family of receptors and co-effector molecules do not show a consistent age-dependent change across model systems. However, there is evidence for impaired downstream signalling events, including inhibition of positive and activation of negative modulators of TLR induced signalling events. In this paper we hypothesize that despite a poor inflammatory response via TLR activation, the ineffective clearance of pathogens by macrophages increases the duration of their activation and contributes to perpetuation of inflammatory responses and ageing. [ABSTRACT FROM AUTHOR]

Gut inflammation is characterized by mucosal recruitment of activated cells from both the innate and adaptive immune systems. In addition to immune cells, inflammation in the gut is associated with an alteration in enteric endocrine cells and various biologically active compounds produced by these cells. Although the change in enteric endocrine cells or their products is considered to be important in regulating gut physiology (motility and secretion), it is not clear whether the change plays any role in immune activation and in the regulation of gut inflammation. Due to the strategic location of enteric endocrine cells in gut mucosa, these gut hormones may play an important role in immune activation and promotion of inflammation in the gut. This review addresses the research on the interface between immune and endocrine systems in gastrointestinal (GI) pathophysiology, specifically in the context of two major products of enteric endocrine systems, namely serotonin (5-hydroxytryptamine: 5-HT) and chromogranins (Cgs), in relation to immune activation and generation of inflammation. The studies reviewed in this paper demonstrate that 5-HT activates the immune cells to produce proinflammatory mediators and by manipulating the 5-HT system it is possible to modulate gut inflammation. In the case of Cgs the scenario is more complex, as this hormone has been shown to play both proinflammatory and anti-inflammatory functions. It is also possible that interaction between 5-HT and Cgs may play a role in the modulation of immune and inflammatory responses. In addition to enhancing our understanding of immunoendocrine interaction in the gut, the data generated from the these studies may have implications in understanding the role of gut hormone in the pathogenesis of both GI and non-GI inflammatory diseases which may lead ultimately to improved therapeutic strategies in inflammatory disorders. [ABSTRACT FROM AUTHOR]

Like many other complex human disorders of unknown aetiology, autoimmune-mediated type 1 diabetes may ultimately be controlled via a therapeutic approach that combines multiple agents, each with differing modes of action. The numerous advantages of such a strategy include the ability to minimize toxicities and realize synergies to enhance and prolong efficacy. The recognition that combinations might offer far-reaching benefits, at a time when few single agents have yet proved themselves in well-powered trials, represents a significant challenge to our ability to conceive and implement rational treatment designs. As a first step in this process, the Immune Tolerance Network, in collaboration with the Juvenile Diabetes Research Foundation, convened a Type 1 Diabetes Combination Therapy Assessment Group, the recommendations of which are discussed in this Perspective paper. [ABSTRACT FROM AUTHOR]

In industrialized nations and high-income regions of the world, the decline of infectious diseases is paralleled by an increase in allergic, autoimmune and chronic inflammatory diseases (AACID). Changes in lifestyle in westernized societies, which impact individually and collectively on intestinal microbiota, may – at least in part – account for the AACID pandemic. Many disease genes that contribute to AACID encode pattern recognition and signalling molecules in barrier-associated cells. Interactions between gene products and environmental factors depend highly upon the host's state of maturation, the composition of the skin and gut microflora, and exposure to pollutants, antibiotics and nutrients. Inflammatory stress responses, if regulated appropriately, ensure immunity, health and relative longevity; when they are dysregulated, they can no longer be terminated appropriately and thus precipitate AACID. The 99th Dahlem Conference brought together experts of various disciplines (genetics, evolution biology, molecular biology, structural biology, cell biology, immunology, microbiology, nutrition science, epidemiology and clinical medicine) to discuss the multi-faceted relationships between infection, immunity and inflammation in barrier organs and the development of AACID. In Clinical and Experimental Immunology we are presenting a compilation of background papers that formed the basis of discussions. Controversial viewpoints and gaps in current knowledge were examined and new concepts for prevention and treatment of CID were formulated. [ABSTRACT FROM AUTHOR]

There is increasing evidence that the functional state of the immune system at birth is predictive of the kinetics of immune maturation in early infancy. Moreover, this maturation process can have a major impact on early vaccine responses and can be a key determinant of risk for communicable and non-communicable diseases in later life. We hypothesize that environmental and genetic factors that are often typical for poor-resource countries may have an important impact on prenatal immune development and predispose populations in low-income settings to different vaccine responses and disease risks, compared to those living in high-income countries. In this paper we aimed to summarize the major differences between neonatal and adult immune function and describe what is known so far about discrepancies in immune function between newborns in high- and low-income settings. Further, we discuss the need to test the immunological feasibility of accelerated vaccination schedules in high-risk populations and the potential of variation in disease specific and non-specific vaccine effects. [ABSTRACT FROM AUTHOR]

Autosomal recessive, autosomal dominant and the sporadic forms of hyperimmunoglobulin E syndrome (HIES) are multi-system disorders. Although HIES patients may present with cold abscesses, the vascular features of HIES are not well recognized. The objective of this review is to characterize the nature and spectrum of vascular abnormalities in HIES patients. Vascular abnormalities in HIES patients were reviewed with Medline and Google Scholar-based searches. In brief, the searches combined terms related to HIES with the terms related to vasculature. Furthermore, reference lists from the original studies and review papers identified were screened. There were vascular abnormalities in 25 patients with HIES. These abnormalities were identified as aneurysms (coronary, aortic, carotid and cerebral), pseudoaneurysms, congenital patent ductus venosus, superior vena cava syndrome, vasculitides, vascular ectasia, thrombosis and others. They may be congenital or acquired, in the veins and arteries, affecting both sexes. These abnormalities can be seen in all subtypes of HIES. They could be also fatal in children and adults. Limited pathological investigations revealed the presence of vasculitis. Three of the patients were found to have overlap diseases. In this review, the spectrum of vascular abnormalities in HIES are documented and discussed in detail for the first time. They highlight a previously under-recognized and potentially devastating complication of these disorders. These vascular abnormalities constitute one of the major clinical characteristics in HIES. The presence of hypereosinophilia, vasculitis and defective angiogenesis in HIES may contribute to the formation of vascular abnormalities in HIES. [ABSTRACT FROM AUTHOR]