International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide

Clinical experience in T cell deficient patients

T cell disorders have been poorly understood until recently. Lack of knowledge of underlying molecular mechanisms together with incomplete data on long term outcome have made it difficult to assess prognosis and give the most effective treatment. Rapid progress in defining molecular defects, improved supportive care and much improved results from hematopoietic stem cell transplantation (HSCT) now mean that curative treatment is possible for many patients. However, this depends on prompt recognition, accurate diagnosis and careful treatment planning

Randomised controlled trial of food elimination diet based on IgG antibodies for the prevention of migraine like headaches

<p>Abstract</p> <p>Background</p> <p>Research suggests that food intolerance may be a precipitating factor for migraine like headaches.</p> <p>Aim</p> <p>To evaluate the effectiveness of the ELISA (Enzyme Linked Immuno-Sorbent Assay) Test and subsequent dietary elimination advice for the prevention of migraine like headaches.</p> <p>Design</p> <p>Randomised controlled trial.</p> <p>Setting</p> <p>Community based volunteers in the UK.</p> <p>Participants</p> <p>Volunteers who met the inclusion criteria for migraine like headaches and had one or more food intolerance were included in the study. Participants received either a true diet (n = 84) or a sham diet (n = 83) sheet. Participants were advised to remove the intolerant foods from their diet for 12 weeks.</p> <p>Main outcome measures</p> <p>Number of headache days over a 12 week period (item A MIDAS questionnaire). Other measures includes the total MIDAS score and total HIT-6 score.</p> <p>Results</p> <p>The results indicated a small decrease in the number of migraine like headaches over 12 weeks, although this difference was not statistically significant (IRR 1.15 95% CI 0.94 to 1.41, p = 0.18). At the 4 week assessment, use of the ELISA test with subsequent diet elimination advice significantly reduced the number of migraine like headaches (IRR 1.23 95%CI 1.01 to 1.50, p = 0.04). The disability and impact on daily life of migraines were not significantly different between the true and sham diet groups.</p> <p>Conclusions</p> <p>Use of the ELISA test with subsequent diet elimination advice did not reduce the disability or impact on daily life of migraine like headaches or the number of migraine like headaches at 12 weeks but it did significantly reduce the number of migraine like headaches at 4 weeks.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRTCN89559672">ISRTCN89559672</a></p

Sexual Selection Halts the Relaxation of Protamine 2 among Rodents

Sexual selection has been proposed as the driving force promoting the rapid evolutionary changes observed in some reproductive genes including protamines. We test this hypothesis in a group of rodents which show marked differences in the intensity of sexual selection. Levels of sperm competition were not associated with the evolutionary rates of protamine 1 but, contrary to expectations, were negatively related to the evolutionary rate of cleaved- and mature-protamine 2. Since both domains were found to be under relaxation, our findings reveal an unforeseen role of sexual selection: to halt the degree of degeneration that proteins within families may experience due to functional redundancy. The degree of relaxation of protamine 2 in this group of rodents is such that in some species it has become dysfunctional and it is not expressed in mature spermatozoa. In contrast, protamine 1 is functionally conserved but shows directed positive selection on specific sites which are functionally relevant such as DNA-anchoring domains and phosphorylation sites. We conclude that in rodents protamine 2 is under relaxation and that sexual selection removes deleterious mutations among species with high levels of sperm competition to maintain the protein functional and the spermatozoa competitive

Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

Mutations of the recombinase Activating Genes 1 and 2 (RAG1, RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment, however high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- NK cells have a mature phenotype, reduced fitness and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT

Axotomy induces axonogenesis in hippocampal neurons through STAT3

After axotomy of embryonic hippocampal neurons in vitro, some of the axotomized axons lose their identity, and new axons arise and grow. This axotomy-induced axonogenesis requires importin, suggesting that some injury-induced signals are transported via axons to elicit axonogenesis after axotomy. In this study, we show that STAT3 is activated in response to axotomy. Because STAT3 was co-immunoprecipitated with importin β in the axotomized neurons, we suggest that STAT3 is retrogradely transported as molecular cargo of importin α/β heterodimers. Indeed, inhibition of importin α binding with STAT3 resulted in the attenuation of axonogenesis. Silencing STAT3 blocked the axonogenesis, demonstrating that STAT3 is necessary for axotomy-induced axonogenesis. Furthermore, the overexpression of STAT3 enhanced axotomy-induced axonogenesis. Taken together, these results demonstrate that activation and retrograde transport of STAT3 in injured axons have key roles in the axotomy-induced axonogenesis of hippocampal neurons

In Vivo Islet Protection by a Nuclear Import Inhibitor in a Mouse Model of Type 1 Diabetes

Insulin-dependent Type 1 diabetes (T1D) is a devastating autoimmune disease that destroys beta cells within the pancreatic islets and afflicts over 10 million people worldwide. These patients face life-long risks for blindness, cardiovascular and renal diseases, and complications of insulin treatment. New therapies that protect islets from autoimmune destruction and allow continuing insulin production are needed. Increasing evidence regarding the pathomechanism of T1D indicates that islets are destroyed by the relentless attack by autoreactive immune cells evolving from an aberrant action of the innate, in addition to adaptive, immune system that produces islet-toxic cytokines, chemokines, and other effectors of islet inflammation. We tested the hypothesis that targeting nuclear import of stress-responsive transcription factors evoked by agonist-stimulated innate and adaptive immunity receptors would protect islets from autoimmune destruction.Here we show that a first-in-class inhibitor of nuclear import, cSN50 peptide, affords in vivo islet protection following a 2-day course of intense treatment in NOD mice, which resulted in a diabetes-free state for one year without apparent toxicity. This nuclear import inhibitor precipitously reduces the accumulation of islet-destructive autoreactive lymphocytes while enhancing activation-induced cell death of T and B lymphocytes derived from autoimmune diabetes-prone, non-obese diabetic (NOD) mice that develop T1D. Moreover, in this widely used model of human T1D we noted attenuation of pro-inflammatory cytokine and chemokine production in immune cells.These results indicate that a novel form of immunotherapy that targets nuclear import can arrest inflammation-driven destruction of insulin-producing beta cells at the site of autoimmune attack within pancreatic islets during the progression of T1D

Cross-talk between cd1d-restricted nkt cells and γδ cells in t regulatory cell response

CD1d is a non-classical major histocompatibility class 1-like molecule which primarily presents either microbial or endogenous glycolipid antigens to T cells involved in innate immunity. Natural killer T (NKT) cells and a subpopulation of γδ T cells expressing the Vγ4 T cell receptor (TCR) recognize CD1d. NKT and Vγ4 T cells function in the innate immune response via rapid activation subsequent to infection and secrete large quantities of cytokines that both help control infection and modulate the developing adaptive immune response. T regulatory cells represent one cell population impacted by both NKT and Vγ4 T cells. This review discusses the evidence that NKT cells promote T regulatory cell activation both through direct interaction of NKT cell and dendritic cells and through NKT cell secretion of large amounts of TGFβ, IL-10 and IL-2. Recent studies have shown that CD1d-restricted Vγ4 T cells, in contrast to NKT cells, selectively kill T regulatory cells through a caspase-dependent mechanism. Vγ4 T cell elimination of the T regulatory cell population allows activation of autoimmune CD8+ effector cells leading to severe cardiac injury in a coxsackievirus B3 (CVB3) myocarditis model in mice. CD1d-restricted immunity can therefore lead to either immunosuppression or autoimmunity depending upon the type of innate effector dominating during the infection