Gene editing technology has emerged as a powerful tool in all aspects of health research and continues to advance our understanding of critical and essential elements in disease pathophysiology. The clustered regularly interspaced short palindromic repeats (CRISPR) gene editing technology has been used with precision to generate gene knockouts, alter genes, and identify genes that cause disease. The full spectrum of allergic/atopic diseases, in part because of shared pathophysiology, is ripe for studies with this technology. In this way, novel culprit genes are being identified and allow for manipulation of triggering allergens to reduce allergenicity and disease. Notwithstanding current limitations on precision and potential off-target effects, newer approaches are rapidly being introduced to more fully understand specific gene functions as well as the consequences of genetic manipulation. In this review, we examine the impact of editing technologies of novel genes relevant to peanut allergy and asthma as well as how gene modification of common allergens may lead to the deletion of allergenic proteins.

The NLRP3 inflammasome is an intracellular, multiprotein complex that promotes the auto-catalytic activation of caspase-1 and the subsequent maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18. Persistent activation of the NLRP3 inflammasome has been implicated in the pathophysiology of a number of inflammatory and autoimmune diseases, including neuroinflammation, cardiovascular disease, non-alcoholic steatohepatitis, lupus nephritis and severe asthma. Here we describe the preclinical profile of JT002, a novel small molecule inhibitor of the NLRP3 inflammasome. JT002 potently reduced NLRP3-dependent proinflammatory cytokine production across a number of cellular assays and prevented pyroptosis, an inflammatory form of cell death triggered by active caspase-1. JT002 demonstrated in vivo target engagement at therapeutically relevant concentrations when orally dosed in mice and prevented body weight loss and improved inflammatory and fibrotic endpoints in a model of Muckle-Wells syndrome (MWS). In two distinct models of neutrophilic airway inflammation, JT002 treatment significantly reduced airway hyperresponsiveness and airway neutrophilia. These results provide a rationale for the therapeutic targeting of the NLRP3 inflammasome in severe asthma and point to the use of JT002 in a variety of inflammatory disorders.

Autophagy involving core machinery proteins such as ATG9A is part of a cytoprotective process whose dysregulation is associated with carcinogenesis, neurodegeneration and autoimmunity, but few examples exist of monogenic diseases to further insights into human disease. In the present studies, we report a patient with novel compound heterozygous mutations in ATG9A after patient and parental DNA were subjected to whole exome sequencing. The patient developed hyperplastic proliferations of T and B cells in lung and brain and exhibited defects in lymphocyte memory cell populations after developing an infection with Epstein-Barr virus (EBV). Peripheral blood leukocytes from the patient exhibited defects in autophagic activity and EBV-transformed cells redemonstrated this defect which was also associated with defective NFKB (nuclear factor kappa B) signaling and accumulation of the pro-proliferative protein MYC (MYC proto-oncogene, bHLH transcription factor) and anti-apoptotic protein BCL2 (BCL2 apoptosis regulator), leading to increased proliferative capacity. Defects were corrected after transformation with plasmids expressing ATG9A and after treatment of cells as well as the patient with the MTOR (mechanistic target of rapamycin kinase) inhibitor, autophagy-inducing immunosuppressant rapamycin. These results point to a novel role of ATG9A and autophagy in human cellular signaling associated with hyperplasia and lymphocyte biology and provide an example how genetic studies may suggest effective specific therapeutic interventions.

The prevalence of atopic diseases has increased with atopic dermatitis (AD) as the earliest manifestation. We assessed if molecular risk factors in atopic mothers influence their infants' susceptibility to an atopic disease.

Cystic fibrosis (CF) is an inherited disorder caused by biallelic mutations of the CF transmembrane conductance regulator (CFTR) gene. Converging evidence suggests that CF carriers with only 1 defective CFTR copy are at increased risk for CF-related conditions and pulmonary infections, but the molecular mechanisms underpinning this effect remain unknown. We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) of CF child-parent trios (proband, father, and mother) and healthy control (HC) PBMCs or THP-1 cells incubated with the plasma of these participants. Transcriptomic analyses revealed suppression of cytokine-enriched immune-related genes (IL-1β, CXCL8, CREM), implicating lipopolysaccharide tolerance in innate immune cells (monocytes) of CF probands and their parents. These data suggest that a homozygous as well as a heterozygous CFTR mutation can modulate the immune/inflammatory system. This conclusion is further supported by the finding of lower numbers of circulating monocytes in CF probands and their parents, compared with HCs, and the abundance of mononuclear phagocyte subsets, which correlated with Pseudomonas aeruginosa infection, lung disease severity, and CF progression in the probands. This study provides insight into demonstrated CFTR-related innate immune dysfunction in individuals with CF and carriers of a CFTR mutation that may serve as a target for personalized therapy.

Die Prävalenz atopischer Erkrankungen nimmt stetig zu, wobei die atopische Dermatitis (AD) die früheste Erscheinungsform darstellt. Bei deren Entstehung spielen genetische Faktoren, Umweltnoxen und in utero Expositionen eine wichtige Rolle. Da bisher weitestgehend unbekannt ist, welche molekularen Mechanismen an der Übertragung atopischer Erkrankungen von der Mutter auf das Kind beteiligt sein könnten, wurden 300 schwangere Frauen mit oder ohne atopischem Phänotyp rekrutiert und ihre Neugeborenen in eine prospektive Geburtskohorte eingeschlossen.

The past several decades have witnessed a rapid evolution of thinking regarding inborn errors of immunity (IEIs), highlighted by expansion of more sophisticated immunology laboratory testing and introduction of diagnostic molecular genetics. Today, more than 400 monogenic diseases of the immune system have been defined, and new ones are regularly identified. Genetic screening of newborns for T-cell immunodeficiency is well established, and targeted drugs for several diseases are being introduced, as is gene therapy. Generally, the diagnosis of a primary immunodeficiency disease (PID)/IEI is no longer delayed for years as in the past because of increased awareness, advances in education of health care providers, and more cost-effective diagnostic tools (including mutation analyses). Well-designed and maintained PID/IEI registries have played a significant role in this progress, advancing our understanding of the complexities of these diseases, the variabilities in their presentation, and their responses to interventions. As an example, Thalhammer et al, on behalf of the pioneering work of the European Society of Primary Immunodeficiency registry on IEI, highlighted variability in the initial presentation of IEIs, with only 68% of the 16,000 patients presenting with infections.1Thalhammer J. Kindle G. Nieters A. Rusch S. Seppänen M.R.J. Fischer A. et al.Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations.J Allergy Clin Immunol. 2021; 148: 1332-1341.e5Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Historically, recurrent infection was considered the sentinel feature of many of these diseases; however, recent registration of patients with IEIs has proved otherwise. We now know that autoimmunity, inflammation, allergy, lymphoproliferative disorders, and malignancy represent a substantial portion of initial clinical manifestations of IEIs. Severe allergic inflammation, in particular, is an important presenting condition that, more recently, has been associated with monogenetic immune dysregulation,2Ma C.A. Stinson J.R. Zhang Y. Abbott J.K. Weinreich M.A. Hauk P.J. et al.Germline hypomorphic CARD11 mutations in severe atopic disease.Nat Genet. 2017; 49: 1192-1201Crossref PubMed Scopus (123) Google Scholar,3Vaseghi-Shanjani M. Smith K.L. Sara R.J. Modi B.P. Branch A. Sharma M. et al.Inborn errors of immunity manifesting as atopic disorders.J Allergy Clin Immunol. 2021; 148: 1130-1139Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar often presenting later in life.3Vaseghi-Shanjani M. Smith K.L. Sara R.J. Modi B.P. Branch A. Sharma M. et al.Inborn errors of immunity manifesting as atopic disorders.J Allergy Clin Immunol. 2021; 148: 1130-1139Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The French National Registry of Primary Immunodeficiencies was established in 2005 with the intent to capture all patients managed within the continental boundaries of France.4CEREDIH: The French PID study groupThe French national registry of primary immunodeficiency diseases.Clin Immunol. 2010; 135: 264-272Crossref PubMed Scopus (127) Google Scholar It was likely the largest national registry of IEI at the time. The captured data were believed to "fairly accurately" represent the prevalence of PID in the entirety of France, which was reported as approximately 1 in 25,000. This cross section allowed for the assessment of regional and national prevalence, age at diagnosis, proportion with a genetic diagnosis, and delay in diagnosis, informing future public health measures and assessment of national trends in diagnosis and treatment. In addition, it facilitated the identification of more homogeneous groups of patients to be studied through additional investigations. In the article by Alligon et al in this issue of the Journal of Allergy and Clinical Immunology, 10-year follow-up (2009-2018) was performed for patients registered in the French National Registry before 2009.5Alligon M. Mahlaoui N. Courteille V. Costes L. Alfonso V. Randrianomenjanahary P. et al.An appraisal of the frequency and severity of non-infectious manifestations in primary immunodeficiencies. A study of a national retrospective cohort of 1375 patients over 10 years.J Allergy Clin Immunol. 2022; 149: 2116-2125Abstract Full Text Full Text PDF Scopus (3) Google Scholar Alligon et al retrospectively examined a cohort of 1375 patients, detailing the incidence of noninfectious manifestations of allergy, autoimmunity and/or inflammation, lymphoproliferation, and malignancy. Overall, 87% of patients who were alive at the enrollment cutoff had follow-up of some type for 7 years. Of these patients, 14.2% died during the follow-up period, with inflammatory complications and malignancy being major factors contributing to their death. Survival over the follow-up period varied with diagnostic category. Common variable immunodeficiency disease (CVID) accounted for the largest number of deaths, and ataxia-telangiectasia had the highest mortality rate. As reported in past studies, malignancy incidence was increased in many patients with IEIs, and it was a frequent cause of early death. Alligon et al5Alligon M. Mahlaoui N. Courteille V. Costes L. Alfonso V. Randrianomenjanahary P. et al.An appraisal of the frequency and severity of non-infectious manifestations in primary immunodeficiencies. A study of a national retrospective cohort of 1375 patients over 10 years.J Allergy Clin Immunol. 2022; 149: 2116-2125Abstract Full Text Full Text PDF Scopus (3) Google Scholar found that malignancy occurred in 7.3% of registrants over the course of the study, far exceeding the rate of less than 1% seen in the general population of the same age. Cancer accounted for almost a quarter of the deaths recorded over the follow-up period. Risk of solid tumor started between ages 11 and 20 years and exceeded the risk of hematologic malignancy for patients who were between 20 and 30 years old when the observation period began. The categories innate nonchronic granulomatous disease and CVID both had higher-than-anticipated solid tumor rates. The finding of increased risk of solid tumor in the innate immunity group was unexpected and warrants confirmatory studies. Increased prevalence of autoimmune and inflammatory disease is also a known feature of IEIs; however, the incidence of these types of complications is often difficult to ascertain. The overall prevalence of inflammatory and autoimmune complications reported by Alligon et al5Alligon M. Mahlaoui N. Courteille V. Costes L. Alfonso V. Randrianomenjanahary P. et al.An appraisal of the frequency and severity of non-infectious manifestations in primary immunodeficiencies. A study of a national retrospective cohort of 1375 patients over 10 years.J Allergy Clin Immunol. 2022; 149: 2116-2125Abstract Full Text Full Text PDF Scopus (3) Google Scholar was 25.9% at the start of the study, which is far higher than that in the healthy population. Remarkably, another 10.5% of the registrants experienced onset of an autoimmune or inflammatory manifestation, giving an incidence of close to 1 affected person per 100 person years among those diagnosed with IEIs (Fig 1). For comparison, the incidence of autoimmune hypothyroidism, the most common autoimmune disease overall, is around 3 per 1000 person years in White individuals.6McLeod D.S.A. Cooper D.S. The incidence and prevalence of thyroid autoimmunity.Endocrine. 2012; 42: 252-265Crossref PubMed Scopus (319) Google Scholar At the end of the study period, nearly one-third of the subjects had autoimmune inflammatory conditions, emphasizing the oversized impact on morbidity among individuals with IEIs. These findings demonstrate why continued surveillance of registry patients is essential. In the report by Alligon et al,5Alligon M. Mahlaoui N. Courteille V. Costes L. Alfonso V. Randrianomenjanahary P. et al.An appraisal of the frequency and severity of non-infectious manifestations in primary immunodeficiencies. A study of a national retrospective cohort of 1375 patients over 10 years.J Allergy Clin Immunol. 2022; 149: 2116-2125Abstract Full Text Full Text PDF Scopus (3) Google Scholar the incidences of cancer and autoimmunity were simultaneously measured for 10 different general categories of IEIs, allowing not only for estimation of event incidence but also for comparison between diseases. The high incidence of solid tumor in the category innate nonchronic granulomatous disease immunodeficiency was surprising. It is important to highlight this group because these patients are rare, and as a result, few cohort studies of innate defects are performed. As the role of innate immune surveillance of cancer becomes an increasing area of attention,7Finn O.J. A believer's overview of cancer immunosurveillance and immunotherapy.J Immunol. 2018; 200: 385-391Crossref PubMed Scopus (74) Google Scholar this finding indicates a need to define in greater detail the propensity of these patients to develop solid tumors. When assessing the value of a registry, it is important to consider that at best, registries are organized systems using observational study methods to collect uniform (clinical and other) data to evaluate specified outcomes for a population defined by a particular disease or condition. They are meant to capture data elements with specific and consistent data definitions without bias, have minimized confounders, and provide a certain strength of evidence. In the case of PID registries, if properly designed and executed, they can provide a real-world view of patient variability and the comparative effectiveness of therapeutic interventions and outcomes. But at best, the value of registries is limited, as they need to be dynamic, longitudinal, and updated regularly as information continues to accumulate. In the French National Registry, less than 45% of the patients had a genetic diagnosis. Further, many patients were labeled as having subclass deficiency, specific antibody deficiency, or CVID, in which case despite these subsets of patients meeting prespecified clinical and laboratory criteria, there was likely to be much heterogeneity among them,8Gelfand E.W. Ochs H.D. Shearer W.T. Controversies in IgG replacement therapy in patients with antibody deficiency diseases.J Allergy Clin Immunol. 2013; 131: 1001-1005Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,9Abbott J.K. Gelfand E.W. Common variable immunodeficiency: diagnosis, management, and treatment.Immunol Allergy Clin North Am. 2015; 35: 637-658Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar thus complicating outcome analyses. Registry efforts are costly to set up and laborious to maintain. In most iterations, great pains are taken to enroll as many patients as possible; however, the continued follow-up of patients has been less emphasized. The value of registries is unquestionable, but funding needs to be provided to maintain them; ensure physician participation; and enable laboratory testing, including advancing molecular genetics and validating disease-specific surrogate markers to further refine classification. To properly assess the need for interventions with "curative therapies," including stem cell transplantation, gene reconstitution, and targeted pharmacologic approaches to affect quality of life or survival, registries must, with rare exceptions, focus on confirmed monogenic diseases. This is not to say that a confirmed genetic diagnosis is a prerequisite for intervention, but as Alligon et al5Alligon M. Mahlaoui N. Courteille V. Costes L. Alfonso V. Randrianomenjanahary P. et al.An appraisal of the frequency and severity of non-infectious manifestations in primary immunodeficiencies. A study of a national retrospective cohort of 1375 patients over 10 years.J Allergy Clin Immunol. 2022; 149: 2116-2125Abstract Full Text Full Text PDF Scopus (3) Google Scholar conclude, "performing genetic documentation is of utmost importance in providing the best level of care for patients with PID." An appraisal of the frequency and severity of noninfectious manifestations in primary immunodeficiencies: A study of a national retrospective cohort of 1375 patients over 10 yearsJournal of Allergy and Clinical ImmunologyVol. 149Issue 6PreviewNoninfectious manifestations—allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies—are known to exist in many primary immunodeficiency diseases (PID) and to participate in prognosis. Full-Text PDF

Despite adequate infection prophylaxis, variation in self-reported quality of life (QOL) throughout the intravenous immunoglobulin (IVIG) infusion cycle is a widely reported but infrequently studied phenomenon. To better understand this phenomenon, subjects with humoral immunodeficiency receiving replacement doses of IVIG were studied over 3 infusion cycles. Questionnaire data from 6 time points spread over 3 IVIG infusions cycles (infusion day and 7 days after each infusion) were collected in conjunction with monitoring the blood for number of regulatory T-cells (Treg) and levels of 40 secreted analytes: primarily cytokines, chemokines, and growth factors. At day 7, self-reported well-being increased, and self-reported fatigue decreased, reflecting an overall improvement in QOL 7 days after infusion. Over the same period, percentage of Treg cells in the blood increased (p<0.01). Multiple inflammatory chemokine and cytokine levels increased in the blood by 1 hour after infusion (CCL4 (MIP-1b), CCL3 (MIP-1a), CCL2 (MCP-1), TNF-α, granzyme B, IL-10, IL-1RA, IL-8, IL-6, GM-CSF, and IFN- γ). The largest changes in analytes occurred in subjects initiated on IVIG during the study. A significant decrease in IL-25 (IL-17E) following infusion was seen in most intervals among subjects already receiving regular infusions prior to study entry. These findings reveal several short-term effects of IVIG given in replacement doses to patients with humoral immunodeficiency: QOL consistently improves in the first week of infusion, levels of a collection of monocyte-associated cytokines increase immediately after infusion whereas IL-25 levels decrease, and Treg levels increase. Moreover, patients that are new to IVIG experience more significant fluctuations in cytokine levels than those receiving it regularly.

Air pollution is associated with early declines in lung function and increased levels of asthma-related cysteinyl leukotrienes (CysLT) but a biological pathway linking this rapid response has not been delineated. In this randomized controlled diesel exhaust (DE) challenge study of 16 adult asthmatics, increased exposure-attributable urinary leukotriene E4 (uLTE4, a biomarker of cysteinyl leukotriene production) was correlated (p = 0.04) with declines in forced expiratory volume in 1-second (FEV1) within 6 hours of exposure. Exposure-attributable uLTE4 increases were correlated (p = 0.02) with increased CysLT receptor 1 (CysLTR1) methylation in peripheral blood mononuclear cells which, in turn, was marginally correlated (p = 0.06) with decreased CysLTR1 expression. Decreased CysLTR1 expression was, in turn, correlated (p = 0.0007) with FEV1 declines. During the same time period, increased methylation of GPR17 (a negative regulator of CysLTR1) was observed after DE exposure (p = 0.02); this methylation increase was correlated (p = 0.001) with decreased CysLTR1 methylation which, in turn, was marginally correlated (p = 0.06) with increased CysLTR1 expression; increased CysLTR1 expression was correlated (p = 0.0007) with FEV1 increases. Collectively, these data delineate a potential mechanistic pathway linking increased DE exposure-attributable CysLT levels to lung function declines through changes in CysLTR1-related methylation and gene expression.

Background Alpha-1 antitrypsin (AAT) is a major serine protease inhibitor. AAT deficiency (AATD) is a genetic disorder characterized by early-onset severe emphysema. In well-selected AATD patients, therapy with plasma-derived AAT (pAAT), “augmentation therapy”, provides modest clinical improvement but is perceived as cumbersome with weekly intravenous infusions. Using mouse models of emphysema, we compared the effects of a recombinant AAT-IgG1 Fc-fusion protein (AAT-Fc), which is expected to have a longer half-life following infusion, to those of pAAT. Methods In an elastase model of emphysema, mice received a single intratracheal instillation of porcine pancreatic elastase (PPE) or human leucocyte elastase (hLE). AAT-Fc, pAAT, or vehicle was administered intraperitoneally 1 day prior to or 3 weeks following elastase instillation. Lung function and histology assessments were performed at 7 and 32 days after elastase instillation. In a cigarette smoke (CS) model of emphysema, mice were exposed to CS daily, 5 days a week, for 6 months and AAT-Fc, pAAT, or vehicle were administered every 10 days during the last 3 months of CS exposure. Assessments were performed 3 days after the last CS exposure. Immune responses to lung elastin peptide (EP) and the effects of AAT-Fc or pAAT treatment on dendritic cell (DC) function were determined ex vivo. Results Both elastase instillation and CS exposure triggered emphysema-like alveolar enlargement, increased lung compliance, and increased markers of inflammation compared to controls. Administration of AAT-Fc either prior to or following elastase instillation or during CS exposure provided greater protection than pAAT against alveolar enlargement, lung dysfunction, and airway inflammation. When challenged ex vivo with EP, spleen mononuclear cells from elastase-exposed mice exhibited dose-dependent production of IFNγ and IL-17, suggesting immune reactivity. In co-culture experiments with splenic CD4 + T cells isolated from elastase-exposed mice, AAT-Fc treatment prior to EP-priming of bone marrow-derived dendritic cells inhibited the production of IFNγ and IL-17. Conclusions Compared to pAAT, AAT-Fc more effectively prevented or attenuated elastase- and CS-induced models of emphysema. These effects were associated with immunomodulatory effects on DC activity. AAT-Fc may provide a therapeutic option to individuals with AATD- and CS-induced emphysema.

The importance of NF-κB to human immune signaling is demonstrated by the large number of monogenetic diseases that arise from defects in the NF-κB subunits and the proteins that regulate them. Hypomorphic variants in IKBKG and N-terminal variants in NFKBIA cause X-linked and dominant ectodermal dysplasia with combined immunodeficiency (EDA-ID), respectively. Biallelic loss of IKBKB (the gene coding the protein IKKβ) causes a severe form of combined immunodeficiency. Monoallelic deficiency of individual NF-κB subunits is associated with common variable immunodeficiency and autoimmunity, and defects in proteins that carry out posttranslational modifications of NF-κB pathway proteins cause immunodeficiency, severe inflammatory disease, or both.

Viral infections are one of the major causes of asthma exacerbations. However, the mechanism underlying virus-induced pathological changes in asthma has not been fully elucidated. It also remains unclear which viral components exacerbate asthma. In this study, we investigated the effects two major viral components, single stranded (ss) RNA and double stranded (ds) RNA, known ligands of Toll-like receptor (TLR) 7 and TLR3, respectively, in an experimental model of asthma. Wild-type C57BL/6 mice were sensitized to ovalbumin (OVA), and subsequent to OVA challenge, two synthesized nucleotides, R848 or poly I:C, which mimic the viral components ssRNA and dsRNA, respectively, were administered intratracheally. After administration of the viral components, AHR, bronchoalveolar lavage cell composition and type 2 cytokine production were determined. OVA-sensitized and -challenged mice developed AHR and airway inflammation with eosinophil infiltration in the lung. Administration ssRNA-R848, failed to alter the induced changes in AHR and airway inflammation. In contrast, administration of dsRNA-poly I:C, significantly enhanced the development of AHR with increased levels of type 2 cytokines (IL-4, IL-5, IL-13) as well as the pro-allergic epithelial cell-derived proteins TSLP, IL-25, and IL-33. The major viral component dsRNA, but not ssRNA, is capable of enhancing lung allergic inflammation, suggesting that the activation of TLR3 but not TLR7 is a critical contributor to virus-mediated asthma exacerbation.

Activation of the steroidogenic enzyme CYP11A1 was shown to be necessary for the development of peanut-induced intestinal anaphylaxis and IL-13 production in allergic mice. We determined if levels of CYP11A1 in peripheral blood T cells from peanut-allergic (PA) children compared to non-allergic controls were increased and if levels correlated to IL-13 production and oral challenge outcomes to peanut. CYP11A1 mRNA and protein levels were significantly increased in activated CD4+ T cells from PA patients. In parallel, IL-13 production was significantly increased; IFNγ levels were not different between groups. There were significant correlations between expression levels of CYP11A1 mRNA and levels of IL13 mRNA and protein, levels of serum IgE anti-Ara h 2 and to outcomes of peanut challenge. The importance of CYP11A1 on cytokine production was tested using a CYP11A1 CRISPR/Cas9 KO plasmid or an inhibitor of enzymatic CYP11A1 activity. Inhibition of CYP11A1 activation in patient cells treated with the inhibitor, aminoglutethimide, or CD4+ T cell line transfected with the CYP11A1 KO plasmid resulted in reduced IL-13 production. These data suggest that the CYP11A1-CD4+Tcell-IL-13 axis in activated CD4+ T cells from PA children is associated with development of PA reactions. CYP11A1 may represent a novel target for therapeutic intervention in PA children.

Ataxia-Telangiectasia (AT) is an immunodeficiency most often associated with T cell abnormalities. We describe a patient with a hyper-IgM phenotype and immune cell abnormalities that suggest a distinct clinical phenotype. Significant B cell abnormalities with increased unswitched memory B cells, decreased naive transitional B cells, and an elevated frequency of CD19(+)CD381(lo)CD27(-)CD10(-)CD21(-/low) W B cells expressing high levels of T-bet and Fas were demonstrated. The B cells were hyporesponsive to in vitro stimulation through the B cell receptor, Toll like receptors (TLR) 7 and 9, and CD40. T cell homeostasis was also disturbed with a significant increase in gamma delta T cells, circulating T follicular helper cells (Tfh), and decreased numbers of T regulatory cells. The ATM mutations in this patient are posited to have resulted in the perturbations in the frequencies and distributions of B and T cell subsets, resulting in the phenotype in this patient. Key messages: A novel mutation creating a premature stop codon and a nonsense mutation in the ATM gene are postulated to have resulted in the unique clinical picture characterized by abnormal B and T cell populations, lymphocyte subset dysfunction, granuloma formation, and a hyper-IgM phenotype. Capsule summary: A patient presented with ataxia-telangiectasia, cutaneous granulomas, and a hyper-IgM phenotype; a novel combination of mutations in the ATM gene was associated with abnormal distributions, frequencies, and function of T and B lymphocyte subsets.

Defective ATM activation skews the B cell repertoire and increases RANKL production, promoting joint erosion in patients with rheumatoid arthritis.

Allergic asthma, a chronic inflammatory airway disease associated with type 2 cytokines, often originates in early life. Immune responses at an early age exhibit a Th2 cell bias, but the precise mechanisms remain elusive. Plasmacytoid dendritic cells (pDCs), which play a regulatory role in allergic asthma, were shown to be deficient in neonatal mice. We report here that this pDC deficiency renders neonatal mice more susceptible to severe allergic airway inflammation than adult mice in an OVA-induced experimental asthma model. Adoptive transfer of pDCs or administration of IFN-α to neonatal mice prevented the development of allergic inflammation in wild type but not in IFNAR1 −/− mice. Similarly, adult mice developed more severe allergic inflammation when pDCs were depleted. The protective effects of pDCs were mediated by the pDC-/IFN-α-mediated negative regulation of the secretion of epithelial cell-derived CCL20, GM-CSF, and IL-33, which in turn impaired the recruitment of cDC2 and ILC2 cells to the airway. In asthmatic patients, the percentage of pDCs and the level of IFN-α were lower in children than in adults. These results indicate that impairment of pDC-epithelial cell crosstalk in neonates is a susceptibility factor for the development of allergen-induced allergic airway inflammation.

The complexity of asthma is underscored by the number of cell types and mediators implicated in the pathogenesis of this heterogeneous syndrome. Type 2 CD4 + T-cells (Th2) and more recently, type 2 innate lymphoid cells dominate current descriptions of asthma pathogenesis. However, another important source of these type 2 cytokines, especially interleukin (IL)-5 and IL-13, are CD8 + T-cells, which are increasingly proposed to play an important role in asthma pathogenesis, because they are abundant and are comparatively insensitive to corticosteroids. Many common triggers of asthma exacerbations are mediated via corticosteroid-resistant pathways involving neutrophils and CD8 + T-cells. Extensive murine data reveal the plasticity of CD8 + T-cells and their capacity to enhance airway inflammation and airway dysfunction. In humans, Tc2 cells are predominant in fatal asthma, while in stable state, severe eosinophilic asthma is associated with greater numbers of Tc2 than Th2 cells in blood, bronchoalveolar lavage fluid and bronchial biopsies. Tc2 cells strongly express CRTH2, the receptor for prostaglandin D2, the cysteinyl leukotriene receptor 1 and the leukotriene B4 receptor. When activated, these elicit Tc2 cell chemotaxis and production of chemokines and type 2 and other cytokines, resulting directly or indirectly in eosinophil recruitment and survival. These factors position CD8 + Tc2 cells as important and underappreciated effector cells contributing to asthma pathogenesis. Here, we review recent advances and new insights in understanding the pro-asthmatic functions of CD8 + T-cells in eosinophilic asthma, especially corticosteroid-resistant asthma, and the molecular mechanisms underlying their pathologic effector function.