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Newborn screening efforts focusing on the quantification of T cell receptor excision circles (TRECs), as a biomarker for abnormal thymic production of T cells, have allowed for the identification and definitive treatment of severe combined immunodeficiency (SCID) in asymptomatic neonates. With the adoption of TREC quantification in Guthrie cards across the USA and abroad, typical, and atypical SCID constitutes only ~ 10% of cases identified with abnormal TRECs associated with T cell lymphopenia. Several other non-SCID-related conditions may be identified by newborn screening in a term infant. Thus, it is important for physicians to recognize that other factors, such as prematurity, are often associated with low TRECs initially, but often improve with age. This paper focuses on a challenge that immunologists face: the diagnostic evaluation and management of cases in which abnormal TRECs are associated with variants of T cell lymphopenia in the absence of a genetically defined form of typical or atypical SCID. Various syndromes associated with T cell impairment, secondary forms of T cell lymphopenia, and idiopathic T cell lymphopenia are identified using this screening approach. Yet there is no consensus or guidelines to assist in the evaluation and management of these newborns, despite representing 90% of the patients identified, resulting in significant work for the clinical teams until a diagnosis is made. Using a case-based approach, we review pearls relevant to the evaluation of these newborns, as well as the management dilemmas for the families and team related to the resolution of genetic ambiguities. [ABSTRACT FROM AUTHOR]

Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype–phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects. [ABSTRACT FROM AUTHOR]

A Correction to this paper has been published: https://doi.org/10.1007/s10875-021-01030-6 [ABSTRACT FROM AUTHOR]

This document is a letter published in the Journal of Clinical Immunology. It discusses a case study of a male patient with Incontinentia Pigmenti and X-linked anhidrotic ectodermal dysplasia with immunodeficiency (IP-EDA-ID). The patient had a pathogenic variant in the NEMO/IKBKG gene, which caused split immunological reconstitution. The study examines the chronological changes in somatic mosaicism of T cells, B cells, and monocytes in the patient. The findings suggest that monitoring mosaicism can guide the appropriate treatment for NEMO deficiency. [Extracted from the article]

Oral lichen planus is a chronic inflammatory disorder of the oral mucosa that represents T cell-mediated autoimmune diseases. The regulation and roles of carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1), a novel immune molecule, in the immunopathogenesis of T cell-mediated autoimmune diseases remain unclear. In the current paper, CEACAM1 was found to be overexpressed in peripheral T cells and epithelial cells in oral lichen planus patients. A fraction of infiltrating inflammatory mononuclear cells in the lamina propria of the oral lichen planus mucosa also expressed CEACAM1. Importantly, for the first time, CEACAM1 expression in T cells and in normal human oral keratinocytes was demonstrated to be regulated differently by osteopontin in vitro. Furthermore, the apoptosis of oral keratinocytes and activated T cells can be markedly suppressed by CEACAM1-specific monoclonal antibodies. In conclusion, OPN-regulated CEACAM1 expression may play a critical role in the immunopathogenesis of oral lichen planus. [ABSTRACT FROM AUTHOR]

Abstract Introduction  The immune response is controlled by several inhibitory mechanisms. These mechanisms include regulatory T cells, which exist in multiple classes. Notable among these are Foxp3-expressing regulatory T cells (Treg), NKT cells, and Tr1 cells. Common to these mechanisms are inhibitory cytokines such as interleukin-10 and transforming growth factor-beta (TGF-β). TGF-β and Foxp3-expressing Treg cells are critical in maintaining self-tolerance and immune homeostasis. Discussions  The immune suppressive functions of TGF-β and Treg cells are widely acknowledged and extensively studied. Nonetheless, recent studies revealed the positive roles for TGF-β and Treg cells in shaping the immune system and the inflammatory responses. In this paper, we will discuss the role of these mechanisms in the control of immunity and autoimmunity and the mechanisms that underlie how these molecules control these responses. [ABSTRACT FROM AUTHOR]

Purpose: Hyper activation of the JAK-STAT signaling underlies the pathophysiology of many human immune–mediated diseases. Herein, the study of 2 adult patients with SOCS1 haploinsufficiency illustrates the severe and pleomorphic consequences of its impaired regulation in the intestinal tract. Methods: Two unrelated adult patients presented with gastrointestinal manifestations, one with Crohn's disease-like ileo-colic inflammation refractory to anti-TNF and the other with lymphocytic leiomyositis causing severe chronic intestinal pseudo-occlusion. Next-generation sequencing was used to identify the underlying monogenic defect. One patient received anti-IL-12/IL-23 treatment while the other received the JAK1 inhibitor, ruxolitinib. Peripheral blood, intestinal tissues, and serum samples were analyzed before-and-after JAK1 inhibitor therapy using mass cytometry, histology, transcriptomic, and Olink assay. Results: Novel germline loss-of-function variants in SOCS1 were identified in both patients. The patient with Crohn-like disease achieved clinical remission with anti-IL-12/IL-23 treatment. In the second patient with lymphocytic leiomyositis, ruxolitinib induced rapid resolution of the obstructive symptoms, significant decrease of the CD8+ T lymphocyte muscular infiltrate, and normalization of serum and intestinal cytokines. Decreased frequencies of circulating Treg cells, MAIT cells, and NK cells, with altered CD56bright:CD16lo:CD16hi NK subtype ratios were not modified by ruxolitinib. Conclusion: SOCS1 haploinsufficiency can result in a broad spectrum of intestinal manifestations and need to be considered as differential diagnosis in cases of severe treatment-refractory enteropathies, including the rare condition of lymphocytic leiomyositis. This provides the rationale for genetic screening and considering JAK inhibitors in such cases. [ABSTRACT FROM AUTHOR]

Purpose: About 20–30% of patients with common variable immunodeficiency (CVID) develop granulomatous-lymphocytic interstitial lung disease (GLILD) as one of several non-infectious complications to their immunodeficiency. The purpose of this study was to identify biomarkers that could distinguish GLILD from other non-infectious complications in CVID. Methods: We analyzed serum biomarkers related to inflammation, pulmonary epithelium injury, fibrogenesis, and extracellular matrix (ECM) remodeling, and compared three subgroups of CVID: GLILD patients (n = 16), patients with other non-infectious complications (n = 37), and patients with infections only (n = 20). Results: We found that GLILD patients had higher levels of sCD25, sTIM-3, IFN-γ, and TNF, reflecting T cell activation and exhaustion, compared to both CVID patients with other inflammatory complications and CVID with infections only. GLILD patients also had higher levels of SP-D and CC16, proteins related to pulmonary epithelium injury, as well as the ECM remodeling marker MMP-7, than patients with other non-infectious complications. Conclusion: GLILD patients have elevated serum markers of T cell activation and exhaustion, pulmonary epithelium injury, and ECM remodeling, pointing to potentially important pathways in GLILD pathogenesis, novel targets for therapy, and promising biomarkers for clinical evaluation of these patients. [ABSTRACT FROM AUTHOR]

Two infants are described who presented with 22q11.2 deletion and a TBNK immune phenotype. For both infants, the initial diagnosis was athymia secondary to complete DiGeorge anomaly. The first infant underwent thymus transplantation but 6 months after transplantation had circulating thymus donor T cells; the patient did not develop recipient naïve T cells. Genetic analyses revealed that both patients had Artemis deficiency, a rare form of severe combined immunodeficiency (SCID). Both infants have subsequently undergone bone marrow transplantation. These cases illustrate the importance and paradox of differentiating SCID from complete DiGeorge anomaly because hematopoietic stem cell transplantation (HSCT) is the preferred treatment for SCID but is ineffective for complete DiGeorge anomaly. However, if the thymus is completely absent, donor stem cells from a HSCT would not be able to be educated. [ABSTRACT FROM AUTHOR]

Purpose: Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes. Methods: In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls. Results: The median age of the patients was 10 years (mean 20.7 years, range 1–44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56bright immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients. Conclusion: Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype. [ABSTRACT FROM AUTHOR]

Purpose: Newborn screening (NBS) for severe combined immunodeficiency (SCID) is based on the detection of T-cell receptor excision circles (TRECs). TRECs are a sensitive biomarker for T-cell lymphopenia, but not specific for SCID. This creates a palette of secondary findings associated with low T-cells that require follow-up and treatment or are non-actionable. The high rate of (non-actionable) secondary findings and false-positive referrals raises questions about the harm-benefit-ratio of SCID screening, as referrals are associated with high emotional impact and anxiety for parents. Methods: An alternative quantitative TREC PCR with different primers was performed on NBS cards of referred newborns (N = 56) and epigenetic immune cell counting was used as for relative quantification of CD3 + T-cells (N = 59). Retrospective data was used to determine the reduction in referrals with a lower TREC cutoff value or an adjusted screening algorithm. Results: When analyzed with a second PCR with different primers, 45% of the referrals (25/56) had TREC levels above cutoff, including four false-positive cases in which two SNPs were identified. With epigenetic qPCR, 41% (24/59) of the referrals were within the range of the relative CD3 + T-cell counts of the healthy controls. Lowering the TREC cutoff value or adjusting the screening algorithm led to lower referral rates but did not prevent all false-positive referrals. Conclusions: Second tier tests and adjustments of cutoff values or screening algorithms all have the potential to reduce the number of non-actionable secondary findings in NBS for SCID, although second tier tests are more effective in preventing false-positive referrals. [ABSTRACT FROM AUTHOR]

Severe combined immune deficiency (SCID) caused by RAG1 or RAG2 deficiency is a genetically determined immune deficiency characterized by the virtual absence of T and B lymphocytes. Unless treated with hematopoietic stem cell transplantation (HSCT), patients with RAG deficiency succumb to severe infections early in life. However, HSCT carries the risk of graft-versus-host disease. Moreover, a high rate of graft failure and poor immune reconstitution have been reported after unconditioned HSCT. Expression of the RAG genes is tightly regulated, and preclinical attempts of gene therapy with heterologous promoters have led to controversial results. Using patient-derived induced pluripotent stem cells (iPSCs) and an in vitro artificial thymic organoid system as a model, here we demonstrate that gene editing rescues the progressive T cell differentiation potential of RAG2-deficient cells to normal levels, with generation of a diversified T cell repertoire. These results suggest that targeted gene editing may represent a novel therapeutic option for correction of this immunodeficiency. [ABSTRACT FROM AUTHOR]

Congenital athymia is an ultra-rare disease characterized by the absence of a functioning thymus. It is associated with several genetic and syndromic disorders including FOXN1 deficiency, 22q11.2 deletion, CHARGE Syndrome (Coloboma, Heart defects, Atresia of the nasal choanae, Retardation of growth and development, Genitourinary anomalies, and Ear anomalies), and Complete DiGeorge Syndrome. Congenital athymia can result from defects in genes that impact thymic organ development such as FOXN1 and PAX1 or from genes that are involved in development of the entire midline region, such as TBX1 within the 22q11.2 region, CHD7, and FOXI3. Patients with congenital athymia have profound immunodeficiency, increased susceptibility to infections, and frequently, autologous graft-versus-host disease (GVHD). Athymic patients often present with absent T cells but normal numbers of B cells and Natural Killer cells (T−B+NK+), similar to a phenotype of severe combined immunodeficiency (SCID); these patients may require additional steps to confirm the diagnosis if no known genetic cause of athymia is identified. However, distinguishing athymia from SCID is crucial, as treatments differ for these conditions. Cultured thymus tissue is being investigated as a treatment for congenital athymia. Here, we review what is known about the epidemiology, underlying etiologies, clinical manifestations, and treatments for congenital athymia. [ABSTRACT FROM AUTHOR]

Purpose: DiGeorge syndrome has substantial heterogeneity with variable immune deficiency and dysregulation. Implicated immunopathology includes reduced thymic output and increased peripheral homeostatic proliferation with Th2 skewing and expansion of self-reactive cells. We hypothesized that T cell lymphopenia severity will be associated with higher odds of autoimmunity and/or asthma. Methods: Using the US Immunodeficiency Network registry, we identified patients with 22q11.2 deletion (and/or TBX1). Initial absolute CD3+ T cell values were stratified: normal, 50–99% and below 50% of the lower limit of age-adjusted normal values. Patients with and without reported autoimmunity and asthma were compared using chi-square tests and multivariate logistic regression. Results: Among 415 patients, autoimmunity was reported in 17 (4.1%), and asthma was reported in 28 (6.7%). Compared with those with no reported autoimmunity, patients with reported autoimmunity more frequently had low CD19+ B cells [3.3% (12/364) vs 28.6% (4/14); p = 0.002] and low IgG [6.2% (20/321) vs 29.4% (5/17); p = 0.005] levels. There were no statistically significant differences in other immune characteristics among those with and without reported asthma. Patients with absolute CD3 levels below 50% of age-adjusted normal values had higher odds of reported autoimmunity (n = 319, OR = 7.56, 95% CI = 1.58–36.17, p = 0.01) and reported asthma (n = 319, OR = 4.5, 95% CI = 1.06–18.93, p = 0.04) as compared with those with normal CD3 values, adjusted for age and low IgG. Conclusions: Absolute CD3+ T cell counts below 50% of age-adjusted normal values may be associated with higher odds of autoimmunity and/or asthma in patients with DiGeorge syndrome and be potentially useful to identify higher-risk patients. [ABSTRACT FROM AUTHOR]

We report the case of a patient with X-linked severe combined immunodeficiency (X-SCID) who survived for over 20 years without hematopoietic stem cell transplantation (HSCT) because of a somatic reversion mutation. An important feature of this rare case included the strategy to validate the pathogenicity of a variant of the IL2RG gene when the T and B cell lineages comprised only revertant cells. We studied the X-inactivation of sorted T cells from the mother to show that the pathogenic variant was indeed the cause of his SCID. One interesting feature was a progressive loss of B cells over 20 years. CyTOF (cytometry time of flight) analysis of bone marrow offered a potential explanation of the B cell failure, with expansions of progenitor populations that suggest a developmental block. Another interesting feature was that the patient bore extensive granulomatous disease and skin cancers that contained T cells, despite severe T cell lymphopenia in the blood. Finally, the patient had a few hundred T cells on presentation but his TCRs comprised a very limited repertoire, supporting the important conclusion that repertoire size trumps numbers of T cells. [ABSTRACT FROM AUTHOR]

Background: Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)–like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte–associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition. Methods: A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA. Results: Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4+ T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy. Conclusions: ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation. [ABSTRACT FROM AUTHOR]

Bloom's syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected, and immunoglobulin serum levels were measured at different time points. In addition, we performed immune phenotyping of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20-80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion, BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR. [ABSTRACT FROM AUTHOR]

The primary objective of population-based newborn screening is the early identification of asymptomatic infants with a range of severe diseases, for which effective treatment is available and where early diagnosis and intervention prevent serious sequelae. Primary immunodeficiency diseases (PID) are a heterogeneous group of inborn errors of immunity. Severe combined immunodeficiency (SCID) is one form of PID which is uniformly fatal without early, definitive therapy, and outcomes are significantly improved if infants are diagnosed and treated within the first few months of life. Screening for SCID using T cell receptor excision circle (TREC) analysis has been introduced in many countries worldwide. The utility of additional screening with kappa recombining excision circles (KREC) has also been described, enabling identification of infants with severe forms of PID manifested by T and B cell lymphopenia. Here, we review the early origins of newborn screening and the evolution of screening methodologies. We discuss current strategies employed in newborn screening programs for PID, including TREC and TREC/KREC-based screening, and consider the potential future role of protein-based assays, targeted sequencing, and next generation sequencing (NGS) technologies, including whole genome sequencing (WGS). [ABSTRACT FROM AUTHOR]

Since the discovery of FOXN1 deficiency, the human counterpart of the nude mouse, a growing body of evidence investigating the role of FOXN1 in thymus and skin, has been published. FOXN1 has emerged as fundamental for thymus development, function, and homeostasis, representing the master regulator of thymic epithelial and T cell development. In the skin, it also plays a pivotal role in keratinocytes and hair follicle cell differentiation, although the underlying molecular mechanisms still remain to be fully elucidated. The nude severe combined immunodeficiency phenotype is indeed characterized by the clinical hallmarks of athymia with severe T cell immunodeficiency, congenital alopecia, and nail dystrophy. In this review, we summarize recent discoveries in the field and give interesting perspective about new and promising therapeutic approaches for disorders of immune system with athymia. [ABSTRACT FROM AUTHOR]

Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Fourteen unrelated patients have been reported since the identification of the first case in 2003. All mutations enhanced the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. The mutation certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient. Eleven mutations, belonging to two groups, were identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients). Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases. All patient cells tested displayed impaired NF-κB-mediated responses to the stimulation of various surface receptors involved in cell-intrinsic (fibroblasts), innate (monocytes), and adaptive (B and T cells) immunity, including TLRs, IL-1Rs, TNFRs, TCR, and BCR. All patients had profound B-cell deficiency. Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. Patients with a missense mutation tended to display more severe phenotypes, probably due to higher levels of GOF proteins. In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom have been on prophylaxis (3 to 21 years post HSCT), whereas one has been well with no prophylaxis. Heterozygous GOF mutations in IκBα underlie a severe and syndromic immunodeficiency, the interindividual variability of which might partly be ascribed to the dichotomy of missense and nonsense mutations, and the hematopoietic component of which can be rescued by HSCT. [ABSTRACT FROM AUTHOR]

Purpose: Leishmania, the causative organisms for leishmaniasis, reside in host macrophages and survive by modulating the microbicidal pathways via attenuation of the oxidative burst and/or suppression of cell-mediated immunity. As post kala-azar dermal leishmaniasis (PKDL), the dermal sequela of visceral leishmaniasis, has no animal model, the underlying mechanism(s) that nullify the microbicidal effector mechanisms remain poorly understood. This study was aimed at assessing the status of dipeptidyl peptidase CD26, a co-stimulatory molecule that is essential for T-cell signal activation. Methods: The frequency/expression of CD26 and CD45RO/RA was evaluated by flow cytometry, while levels of soluble CD26 (sCD26), CXCL-10, RANTES, IL-10 and TGF-β along with adenosine deaminase (ADA) activity were measured using ELISA. Results: In patients with PKDL vis-à-vis healthy individuals, there was a significant decrease in the frequency and expression of CD26 on CD3CD8 T-cells, which was accompanied by a significant lowering of plasma levels of sCD26. Furthermore, these patients showed a significant decrease in the frequency of CD45RO/CD8 T-cells, concomitant with a significant increase in the proportion of CD45RA/CD8 T-cells. This could collectively translate into reduced formation of the immunological synapse of CD26, CD45RO, and ADA, and lead to an attenuation of the Th1 responses. The decreased levels of CD26 and sCD26 correlated negatively with raised levels of Th2 cytokines, IL-10, and TGF-β along with the lesional parasite load, indicating disease specificity. Conclusions: Taken together, the decreased expression and secretion of CD26 in patients with PKDL resulted in impairment of the CD26-ADA interaction, and thereby possibly contributed to T-cell unresponsiveness, emphasizing the need to develop immunomodulatory therapies against PKDL and by extension, the leishmaniases. [ABSTRACT FROM AUTHOR]

IgM exists as both a monomer on the surface of B cells and a pentamer secreted by plasma cells. Both pre-immune 'natural' and antigen-induced 'immune' IgM antibodies are important for protective immunity and for immune regulation of autoimmune processes by recognizing pathogens and self-antigens. Effector proteins interacting with the Fc portion of IgM, such as complement and complement receptors, have thus far been proposed but fail to fully account for the IgM-mediated protection and regulation. A major reason for this deficit in our understanding of IgM function seems to be lack of data on a long elusive Fc receptor for IgM (FcμR). We have recently identified a bona fide FcμR in both humans and mice. In this article we briefly review what we have learned so far about FcμR. [ABSTRACT FROM AUTHOR]

Objectives: There is paucity of data on Primary immunodeficiency disorders (PID) from India. Here we describe the frequency of different primary immunodeficiency disorders, their clinical features and disease complications of 159 patients with PID diagnosed in a tertiary care center from India over the last 3 years. Methods: We retrospectively reviewed the records of all the patients identified to have specific PID from 2008 to 2011. The diagnosed patients were classified according to guidelines of International Union of Immunological Society (IUIS) into eight different sub groups. Results: The distribution pattern was as follows: diseases of immune dysregulation (29 %), phagocytic defects (29 %), predominant antibody deficiency (13 %), combined T and B cell deficiency (19 %) and other well defined diseases (10 %). Conclusion: The distribution pattern of PID varied significantly from those reported by western studies. This study highlights the need for development of more advanced facilities for diagnosis and management of PID in India and also the need for establishing population and hospital based registries. [ABSTRACT FROM AUTHOR]

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent flat warts or pityriasis versicolor-like lesions caused by betapapillomaviruses (EV-HPVs). Autosomal recessive EVER1 and EVER2 deficiencies account for EV in most patients. The mechanisms by which mutations in these partners of the Zinc transporter ZnT1 impair host defense against EV-HPVs are still poorly understood. Keratinocytes of EVER-deficient patients display an alteration of zinc homeostasis and an enhanced proliferative activity. Since EVER proteins are highly expressed in T lymphocytes, we aimed to assess the impact of EVER2 deficiency on T-cell development and function. We studied circulating lymphocyte populations in three adult EV patients sharing the same EVER2 mutation (T150fsX3). We found a normal count of CD4 and CD8 T cells and a normal proliferative capacity in response to anti-CD3 stimulation. However, we observed a significant increase of memory CD4 and effector memory CD8 T cells, a bias of the TCR Vαβ and Vγδ repertoires and an increase of skin-homing CD4 T-cell subsets. Our findings suggest that EVER2-deficient patients display mild T-cell abnormalities. It remains unclear whether these abnormalities result from EVER deficiency, chronic EV-HPV infection, or both. [ABSTRACT FROM AUTHOR]

A correction to the article "Small RNA Regulators of T Cell-Mediated Autoimmunity" that was published in Volume 30, Issue 3 of the publication is presented.

We describe a family with the rare mutation R11X that leads to a truncated CD40 ligand (CD40L) missing the intracellular domain. The index case had detectable CD40L expression and presented at the age of 41 years with cerebral toxoplasmosis. A brother and two nephews were also identified as having the same mutation but exhibited milder and variable phenotypes. The older affected nephew had a moderately depressed immunoglobulin G level and a history of pneumonia at 4 months of age. The younger nephew suffered from sinusitis with normal immunoglobulin levels. Both nephews had absent antibody responses to a protein antigen with conserved responses to polysaccharide antigens. The two sisters of the index case are carriers who had elevated levels of IgM but remain well. This mutation may affect CD40 ligand function by reducing cell surface levels, diminishing CD40 interaction or disrupting CD40L intracellular signalling in T cells. The variable phenotype in members of this family offers an opportunity to further understand the CD40-CD40L signalling pathway in human immune responses. [ABSTRACT FROM AUTHOR]

Thirty-five rheumatoid arthritis (RA) patients and 27 healthy volunteers were enrolled in the study. Regulatory T (Treg) cell numbers were significantly reduced in RA patients. RA Treg cells exhibited an impaired capacity to inhibit proliferation and cytokine secretion of autologous T effector (Teff) cells. However, the crossover experiments further indicated that this impaired suppression was due to resistance of Teff cells but not to an intrinsic defect of Treg cells in RA patients. RA Teff cells showed a higher expression of membrane tumor necrosis factor-related apoptosis-inducing ligand and secreted more soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL could induce apoptosis in Treg cells. Neutralization of TRAIL restored the regulation of Teff by Treg in RA patients. In summary, our data suggest that reduced peripheral Treg cell numbers and an increased resistance of Teff cells to suppression by Treg cells were present in RA patients, and TRAIL may be an underlying mechanism for the impaired regulation of Teff cells by Treg cells. [ABSTRACT FROM AUTHOR]

Natalizumab is a widely accepted drug for the relapsing-remitting subtype of multiple sclerosis (RRMS). The present longitudinal exploratory study in RRMS patients analyzes the effects of natalizumab treatment on the levels of pro-inflammatory and anti-inflammatory cytokine protein levels and also the frequency and suppressor function of regulatory T cells. Flow cytometry was used to determine cytokines and regulatory T cell frequency while regulatory T cell suppressor function was assayed in vitro at different time-points after starting with natalizumab. Results showed serum levels of pro-inflammatory interferon gamma and interleukin (IL)-12p70, as well as anti-inflammatory IL-4 and IL-10, were elevated just a few hours or days after first IV infusion of natalizumab. Interestingly, other cytokines like IL-5 or IL-13 were also elevated while pro-inflammatory IL-17, IL-2, and IL-1β increased only after a long-term treatment, suggesting different immune mechanisms. In contrast, we did not observe any effect of natalizumab treatment on regulatory T cell frequency or activity. In conclusion, these results suggest natalizumab has other immunological effects beyond VLA-4 interaction and inhibition of CNS extravasation, the relevance of which is as yet unknown and warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Regulatory T cells (Tregs) have an essential role in tolerance and immune regulation. However, few and controversial data have been published to date on the role and number of these cells in food allergic children. The forkhead/winged-helix transcription factor box protein 3 (FOXP3) is considered the most reliable marker for Tregs. Objective: This study aims to investigate the FOXP3, interleukin (IL)-10, and transforming growth factor (TGF-β) genes expression in children with IgE-dependent food allergy. Material and Methods: The study group consisted of 54 children with IgE-dependent food allergy (FA) and a control group of 26 non-atopic healthy children. The diagnosis of FA was established using questionnaires, clinical criteria, skin prick tests, serum sIgE antibodies (UniCAP 100 Pharmacia Upjohn), and a double-blind placebo control food challenge. In order to assess gene expression, the isolation of nucleated cells was performed using Histopaque-1077 (Sigma-Aldrich, Germany). The concentration of RNA obtained was measured using a super-sensitive NanoDrop ND1000 spectrophotometer (Thermo Scientific, USA). A reverse transcription reaction was performed using a commercially available set of High Capacity cDNA Archive Kit (Applied Biosystems, USA). Analysis have been carried out in the genetic analyzer 7900HT Real-Time PCR (Applied Biosystems, USA). Results: The average level of the FOXP3 gene expression in the studied group was 2.19 ± 1.16 and in the control group 2.88 ± 1.66 ( p = 0.03). The average level of IL10 mRNA expression in the study group was 13.6 ± 1.07 and was significantly lower than corresponding values in the control group 14.3 ± 1.1 ( p = 0.01). There were no significant differences in the average level of the TGF-β mRNA expression in the study group (3.4 ± 0.4) and controls (3.5 ± 0.3; p > 0.05). The FOXP3 gene expression was the highest in children who acquired tolerance to food (3.54 ± 0.75), lower in heated allergen-tolerant children (2.43 ± 0.81), and the lowest in heated allergen-reactive children (1.18 ± 0.5; p = 0.001 control vs heated allergen reactive; p = 0.005 heated allergen tolerant vs heated allergen reactive; p = 0.001 outgrown vs heated allergen reactive). The significant tendency toward lower total IgE levels with a higher FOXP3 mRNA expression was detected ( n = 54; Pearson r = −0.4393; p = 0.001). Conclusions: Children with FA showed statistically significant lower level of the FOXP3 and IL10 gene expression than healthy children. Children acquiring tolerance to the food show significantly higher levels of the FOXP3 gene expression than children with active FA. The correlation between the level of FOXP3 and total IgE was detected. [ABSTRACT FROM AUTHOR]

Although interleukin-17 (IL-17) has been reported to participate in the pathogenesis of infectious, autoimmune and allergic disorders, the precise role in allograft rejection remains uncertain. This study illustrates that IL-17 contributes to the pathogenesis of chronic allograft rejection. Utilizing a murine heterotopic heart transplant model system, IL-17-deficient recipient mice had decreased allograft inflammatory cell recruitment, decreased IL-6, MCP-1, and KC production, and reduced graft coronary artery disease (GCAD). Intragraft gamma delta (γδ) T cells appear to be the predominant source of IL-17 production. Therefore, IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection. [ABSTRACT FROM AUTHOR]

Abstract Introduction  Sixty-four primary immunodeficiency patients were registered at the Pediatric Allergy and Immunology Department, Children’s Hospital, Ain Shams University, Cairo, Egypt. Data  Predominantly antibody deficiencies were the most common category (35.9%) followed by combined T- and B-cell immunodeficiencies (29.7%), other well defined immunodeficiency syndromes (18.7%), congenital defects of phagocyte number, function or both (12.5%), and diseases of immune dysregulation (3.1%). The most frequent disorder was common variable immunodeficiency (18.7%). The mean age at diagnosis was 29.9 months. The consanguinity rate was 62.5%. Recurrent severe infections were seen in all categories. Fifteen patients died (23.4%) from infections with the highest mortality for combined T- and B-cell immunodeficiencies (15.6%). Conclusions  Primary immunodeficiency disorders are not rare in Egyptian children. The observed frequency of combined T- and B-cell immunodeficiencies in our cohort is relatively higher than other countries. It is a prerequisite to establish a national registry of primary immunodeficiency in Egypt. [ABSTRACT FROM AUTHOR]

Abstract Background  Peripheral blood CD4+ and CD8+ T-cell subsets lacking surface CD28 have been suggested to predispose patients to immune-mediated disorders. Materials and Methods  To determine the role of CD28− T-cell subset in Graves’ disease (GD), we characterized peripheral blood CD4+CD28− and CD8+CD28− T cell from early onset GD patients. Results and Discussion  GD patients had significantly higher percentages of CD4+CD28− and CD8+CD28− T cells than did healthy donors. Both CD28− T cells expressed mostly CD45RO, suggesting that they are activated and/or are memory T cells. GD patient-derived CD4+CD28− and CD8+CD28− T cells produced more intracellular IFN-γ than their counterparts from healthy donors. Furthermore, CD4+CD28− and CD8+CD28− T cells from GD patients with Graves’ ophthalmopathy (GO) secreted higher level of intracellular IFN-γ than those CD28− T cells from GD patients without GO. Retrospective analysis showed that the increased levels of CD4+CD28− T cells and their IFN-γ-producing subgroups were positively correlated to the serum anti-thyrotropin receptor (TSHR) autoantibodies (TRAb). Our observations suggest that increased IFN-γ-producing CD28− T cells in GD patients may play an important role in the pathogenesis of GD. [ABSTRACT FROM AUTHOR]

Abstract Background  Resistance to recombinant human erythropoietin (rhEPO) occurs in some chronic kidney disease (CKD) patients, which may be due to enhanced systemic inflammatory response and to the erythropoiesis-suppressing effect of pro-inflammatory cytokines, some of which are produced by T cells. Aim of study  The aim of this study was to investigate the relationship between resistance to rhEPO therapy in hemodialysis CKD patients and inflammatory markers [C-reactive protein (CRP), soluble interleukin (IL)-2 receptor (sIL2R), and serum albumin levels], blood cell counts, T-cell phenotype, cytokine production by T cells, and serum cytokine levels. Materials and Methods  We studied 50 hemodialysis CKD patients, 25 responders and 25 nonresponders to rhEPO, and compared them to each other and with 25 healthy controls. When compared to controls, CKD patients showed increased serum levels of CRP, IL-6, and sIL2R and a T-cell lymphopenia, due to decreased numbers of both CD4+ and CD8+ T cells. T cells from CKD patients had an immunophenotype compatible with chronic T-cell stimulation as shown by the increased percentage of CD28−, CD57+, HLA-DR+, CD28−HLA-DR+, and CD57+ HLA-DR+ T cells and produce higher levels of IL-2, INF-γ, and TNF-α after short-term in vitro stimulation, although Th1 cytokines were not detectable in serum. Statistically significant differences were found between responders and nonresponders to rhEPO therapy for total lymphocyte and CD4+ T-lymphocyte counts, albumin (lower in nonresponders) and CRP (higher in nonresponders) levels. Conclusion  CKD patients under hemodialysis present with raised inflammatory markers and decrease of total lymphocyte and CD4+ T-lymphocyte counts when compared with controls. Some of those markers are even further enhanced in nonresponders to rhEPO therapy patients, but resistance to this therapy cannot be justified by a Th1 polarized T-cell response. [ABSTRACT FROM AUTHOR]

In a previous study we found an expansion of circulating memory (CD45RO+) CD4+ T cells in patients with Crohn's disease (CD). The aim of this work was to investigate the phenotypic and functional characteristics of this T-cell subset in CD. We analyzed in peripheral blood CD4+CD45RO+ T cells from CD patients the expression of surface markers associated to immune activation, costimulation, and apoptosis. In sorted CD4+CD45RO+ T cells apoptosis was quantified by fluorescent annexing V binding. Healthy subjects and patients with ulcerative colitis and acute bacterial enterocolitis served as control groups. An increased percentage of memory CD4+CD45RO+ T cells lacking the expression of costimulatory receptor CD28 was detected in patients with active CD when compared to the other groups evaluated. This expanded CD4+CD45RO+CD28null T-cell subset expressed mostly the effector-cell marker CD57+. Both CD28 downregulation and CD57 expression correlated to CDAI and surrogate markers of disease activity. These phenotypic changes observed on CD4+CD45RO+ T cells from active CD returned to values similar to healthy controls after clinical remission. Moreover, this memory CD28 T-cell subset might express more intracytoplasmic TNF and IFN-γ than their CD28+ counterpart. Significantly lower frequencies of memory CD4+CD45RO+ T cells expressing CD95 apoptosis receptor were found in patients with active CD. Moreover, sorted CD4+CD45RO+and CD4+CD45RO+ CD28null T cells from patients with active CD exhibited a lower apoptotic rate than that found in healthy controls and inactive CD patients. According to our data, circulating T lymphocytes from active CD patients show distinctive phenotypic and functional changes, characterized by an expansion of memory CD4+CD45RO+CD28null T cells expressing effector-associated cell surface molecules and displaying enhanced resistance to apoptosis. [ABSTRACT FROM AUTHOR]

Receptors belonging to the tumor necrosis factor receptor family have long been thought to play an important role in the regulation of immunity. Although this family is composed of a large number of surface receptors that potentiate myriad functions in vivo, a subset is known to directly convey apoptotic signals. One such molecule belonging to this subset is CD95. Ligation of CD95 instigates the formation of a complex known as the "death-inducing signaling complex" or DISC, which is composed of molecules including FADD (Fas associated with death domain) and RIP (receptor-interacting kinase), as well as procaspases-8 and -10, and a caspase-8-like molecule that lacks proteolytic activity called c-FLIP. Although the DISC was initially thought to serve an exclusively proapoptotic role, humans and mice with defects in various components of this complex demonstrate a variety of developmental and hematopoietic defects that are not apparently due to abenant apoptosis. These findings paint a far more complex picture of the numerous components of the DISC, and provide evidence that these complexes serve nonapoptotic functions. Herein, we summarize the experimental evidence challenging the notion that the DISC imparts an exclusively apoptotic function and provide hypotheses to account for these alternative roles. Rather than operating as a binary system, we propose that the DISCs formed around various DRs transduce signals leading to a variety of cellular fates. [ABSTRACT FROM AUTHOR]