The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with ...inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2
γδ T, mucosal-associated invariant T and CD56
natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT
CD4
CD8
double-negative αβ T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.
Severe combined immunodeficiency (SCID) is the most serious PID, characterized by T cell lymphopenia and lack of antigen-specific T cell and B cell immune responses, inevitably leading to death ...within the first year of life if hematopoietic stem cell transplantation (HSCT) is not performed.
Purpose and Methods
Since SCID is a common type of PID with an estimated incidence of 1/10.000 in Turkey, a retrospective analysis of HSCT characteristics, survival, immune recovery, and the major clinical features of SCID prior to HSCT is the aim of this multi-transplant center-based analysis.
Results
A total of 234 SCID patients transplanted between the years 1994 and 2014 were included in the study. Median age at diagnosis was 5 months, at transplantation, 7 months, B− phenotype and RAGs were the most common defects among others. Immune phenotype did not seem to have an effect on survival rate (
p
> 0.05), Immunoglobulin (Ig) requirement following HSCT did not differ between B+ and B− phenotypes (
p
> 0.05). Overall survival rate was 65.7% over a period of 20 years. It increased from 54% (1994–2004) to 69% (
p
= 0.052) during the last 10 years (2005–2014). Ten-year survival after HSCT has improved over time although the difference was not significant. Infection at the time of transplantation (
p
= 0.006), mismatched related donor (MMRD) (haploidentical parents), and matched unrelated donor (MUD) donor transplants
p
< 0.001 were the most important factors, significantly affecting the outcome.
Conclusions
This is the first multicenter study with the largest data obtained from transplanted SCID patients in Turkey. Early diagnosis with newborn screening (NBS) together with emerging referrals, treatment by transplantation centers, and specialized teams are mandatory in countries with high parental consanguinity such as Turkey.
Severe combined immunodeficiency is an inborn error of immunity characterized by impairments in the numbers and functions of T and B lymphocytes due to various genetic causes, and if it remains ...untreated, patients succumb to infections during the first 2 years of life.
Purpose and Methods
This study reported retrospective data from 72 infants diagnosed with SCID including their major clinical features, HSCT characteristics, and outcomes over a 20-year period (1997–2017).
Results
Sixty-one of 72 SCID patients in the study underwent HSCT from 1997 to 2017. Median ages at the time of diagnosis and transplantation were 3.5 months and 5 months, respectively. Consanguinity was present in 68% of the patients, and T − B − NK + phenotype was predominantly identified. The overall survival was 80.3% over a 20-year period. However, the patients transplanted during an active infection had a lower survival rate of 73.9% compared to 100% for patients transplanted infection-free or with a previous infection that had resolved. The survival rate was significantly higher among recipients of HLA-identical transplants (92.9%), compared to recipients of mismatched related transplants (70%). The overall survival increased from 50 (1997–2006) to 85% (2007–2017) during the last 10 years.
Conclusions
This is one of the largest single-center studies in Turkey with extensive experience about SCID patients. Early diagnosis of SCID patients before the onset of an infection and early transplantation are shown to be extremely important factors affecting the outcome and increasing the survival regardless of the donor type based on the results of this study.
Human nude SCID is a rare autosomal recessive inborn error of immunity (IEI) characterized by congenital athymia, alopecia, and nail dystrophy. Few cases have been reported to date. However, the ...recent introduction of newborn screening for IEIs and high-throughput sequencing has led to the identification of novel and atypical cases. Moreover, immunological alterations have been recently described in patients carrying heterozygous mutations. The aim of this paper is to describe the extended phenotype associated with
FOXN1
homozygous, compound heterozygous, or heterozygous mutations. We collected clinical and laboratory information of a cohort of 11 homozygous, 2 compound heterozygous, and 5 heterozygous patients with recurrent severe infections. All, except one heterozygous patient, had signs of CID or SCID. Nail dystrophy and alopecia, that represent the hallmarks of the syndrome, were not always present, while almost 50% of the patients developed Omenn syndrome. One patient with hypomorphic compound heterozygous mutations had a late-onset atypical phenotype. A SCID-like phenotype was observed in 4 heterozygous patients coming from the same family. A spectrum of clinical manifestations may be associated with different mutations. The severity of the clinical phenotype likely depends on the amount of residual activity of the gene product, as previously observed for other SCID-related genes. The severity of the manifestations in this heterozygous family may suggest a mechanism of negative dominance of the specific mutation or the presence of additional mutations in noncoding regions.
Invasive aspergillosis (IA) is a major cause of morbidity and mortality. This study aimed to present our 10-year IA experience at a single center. Fifty-nine pediatric patients with IA were included ...in this study. The male-to-female ratio was 42/17. The median age was 8.75 years. Hematologic malignancy was present in the majority of the patients (40/59, 68%). The mean neutropenia duration was 18.5 days. Cytosine arabinoside was the most common immunosuppressive therapy directed at T cells during IA diagnosis. IA cases were categorized as proven (27%), probable (51%), or possible (22%) according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. The lungs (78%) were the most common site of IA, and nodules were the most frequent radiological findings (75.5%). In 38 patients (64.4%) receiving antifungal prophylaxis, prophylactic agents included fluconazole (30.5%), liposomal amphotericin B (23.7%), posaconazole (8.5%), and voriconazole (1.7%). Initial treatment was most commonly administered as monotherapy (69.5%). The median antifungal treatment duration was 67 days. Eleven deaths (18.6%) were due to aspergillosis. With the increased use of corticosteroids, biological agents, and intensive immunosuppressive chemotherapy, IA will most likely continue to occur frequently in pediatric patients.
Loss-of-function mutations in magnesium transporter 1 (MAGT1) gene cause X-linked magnesium deficiency with Epstein-Barr virus (EBV) infection and neoplasm (X-MEN), a disease with quite diverse ...clinical and immunological consequences. The phenotypic characteristics of the initially described patients included CD4+ T cell lymphopenia, immune deficiency, EBV viremia, and EBV-related lymphoproliferative disease. To date, a total of 25 patients have been reported. The spectrum of the MAGT1 defect ranges from other viral infections (HSV, VZV, CMV, MCV) and sinopulmonary bacterial infections, autoimmune diseases, non-EBV driven lymphoproliferative disease, Castleman disease, HHV8+ Kaposi's sarcoma, vasculitis (Kawasaki) to glycosylation defects in new patients. Here, we report 2 patients from two different families with novel MAGT1 mutations and different clinical features. The first patient presented with B cell lymphoma and low IgM level without recurrent infections. The second patient presented with recurrent upper respiratory tract infections, Kawasaki-like disease, hypogammaglobulinemia, and T cell lymphopenia. X-MEN disease is the first phenotype identified due to MAGT1 mutation. The identification of new mutations and atypical presentations will clarify whether there is a relationship between the genotype and the phenotype and the characteristics of the disease.
Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency with microthrombocytopenia, eczema, recurrent infections, autoimmune disorders, and malignancies that are life-threatening in the ...majority of patients. In this long-term, retrospective, multicenter study, we analyzed events that occurred in 96 WAS patients who received transplants between 1979 and 2001 who survived at least 2 years following hematopoietic stem-cell transplantation (HSCT). Events included chronic graft-versus-host disease (cGVHD), autoimmunity, infections, and sequelae of before or after HSCT complications. Three patients (3%) died 2.1 to 21 years following HSCT. Overall 7-year event-free survival rate was 75%. It was lower in recipients of mismatched related donors, also in relation with an older age at HSCT and disease severity. The most striking finding was the observation of cGVHD-independent autoimmunity in 20% of patients strongly associated with a mixed/split chimerism status (P < .001), suggesting that residual-host lymphocytes can mediate autoimmune disease despite the coexistence of donor lymphocytes. Infectious complications (6%) related to splenectomy were also significant and may warrant a more restrictive approach to performing splenectomy in WAS patients. Overall, this study provides the basis for a prospective, standardized, and more in-depth detailed analysis of chimerism and events in long-term follow-up of WAS patients who receive transplants to design better-adapted therapeutic strategies.
There is a continuing debate about whether monoallergen subcutaneous immunotherapy (SCIT) is able to modulate immune and clinical responses toward main causal allergen in polysensitized patients.
To ...investigate short-term immunologic changes and clinical effectiveness of SCIT with Dermatophagoides pteronyssinus in monosensitized and polysensitized patients who have rhinitis with or without asthma.
Nineteen monosensitized and 24 polysensitized patients participated in this prospective, self-placebo-controlled, interventional study. Cluster immunotherapy with D pteronyssinus was administered after 2 months of placebo in both groups. Immunologic parameters, including CD203c expression on basophils after allergen stimulation, total IgE, specific IgE, and specific IgG4, were evaluated at baseline, after placebo, and after immunotherapy. Clinical effectiveness was assessed using monthly symptom-medication scores, visual analog scale, quality-of-life questionnaire, and nasal allergen provocation test.
At baseline, polysensitized patients had higher CD203c expression on basophils than monosensitized patients (P = .007). Activated basophils expressing CD203c, total IgE, and specific IgG4 were significantly increased after immunotherapy compared with baseline and placebo in the polysensitized group (P < .025). After immunotherapy, specific IgE and D pteronyssinus-induced CD203c expression were significantly higher in polysensitized than monosensitized patients (P < .05). The total symptom scores and the Mini Rhinoconjunctivitis Quality of Life Questionnaire scores in polysensitized patients and the visual analog scale scores in both groups were lower after immunotherapy compared with baseline and placebo (P < .025). Titrated nasal allergen provocation test with D pteronyssinus increased after immunotherapy in the monosensitized group (P < .05).
This study indicates that monosensitized and polysensitized patients have distinct humoral response and basophil behavior to SCIT. However, a single-allergen immunotherapy corresponding to the most clinically troublesome allergy in polysensitized patients can lead to early clinical efficacy comparable to that seen in monosensitized patients.
clinicaltrials.gov Identifier: NCT01795846.
Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) gene causes autosomal dominant hyper immunoglobulin E syndrome (AD-HIES or Job’s Syndrome), a rare and ...complex primary immunodeficiency (PID) syndrome characterized by increased levels of IgE (>2000 IU/mL), eosinophilia, recurrent staphylococcal skin abscesses, eczema, recurrent pneumonia, skeletal and connective tissue abnormalities. Although bacterial and fungal infections are common in AD-HIES, susceptibility to parasitic infections has not been reported. Alveolar echinococcosis (AE), a zoonosis caused by the growth of the Echinococcus multilocularis (EM) metacestode, mimics slow-growing liver cancer. The mortality rate of AE is very high when it is diagnosed late or under-treated. Here, we report a 14-year-old boy with AE infections of the liver and the lung resulting in liver failure and diagnosed as STAT3-LOF. To our knowledge, the association between these two conditions has not been reported in the literature before.
Background The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory ...responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired TH17 differentiation. Objective To elucidate mechanisms underlying different forms of HIES. Methods A cohort of 25 Turkish children diagnosed with HIES were examined forSTAT3mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-α was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. TH17 and TH1 cell differentiation was assessed by measuring the production of IL-17 and IFN-γ, respectively. Results Six subjects hadSTAT3mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired TH17 responses, but whereas STAT3 mutations abrogated early steps in TH17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. Conclusion In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired TH17 responses were evident irrespective of theSTAT3mutation status, indicating that different genetic forms of HIES share a common functional outcome.
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