Manish Butte

Front Immunol. 2021 Dec 24;12:758373. doi: 10.3389/fimmu.2021.758373. eCollection 2021.

ABSTRACT

Due to heightened awareness and advanced genetic tools, inborn errors of immunity (IEI) are increasingly recognized in children. However, diagnosing of IEI in premature infants is challenging and, subsequently, reports of IEI in premature infants remain rare. This review focuses on how common disorders of prematurity, such as sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia, can clinically overlap with presenting signs of IEI. We present four recent cases from a single neonatal intensive care unit that highlight diagnostic dilemmas facing neonatologists and clinical immunologists when considering IEI in preterm infants. Finally, we present a conceptual framework for when to consider IEI in premature infants and a guide to initial workup of premature infants suspected of having IEI.

PMID:35003071 | PMC:PMC8738084 | DOI:10.3389/fimmu.2021.758373

J Clin Immunol. 2022 Jan 9. doi: 10.1007/s10875-021-01188-z. Online ahead of print.

ABSTRACT

PURPOSE: X-linked inhibitor of apoptosis protein (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome of type 2 (XLP-2), is a rare immunodeficiency characterized by recurrent hemophagocytic lymphohistiocytosis, splenomegaly, and inflammatory bowel disease. Variants in XIAP including missense, non-sense, frameshift, and deletions of coding exons have been reported to cause XIAP deficiency. We studied three young boys with immunodeficiency displaying XLP-2-like clinical features. No genetic variation in the coding exons of XIAP was identified by whole-exome sequencing (WES), although the patients exhibited a complete loss of XIAP expression.

METHODS: Targeted next-generation sequencing (NGS) of the entire locus of XIAP was performed on DNA samples from the three patients. Molecular investigations were assessed by gene reporter expression assays in HEK cells and CRISPR-Cas9 genome editing in primary T cells.

RESULTS: NGS of XIAP identified three distinct non-coding deletions in the patients that were predicted to be driven by repetitive DNA sequences. These deletions share a common region of 839 bp that encompassed the first non-coding exon of XIAP and contained regulatory elements and marks specific of an active promoter. Moreover, we showed that among the 839 bp, the exon was transcriptionally active. Finally, deletion of the exon by CRISPR-Cas9 in primary cells reduced XIAP protein expression.

CONCLUSIONS: These results identify a key promoter sequence contained in the first non-coding exon of XIAP. Importantly, this study highlights that sequencing of the non-coding exons that are not currently captured by WES should be considered in the genetic diagnosis when no variation is found in coding exons.

PMID:35000057 | DOI:10.1007/s10875-021-01188-z

J Allergy Clin Immunol. 2022 Jan;149(1):24-28. doi: 10.1016/j.jaci.2021.11.016.

ABSTRACT

Anticytokine autoantibodies can cause immunodeficiency or dysregulate immune responses. They may phenocopy genetically defined primary immunodeficiencies. We review current anti-type 1 and anti-type 2 interferon; anti-IL-12/23, anti-IL-17, and anti-GM-CSF autoantibodies; HLA associations; disease associations; and mechanistically based treatment options. Suspecting the presence of these autoantibodies in patients and identifying them at the onset of symptoms should ameliorate disease and improve outcomes.

PMID:34998474 | DOI:10.1016/j.jaci.2021.11.016

Orphanet J Rare Dis. 2022 Jan 8;17(1):11. doi: 10.1186/s13023-021-02161-0.

ABSTRACT

BACKGROUND: The “Primary Immunodeficiencies (PIDs) principles of care” were published in 2014 as the gold standard for care of patients with PIDs, setting a common goal for stakeholders to ensure that patients with PID have access to appropriate care and good quality of life. Since then, IPOPI (the International Patient Organisation for Primary Immunodeficiencies), has been working with national PID patient organisations as well as collaborating with scientific and medical institutions and experts to bring these principles closer to the day-to-day life of individuals with PIDs.

METHOD: The six PID Principles of Care were revised to consider advances in the field, as well as political developments that had occurred after their initial publication in 2014. Based on this revision the list was updated, and a new principle was added. The six established principles were: diagnosis, treatment, universal health coverage, specialised centres, national patient organisations and registries. Each principle was structured and measured through a series of criteria, and was given the same weight, as they have been considered to all be equally important. Specific weights were attributed to the criteria depending on their relevance and importance to quantify the principle. The index was translated into a survey for data collection: initially involving data from selected countries for a pilot, followed by integration of data from IPOPI’s national member organisations and key countries.

RESULTS: The PID Life Index was developed in 2020 to assess the status of the PID environment and the implementation of the 6 principles worldwide. The Index allows for benchmarking countries either according to a set of principles and criteria or based on the user’s preferences. This can be displayed in an interactive map or through a data visualisation system.

CONCLUSION: The PID Life Index has been developed successfully and has potential to become an important source of information for PID stakeholders, to increase awareness and information as well as support advocacy initiatives on PIDs nationally, regionally or globally.

PMID:34998414 | DOI:10.1186/s13023-021-02161-0

J Appl Lab Med. 2022 Jan 5;7(1):151-164. doi: 10.1093/jalm/jfab139.

ABSTRACT

BACKGROUND: Anti-cytokine autoantibodies (AAbs) associated with an infectious phenotype are now included along with anti-complement AAbs and somatic pathogenic gene variants as a distinct category termed ‘phenocopies of primary immunodeficiencies’ in the classification of inborn errors of immunity. Anti-cytokine AAbs target specific cytokine pathways, leading to inordinate susceptibility to specific organisms, generally in the setting of immunocompetence.

CONTENT: Anti-cytokine AAbs are detected in the majority of healthy individuals and may play a regulatory role in limiting exaggerated responses to cytokines. While it is not well understood why some individuals with anti-cytokine AAbs develop increased susceptibility to organisms of low pathogenicity and others do not, it is likely that genetics and environment play a role. To date, AAbs to interferon gamma (IFNγ), interferon alpha (IFNα), interleukins-17 and 22 (IL-17/IL-22), interleukin-6 and granulocyte macrophage colony stimulating factor (GM-CSF) and their association with increased susceptibility to nontuberculous mycobacteria and other intracellular organisms, viral infections, Candida albicans, Staphylococcus aureus and other pyogenic organisms, and fungal infections respectively, have been described. The clinical phenotype of these patients is very similar to that of individuals with pathogenic gene variants in the specific cytokine pathway that the autoantibody targets, hence the term ‘phenocopy.’ Recognition of anti-cytokine AAbs as a distinct cause of immunodeficiency or immune dysregulation is important for appropriate management of such patients.

SUMMARY: Understanding the roles that anti-cytokine AAbs play in health and disease continues to be a fascinating area of research. Evaluating generally immunocompetent individuals who present with chronic, treatment refractory, or unusual infections for anti-cytokine AAbs is critical as it may direct therapy and disease management.

PMID:34996092 | DOI:10.1093/jalm/jfab139

Front Immunol. 2021 Dec 21;12:813261. doi: 10.3389/fimmu.2021.813261. eCollection 2021.

ABSTRACT

Activated phosphoinositide 3-kinase δ syndrome (APDS) is an autosomal dominant primary immunodeficiency caused by acquired gene function mutation (GOF). APDS has a variety of clinical phenotypes, particularly recurrent respiratory infections and lymphoproliferation. Here we report a pediatric patient with APDS who presented with recurrent respiratory infections, lymphoproliferation, hepatosplenomegaly, bronchoscopy suggesting numerous nodular protrusions in the airways and a decrease in both T and B lymphocytes, and progression to plasmablastic lymphoma (PBL) after 1 year. Whole exome sequencing revealed a heterozygous mutation in the PIK3CD gene (c.3061 G>A p.E1021K). This is the first reported case of APDS combined with PBL and pediatricians should follow up patients with APDS regularly to be alert for secondary tumours.

PMID:34992612 | PMC:PMC8724197 | DOI:10.3389/fimmu.2021.813261

Front Immunol. 2021 Dec 21;12:780134. doi: 10.3389/fimmu.2021.780134. eCollection 2021.

ABSTRACT

OBJECTIVE: Inborn errors of immunity (IEI) are a heterogeneous group of disorders, affecting different components of the immune system. Over 450 IEI related genes have been identified, with new genes continually being recognized. This makes the early application of next-generation sequencing (NGS) as a diagnostic method in the evaluation of IEI a promising development. We aimed to provide an overview of the diagnostic yield and time to diagnosis in a cohort of patients suspected of IEI and evaluated by an NGS based IEI panel early in the diagnostic trajectory in a multicenter setting in the Netherlands.

STUDY DESIGN: We performed a prospective observational cohort study. We collected data of 165 patients with a clinical suspicion of IEI without prior NGS based panel evaluation that were referred for early NGS using a uniform IEI gene panel. The diagnostic yield was assessed in terms of definitive genetic diagnoses, inconclusive diagnoses and patients without abnormalities in the IEI gene panel. We also assessed time to diagnosis and clinical implications.

RESULTS: For children, the median time from first consultation to diagnosis was 119 days versus 124 days for adult patients (U=2323; p=0.644). The median turn-around time (TAT) of genetic testing was 56 days in pediatric patients and 60 days in adult patients (U=1892; p=0.191). A definitive molecular diagnosis was made in 25/65 (24.6%) of pediatric patients and 9/100 (9%) of adults. Most diagnosed disorders were identified in the categories of immune dysregulation (n=10/25; 40%), antibody deficiencies (n=5/25; 20%), and phagocyte diseases (n=5/25; 20%). Inconclusive outcomes were found in 76/165 (46.1%) patients. Within the patient group with a genetic diagnosis, a change in disease management occurred in 76% of patients.

CONCLUSION: In this cohort, the highest yields of NGS based evaluation for IEI early in the diagnostic trajectory were found in pediatric patients, and in the disease categories immune dysregulation and phagocyte diseases. In cases where a definitive diagnosis was made, this led to important disease management implications in a large majority of patients. More research is needed to establish a uniform diagnostic pathway for cases with inconclusive diagnoses, including variants of unknown significance.

PMID:34992599 | PMC:PMC8724043 | DOI:10.3389/fimmu.2021.780134

Pathog Immun. 2021 Oct 27;6(2):105-118. doi: 10.20411/pai.v6i2.405. eCollection 2021.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency characterized by low serum antibody levels and recurrent infections. The cellular response to immunization in patients with CVID has not been fully investigated. In this study, we aimed to characterize vaccination-induced influenza-specific memory B-cell responses in CVID.

METHODS: Eleven individuals affected with CVID and 9 unaffected control individuals were immunized with the 2010-2011 non-adjuvanted seasonal influenza vaccine. Blood samples were collected on the day of vaccination and at week 8 and week 16 after vaccination, and PBMCs were immunophenotyped by flow cytometry. Influenza specific serology was determined using hemagglutination inhibition and microneutralization against vaccine antigens. Influenza-specific memory B-cell responses were determined by ELISpot.

RESULTS: Individuals with CVID showed wide variability in the frequency of CD19+ B cells in blood. The CVID group had significantly reduced frequencies of CD19+CD27+ memory B cells. Frequencies of circulating T follicular helper (CD4+CXCR5+) cells were similar between those with CVID and healthy controls. In terms of serology, compared to healthy controls, the CVID group overall showed significantly reduced boosting to vaccine antigens by hemagglutination inhibition and microneutralization assays at 8 weeks compared to controls and failed to maintain responses by 16 weeks compared to controls, resulting in a post-vaccination geometric mean titer (GMT) ≥ 40 to strain A/H1N1 in only 27% at 8 weeks, and 22% at 12 weeks for patients with CVID vs 78% and 75%, respectively for healthy controls. In addition, there was a GMT ≥ 40 to A/H3N2 in only 9% at 8 weeks and 22% at 12 weeks for patients with CVID vs 56% and 50%, respectively for healthy controls. Healthy participants showed significant increases in flu-specific IgM-secreting memory B cells after vaccination, whereas patients with CVID showed non-signifi-cant mild increases. Before vaccination, patients with CVID had significantly lower frequencies of background level influenza-specific IgG and IgA memory B cells. Half of the patients with CVID showed an increase in influenza-specific IgG-secreting memory B cells post vaccination, whereas the other half showed none. All control participants exhibited an increase in influenza-specific IgG-secreting B cells. None of the patients with CVID developed influenza-specific IgA memory B-cell response post vaccination, compared to 5/8 in healthy controls. At week 16, the frequency of influenza-specific memory B-cell responses decayed but to non-zero baseline in healthy controls and to zero baseline in patients with CVID.

CONCLUSIONS: Together, these data demonstrate that patients with CVID respond heterogeneously, but as a group poorly, to non-adjuvanted influenza vaccine, with a subgroup unable to generate influenza-specific memory B-cell responses. No patient with CVID was able to maintain memory response for prolonged periods. Together, our results suggest a defect in Ig class switching and memory B-cell maintenance in patients with CVID during a de novo vaccine immune response.

PMID:34988341 | PMC:PMC8714177 | DOI:10.20411/pai.v6i2.405

Front Immunol. 2021 Dec 20;12:760019. doi: 10.3389/fimmu.2021.760019. eCollection 2021.

ABSTRACT

PURPOSE: Heterozygous missense STAT1 mutations leading to a gain of function (GOF) are the most frequent genetic cause of chronic mucocutaneous candidiasis (CMC). We describe the case of a patient presenting a new GOF mutation of STAT1 with the clinical symptoms of CMC, recurrent pneumonia, and persistent central erythema with papulopustules with ocular involvement related to rosacea-like demodicosis.

METHODS: Genetic analysis via targeted next-generation sequencing (NGS; NGS panel DIPAI v.1) exploring the 98 genes most frequently involved in primary immunodeficiencies, including STAT1, was performed to identify an underlying genetic defect.

RESULTS: NGS identified a novel variant of STAT1, c.884C>A (exon 10), p.T295Y, not previously described. This variant was found to be gain of function using an in vitro luciferase reporter assay. Rosacea-like demodicosis was confirmed by substantial Demodex proliferation observed via the microscopic examination of a cutaneous sample. A review of literature retrieved 20 other cases of STAT1 GOF mutations associated with early-onset rosacea-like demodicosis, most with ocular involvement.

CONCLUSION: We describe a new STAT1 GOF mutation associated with a phenotype of CMC and rosacea-like demodicosis. Rosacea-like demodicosis appears as a novel and important clinical phenotype among patients with STAT1 GOF mutation.

PMID:34987506 | PMC:PMC8721043 | DOI:10.3389/fimmu.2021.760019

Front Immunol. 2021 Dec 20;12:747738. doi: 10.3389/fimmu.2021.747738. eCollection 2021.

ABSTRACT

X-linked lymphoproliferative disease (XLP1) is a combined immunodeficiency characterized by severe immune dysregulation caused by mutations in the SH2D1A/SAP gene. Loss or dysfunction of SH2D1A is associated with the inability in clearing Epstein-Barr-Virus (EBV) infections. Clinical manifestation is diverse and ranges from life-threatening hemophagocytic lymphohistiocytosis (HLH) and fulminant infectious mononucleosis (FIM) to lymphoma and antibody deficiency. Rare manifestations include aplastic anemia, chronic gastritis and vasculitis. Herein, we describe the case of a previously healthy eight-year old boy diagnosed with XLP1 presenting with acute non-EBV acute meningoencephalitis with thrombotic occlusive vasculopathy. The patient developed multiple cerebral aneurysms leading to repeated intracerebral hemorrhage and severe cerebral damage. Immunological examination was initiated after development of a susceptibility to infections with recurrent bronchitis and one episode of severe pneumonia and showed antibody deficiency with pronounced IgG1-3-4 subclass deficiency. We could identify a novel hemizygous SH2D1A point mutation affecting the start codon. Basal levels of SAP protein seemed to be detectable in CD8⁺ and CD4⁺ T- and CD56⁺ NK-cells of the patient what indicated an incomplete absence of SAP. In conclusion, we could demonstrate a novel SH2D1A mutation leading to deficient SAP protein expression and a rare clinical phenotype of non-EBV associated acute meningoencephalitis with thrombotic occlusive vasculopathy.

PMID:34987501 | PMC:PMC8721048 | DOI:10.3389/fimmu.2021.747738