Sci Immunol. 2021 Oct 15;6(64):eabh0891. doi: 10.1126/sciimmunol.abh0891. Epub 2021 Oct 8.
ABSTRACT
[Figure: see text].
PMID:34623902 | DOI:10.1126/sciimmunol.abh0891
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Stanford Alliance for Primary Immunodeficiency
Stanford University
By Manish Butte
Sci Immunol. 2021 Oct 15;6(64):eabh0891. doi: 10.1126/sciimmunol.abh0891. Epub 2021 Oct 8.
ABSTRACT
[Figure: see text].
PMID:34623902 | DOI:10.1126/sciimmunol.abh0891
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By Manish Butte
Infect Dis Ther. 2021 Oct 8. doi: 10.1007/s40121-021-00528-1. Online ahead of print.
ABSTRACT
INTRODUCTION: Histopathological characteristics of cytomegalovirus (CMV) lymphadenitis have been well described. Rare studies have reported the immune status and clinical features. Clinically, experts believed that CMV lymphadenitis develops in immunocompromised and immunocompetent patients. Infectious mononucleosis (IM)-like syndrome is the most well-known clinical presentation.
METHODS: We reviewed archived CMV immunohistochemical stains on lymphoid tissues. The clinicopathological features of CMV-positive cases were studied.
RESULTS: For lymph nodes, we detected CMV in 29% (5/17) allogeneic peripheral blood hematopoietic stem cell transplantation (PBSCT) recipients, 29% (4/14) post-autologous PBSCT patients, 13% (6/47) patients treated with intravenous chemotherapy, and 9% (9/96) immunocompetent patients. We detected CMV in 7% (2/24) of tonsils but not in the nasopharynx, tongue base, or spleen specimens. The patients with iatrogenic immunodeficiency ranged from 37 to 76 years old. CMV infections developed a few years after lymphoma treatment (median duration after allogeneic PBSCT, 932 days; after autologous PBSCT, 370 days; and after chemotherapy, 626 days). The most common clinical presentation was neck mass (13/25, 42%), followed by asymptomatic image finding (10/25, 40%). Positron emission tomography/computed tomography (PET/CT) scan showed increased uptake compared to the liver in all patients (11/11, 100%). Of 10 lymphoma patients, 8 (80%) had a Deauville score of 4-5; they accounted for 30% (8/27) of lymphoma patients with false-positive PET/CT scan results. All cases were self-limiting. 96% (23/25) cases had Epstein-Barr virus coinfection, and EBER-positive cells were predominantly in a few germinal centers.
CONCLUSIONS: Cytomegalovirus (CMV) lymphadenitis and tonsillitis were subclinical infections, not primary CMV infection with IM-like syndrome. The lymphadenopathy typically developed a few years after lymphoma treatments in the middle-aged and the elderly. The lesions mimicked lymphoma relapse in PET scans. Therefore, recognizing CMV infection in lymphoid tissues is of clinical importance.
PMID:34623624 | DOI:10.1007/s40121-021-00528-1
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By Manish Butte
Acta Parasitol. 2021 Oct 8. doi: 10.1007/s11686-021-00473-6. Online ahead of print.
ABSTRACT
PURPOSE: To assess the IgG seroprevalence of Toxoplasma gondii as an indicator of past exposure and immunity against infection among children with Down syndrome (DS) in Sana’a city, Yemen. This preliminary study is justified by the primary immunodeficiency of children with DS and the opportunistic nature of the parasite, considering the vague situation of anti-Toxoplasma IgG seroprevalence among children with DS because of neglecting its study on local and global scales.
METHODS: This descriptive, facility-based, cross-sectional study was conducted among 107 children with DS hosted in six randomly selected rehabilitation centers for children with special needs in Sana’a city. Demographics of children and their mothers’ knowledge of toxoplasmosis were collected using a pre-designed, structured questionnaire. Anti-Toxoplasma IgG antibodies were measured in the sera of children using electrochemiluminescence assay.
RESULTS: Of 107 children with DS, 3 (2.8%) were seropositive for anti-Toxoplasma IgG. Approximately two-thirds (71/106) of the mothers of children with DS were aware of toxoplasmosis. Of whom, 83.1% (59/71) were aware of its congenital complications.
CONCLUSION: The majority of children with DS in Sana’a city are seronegative for anti-Toxoplasma IgG, where the seropositivity rate is lower than 3.0%. Therefore, children with DS are non-immune and susceptible to the acquisition of primary infections during their life. Further analytical studies are recommended to determine whether the defective immune response of children with DS is associated with false seronegativity, to assess the role of their mothers’ knowledge in reducing their exposure to infection if they were confirmed truly seronegative and to identify the predictors of infection among them.
PMID:34623612 | DOI:10.1007/s11686-021-00473-6
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By Manish Butte
JCI Insight. 2021 Oct 8;6(19):e144777. doi: 10.1172/jci.insight.144777.
ABSTRACT
Common variable immunodeficiency (CVID) is characterized by profound primary antibody defects and frequent infections, yet autoimmune/inflammatory complications of unclear origin occur in 50% of individuals and lead to increased mortality. Here, we show that circulating bacterial 16S rDNA belonging to gut commensals was significantly increased in CVID serum (P < 0.0001), especially in patients with inflammatory manifestations (P = 0.0007). Levels of serum bacterial DNA were associated with parameters of systemic immune activation, increased serum IFN-γ, and the lowest numbers of isotype-switched memory B cells. Bacterial DNA was bioactive in vitro and induced robust host IFN-γ responses, especially among patients with CVID with inflammatory manifestations. Patients with X-linked agammaglobulinemia (Bruton tyrosine kinase [BTK] deficiency) also had increased circulating bacterial 16S rDNA but did not exhibit prominent immune activation, suggesting that BTK may be a host modifier, dampening immune responses to microbial translocation. These data reveal a mechanism for chronic immune activation in CVID and potential therapeutic strategies to modify the clinical outcomes of this disease.
PMID:34622805 | DOI:10.1172/jci.insight.144777
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By Manish Butte
JCI Insight. 2021 Oct 8;6(19):e148887. doi: 10.1172/jci.insight.148887.
ABSTRACT
Hypomorphic RAG1 or RAG2 mutations cause primary immunodeficiencies and can lead to autoimmunity, but the underlying mechanisms are elusive. We report here a patient carrying a c.116+2T>G homozygous splice site mutation in the first intron of RAG1, which led to aberrant splicing and greatly reduced RAG1 protein expression. B cell development was blocked at both the pro-B to pre-B transition and the pre-B to immature B cell differentiation step. The patient B cells had reduced B cell receptor repertoire diversity and decreased complementarity determining region 3 lengths. Despite B cell lymphopenia, the patient had abundant plasma cells in the BM and produced large quantities of IgM and IgG Abs, including autoantibodies. The proportion of naive B cells was reduced while the frequency of IgD-CD27- double-negative (DN) B cells, which quickly differentiated into Ab-secreting plasma cells upon stimulation, was greatly increased. Immune phenotype analysis of 52 patients with primary immunodeficiency revealed a strong association of the increased proportion of DN B and memory B cells with decreased number and proportion of naive B cells. These results suggest that the lymphopenic environment triggered naive B cell differentiation into DN B and memory B cells, leading to increased Ab production.
PMID:34622798 | DOI:10.1172/jci.insight.148887
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By Manish Butte
Immunol Res. 2021 Oct 7. doi: 10.1007/s12026-021-09239-8. Online ahead of print.
ABSTRACT
In the diagnosis of primary immunodeficiencies which are heterogeneous groups of genetic disorders, next-generation sequencing strategies take an important place. Protein expression analyses and some functional studies which are fundamental to determine the pathogenicity of the mutation are also performed to accelerate the diagnosis of PIDs before sequencing. However, protein expressions and functions do not always reflect the genetic and clinical background of the disease even the existence of a pathogenic variant or vice versa. In this study, it was aimed to understand genotype-proteophenotype-clinicophenotype correlation by investigating the effect of mutation types on protein expression, function, and clinical severity in X-linked, autosomal dominant, and autosomal recessive forms of PIDs. It was searched in PubMed and Web of Science without any restrictions on study design and publication time. Totally, 1178 patients with PIDs who have 553 different mutations were investigated from 174 eligible full-text articles. For all mutations, the effect of mutation type on protein expressions and protein functions was analyzed. Furthermore, the most frequent missense and nonsense mutations that were identified in patients with PIDs were evaluated to determine the genotype-clinicophenotype correlation. Protein expressions and functions were changed depending on the mutation type and the affected domain. A significant relationship was observed between protein expression level and clinical severity among all investigated patients. There was also a positive correlation between clinical severity and the affected domains. Mutation types and affected domains should be carefully evaluated with respect to protein expression levels and functional changes during the evaluation of clinico-phenotype.
PMID:34622368 | DOI:10.1007/s12026-021-09239-8
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By Manish Butte
J Transl Genet Genom. 2021;5:200-217. doi: 10.20517/jtgg.2021.08. Epub 2021 Jun 17.
ABSTRACT
AIM: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.
METHODS: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.
RESULTS: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity.
CONCLUSION: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.
PMID:34622145 | PMC:PMC8494431 | DOI:10.20517/jtgg.2021.08
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By Manish Butte
Adv Anat Pathol. 2021 Oct 7. doi: 10.1097/PAP.0000000000000323. Online ahead of print.
ABSTRACT
Very early onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella classification composed of IBD-like diseases encompassing both classic IBD (Crohn’s disease and ulcerative colitis) and monogenic disorder, both arising before 6 years of age. VEO-IBD patients present significant clinical differences from IBD occurring in older children and in adults, including more severe disease, often unresponsive to conventional IBD therapy and a greater proportion of cases featuring an underlying genetic alteration. Histologic findings of gastrointestinal biopsies can show an IBD-like pattern (both Crohn’s disease-like and ulcerative colitis-like pattern), an apoptotic-like and enterocolitis-like pattern. Findings of specific morphologic alterations, such as villous blunting, apoptosis, dense eosinophilic infiltrates, lack of plasma cells and severe glandular atrophy, can suggest a monogenic disorder. Moreover, individuals with monogenic disorders may develop significant problems such as primary immunodeficiency, impacting treatment options. Finally, IBD histology in childhood can differ from that in older patients and adults. This complexity makes a differential diagnosis between IBD and other pediatric diseases involving the gastrointestinal tract difficult, especially considering that histologic features can be similar between different diseases. Without an appropriate diagnosis, the clinical course of VEO-IBD has greater potential for escalated treatment regimens involving extensive surgery and more intensive medical therapies rather than specific therapy directed toward the underlying defect. For these reasons, a pattern-based histologic approach correlated with clinical and laboratory findings with a multidisciplinary approach is fundamental to reach a correct diagnosis in an adequate clinical context.
PMID:34620740 | DOI:10.1097/PAP.0000000000000323
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By Manish Butte
Int Arch Allergy Immunol. 2021 Oct 7:1-13. doi: 10.1159/000519199. Online ahead of print.
ABSTRACT
INTRODUCTION: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders characterized by increased susceptibility to infections, immune dysregulation, and/or malignancy. Genetic studies, especially during the last decade, led to a better understanding of the pathogenesis of primary immunodeficiencies and contributed to their classification into distinct monogenic disorders falling under one of the >430 currently known inborn errors of immunity (IEI). The growing availability of molecular genetic testing resulted in the increasing identification of patients with IEI. Here, we evaluated the diagnostic yield and the clinical consequences of targeted next-generation sequencing (tNGS) in a cohort of 294 primary immunodeficiency patients, primarily consisting of cases with sporadic primary antibody deficiency.
METHOD: We have custom designed a tNGS panel to sequence a cohort of PID patients. Agilent’s HaloPlex Target Enrichment System for Illumina was used for DNA target enrichment.
RESULTS: tNGS identified a definite or predicted pathogenic variant in 15.3% of patients. The highest diagnostic rate was observed among patients with combined immunodeficiency or immune dysregulation, for whom genetic diagnosis may affect therapeutic decision-making.
CONCLUSION: Next-generation sequencing has changed diagnostic assignment and paved the way for targeted therapeutic intervention with agents directed at reverting the disease-causing molecular abnormality or its pathophysiological consequences. Therefore, such targeted therapies and identifying the genetic basis of PID can be essential for patients with manifested immune dysregulation as conventional immunomodulatory regimens may exert an immunosuppressive effect, aggravating their immunodeficiency or may only inadequately control autoimmune or lymphoproliferative manifestations.
PMID:34619682 | DOI:10.1159/000519199
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By Manish Butte
J Clin Immunol. 2021 Oct 7. doi: 10.1007/s10875-021-01144-x. Online ahead of print.
ABSTRACT
PURPOSE: The aim was to review the compliance, side effects and effectiveness of subcutaneous immunoglobulin (SCIG) supplementation in patients with primary immunodeficiencies (PID) who had previously received intravenous immunoglobulin (IVIG) therapy and subsequently switched to SCIG, as well as to compare these parameters in patients while considering body weight.
METHODS: Demographic data, clinical and laboratory findings, SCIG dose, and side effects of 87 patients were retrospectively obtained from patient files. In patients who first received IVIG and then SCIG, the monthly SCIG dose was calculated by multiplying the IVIG dose by 1.37. The total monthly SCIG dose was distributed via injection across three or four doses per month, thus every 7 or 10 days.
RESULTS: Of the 87 patients aged between one and 22 years, 50 were male (57.5%) and 37 were female (42.5%). The serum IgG levels of the SCIG group were higher and more stable than those of the IVIG group. The number of hospitalizations and infections decreased significantly after initiation of SCIG. Thirteen patients (14.9%) had low body weight (LBW) for their age, seven of whom were male (53.8%). Serum IgG levels of the LBW cohort were significantly elevated and more stable during the SCIG period than the IVIG period. Mild, local side effects were detected in 153 administrations (3.3%) in 30 patients with normal body weight, while no local reactions were recorded in the patients with LBW.
CONCLUSION: SCIG supplementation is an effective treatment for pediatric patients with PID. The preliminary data from the present study suggest that such treatment is also safe for LBW children. The numbers of patient hospitalizations and family visits to clinics were reduced, allowing our patients and their parents to live more normal lives.
PMID:34617265 | DOI:10.1007/s10875-021-01144-x
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