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PloS One 2022Primary antibody deficiencies (PADs) without an identified monogenetic origin form the largest and most heterogeneous group of primary immunodeficiencies. These patients...
BACKGROUND
Primary antibody deficiencies (PADs) without an identified monogenetic origin form the largest and most heterogeneous group of primary immunodeficiencies. These patients often remain undiagnosed for years and many present to medical attention in adulthood after several infections risking structural complications. Not much is known about their treatment, comorbidities, or prognosis, nor whether the various immunological forms (decreased total IgG, IgG subclass(es), IgM, IgA, specific antibody responses, alone or in combination(s)) should be considered as separate, clearly definable subgroups. The unclassified primary antibody deficiency (unPAD) study aims to describe in detail all PAD patients without an identified specific monogenetic defect regarding their demographical, clinical, and immunological characteristics at presentation and during follow-up. In constructing these patterns, the unPAD study aims to reduce the number of missed and unidentified PAD patients in the future. In addition, this study will focus on subclassifying unPAD to support the identification of patients at higher risk for infection or immune dysregulation related complications, enabling the development of personalized follow-up and treatment plans.
METHODS AND ANALYSIS
We present a protocol for a multicenter observational cohort study using the ESID online Registry. Patients of all ages who have given informed consent for participation in the ESID online Registry and fulfill the ESID Clinical Working Definitions for 'unclassified antibody deficiency', 'deficiency of specific IgG', 'IgA with IgG subclass deficiency', 'isolated IgG subclass deficiency', 'selective IgM deficiency', 'selective IgA deficiency' or 'common variable immunodeficiency' will be included. For all patients, basic characteristics can be registered at first registration and yearly thereafter in level 1 forms. Detailed characteristics of the patients can be registered in level 2 forms. Consecutive follow-up forms can be added indefinitely. To ensure the quality of the collected data, all data will be fully monitored before they are exported from the ESID online Registry for analysis. Outcomes will be the clinical and immunological characteristics of unPAD at presentation and during follow-up. Subgroup analyses will be made based on demographical, clinical and immunological characteristics.
Topics: Adult; Humans; IgA Deficiency; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Multicenter Studies as Topic; Observational Studies as Topic; Primary Immunodeficiency Diseases; Registries
PubMed: 35333892
DOI: 10.1371/journal.pone.0266083 -
Scandinavian Journal of Immunology Jul 2022
Topics: CD40 Ligand; Cytidine Deaminase; Humans; Hyper-IgM Immunodeficiency Syndrome; Mutation
PubMed: 35271747
DOI: 10.1111/sji.13155 -
Annals of Clinical and Translational... Apr 2022An association between movement disorders and immune-system dysfunction has been described in the context of rare genetic diseases such as ataxia telangiectasia as well...
An association between movement disorders and immune-system dysfunction has been described in the context of rare genetic diseases such as ataxia telangiectasia as well as infectious encephalopathies. We encountered a male patient who presented immunodeficiency of unknown etiology since childhood. A medication-refractory, progressive choreodystonic movement disorder emerged at the age of 42 years and prompted an exome-wide molecular testing approach. This revealed a pathogenic hemizygous variant in CD40LG, the gene implicated in X-linked hyper-IgM syndrome. Only two prior reports have specifically suggested a causal relationship between CD40LG mutations and involuntary hyperkinetic movements. Our findings thus confirm the existence of a particular CD40LG-related condition, combining features of compromised immunity with neurodegenerative movement abnormalities. Establishing the diagnosis is crucial because of potential life-threatening immunological complications.
Topics: Adult; CD40 Ligand; Child; Humans; Hyper-IgM Immunodeficiency Syndrome, Type 1; Male; Mutation
PubMed: 35267244
DOI: 10.1002/acn3.51538 -
Scientific Reports Mar 2022Germline ATM gene variations result in phenotypic heterogeneity characterized by a variable degree of disease severity. We retrospectively collected clinical, genetic,...
Germline ATM gene variations result in phenotypic heterogeneity characterized by a variable degree of disease severity. We retrospectively collected clinical, genetic, and immunological data of 26 cases with A-T. Clinical manifestations included oculocutaneous telangiectasia (100%), ataxia (100%), fever, loose stools or infection (67%), cerebellar atrophy (50%), nystagmus (8%), dysarthria (15.38%), and visual impairment (8%). Genetic analysis confirmed ATM gene variations in 16 unrelated cases. The most common type of variation was stopgain variants (56%). Immunoglobulin profile indicated reduced IgA, IgG, and IgM in 94%, 50%, and 20% cases, respectively. T cell lymphopenia was observed in 80% of cases among those investigated. Unusual presentations included an EBV-associated smooth muscle tumour located in the liver in one case and Hyper IgM syndrome-like presentation in two cases. Increased immunosenescence was observed in T-cell subsets (CD4+CD57+ and CD8+CD57+). T-cell receptor excision circles (TRECs) were reduced in 3/8 (37.50%) cases.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Humans; Hyper-IgM Immunodeficiency Syndrome; Mutation; Retrospective Studies; T-Lymphocyte Subsets
PubMed: 35260754
DOI: 10.1038/s41598-022-08019-0 -
Supportive Care in Cancer : Official... Jun 2022In secondary immunodeficiency, immunoglobulin replacement therapy (IgRT) is recommended by guidelines (GL) for patients with IgG level < 4 g/l and more than 3...
Immunoglobulin substitution in patients with secondary antibody deficiency in chronic lymphocytic leukemia and multiple myeloma: a representative analysis of guideline adherence and infections.
INTRODUCTION
In secondary immunodeficiency, immunoglobulin replacement therapy (IgRT) is recommended by guidelines (GL) for patients with IgG level < 4 g/l and more than 3 infections or a severe infection. IgRT may be appropriate if IgG level < 4 g/l and/or 1-3 less severe infections (≤ grade 2).
METHODS
This was a retrospective sample analysis representative for practices and hospitals in Germany. The treatments and infection data were collected from patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). GL adherence (GLAD) was analyzed.
RESULTS
Data from 1086 patients (CLL 490, MM 596) were collected from 86 centers. Of all patients, 34.8% developed IgG deficiency during therapy (CLL 35.5%; MM 34.2%). IgRT was given in 23.5% of CLL and 14.4% of MM patients. GLAD in hypogammaglobulinemia and indication to IgRT was 23.3% of 86 CLL and 22.1% of 77 MM patients. Without GLAD, the hazard ratio (HR) for any infection was 4.49 (95% CI 3.72-5.42; p < 0.001) and for severe infections (grade ≥ 3) 10.64 (95% CI 7.54-15.00; p < 0.001). Significant independent risk factors for infections were a higher Charlson Comorbidity Index, IgG deficiency, and 3 + line treatment, as well as therapy with BTK inhibitors or chemotherapy in CLL. Multivariable analysis showed a significantly lower risk of severe infections after start of IgRT with a HR of 0.47 (95% CI 0.28-0.77; p = 0.003).
CONCLUSIONS
Guideline adherence correlated with fewer and less severe infections but was low in patients with indication to IgRT. Risk factors for infection can be identified. Risk of severe infections was significantly lower in patients with IgRT.
Topics: Guideline Adherence; Humans; IgG Deficiency; Immunoglobulin G; Immunologic Deficiency Syndromes; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Retrospective Studies
PubMed: 35257229
DOI: 10.1007/s00520-022-06920-y -
Journal of Clinical Immunology May 2022Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which...
Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients.
Topics: Cytidine Deaminase; Humans; Hyper-IgM Immunodeficiency Syndrome; Immunoglobulin Class Switching; Mutation; Phenotype; Siblings; Somatic Hypermutation, Immunoglobulin
PubMed: 35246784
DOI: 10.1007/s10875-022-01233-5 -
Disease Markers 2021Selective IgA deficiency (SIgAD) is the most frequent primary immune defect. Since SIgAD is not characterized by relevant infectious issues in most cases, it is often... (Review)
Review
Selective IgA deficiency (SIgAD) is the most frequent primary immune defect. Since SIgAD is not characterized by relevant infectious issues in most cases, it is often diagnosed during the diagnostic work up of several and different autoimmune disorders, which are associated with this primary immune defect. The genetic background of SIgAD is complex and three HLA haplotypes resulted to be more frequently associated with it; in detail, two of them include HLA-DQB102 allelic variants, which are essential predisposing factors to develop Celiac Disease (CD). Here, we discuss the evidence regarding the role of HLA in the etiopathogenesis of SIgAD and its association with CD. Actually, the HLA region seems to play a modest role in the genetic predisposition to SIgAD and we may speculate that the association with the HLA-DQB102 alleles (or haplotypes including them) could derive from its link with CD. Indeed, SIgAD and some related immunological alterations are likely to predispose to several autoimmune diseases (with and despite different HLA backgrounds), including CD, which is relatively common and directly associated with the HLA-DQB102 allelic variants coding the DQ2 heterodimer. Further and specific studies are needed to make final conclusions in this regard.
Topics: Celiac Disease; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; HLA-DQ beta-Chains; Haplotypes; Humans; IgA Deficiency
PubMed: 35186163
DOI: 10.1155/2021/8632861 -
Molecular Genetics & Genomic Medicine Mar 2022X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare primary immunodeficiency disorder characterized by severe immune dysregulation often after viral infection....
BACKGROUND
X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare primary immunodeficiency disorder characterized by severe immune dysregulation often after viral infection. It is caused by hemizygous mutations in the X-linked SH2D1A gene. People with XLP1 have complex and variable phenotype manifestations as EBV-driven severe or fulminant mononucleosis, hemophagocytic lymphohistiocytosis (EBV-HLH), dysgammaglobulinemia, and B-cell lymphoma.
METHODS
Immunological analyses, clinical laboratory testing, and whole exome sequencing (WES) were performed to help the disease diagnosis for the patient with severe immune dysregulation. Routine and extended WES analysis pipelines were applied to explore candidates. A complex genomic structural variation in SH2D1A was detected and verified by Inverse-PCR, Gap-PCR, and RT-PCR.
RESULTS
Here we reported that a five-year-old male patient manifested with EBV-HLH, recurrent infection by severe immune dysregulation, and successfully managed with HSCT. He finally established precise disease diagnosis as XLP1 caused by a complex genomic structural variation in SH2D1A (NC_000023.11:g. [124,350,560_124365777del; 124,365,777_124365917inv; 124,365,911_124365916del]). The mother and grandmother of the proband were confirmed to be carriers. The complex variant resulted in the exon 2 skipping and was predicted to generate a prematurely truncated protein.
CONCLUSION
The complex structural variant combined with paracentric inversion and large size deletions was first reported in XLP1 cases. It is considered to be pathogenic based on the truncation of the mRNA sequence and cosegregation with the disease in three-generation pedigree analysis. This finding has expanded the known XLP-related mutation spectrum in Chinese patients and indicated remarkable effects on the early diagnosis and therapeutic implication using proper molecular testing techniques.
Topics: Child, Preschool; Exons; Humans; Lymphoproliferative Disorders; Male; Mutation; Pedigree; RNA, Messenger; Signaling Lymphocytic Activation Molecule Associated Protein
PubMed: 35092357
DOI: 10.1002/mgg3.1873 -
Frontiers in Immunology 2021Individuals with immunoglobulin G deficiency (IgGsd) often complain of fatigue. The correlation between systemic inflammation and fatigue is unknown. In this study...
PURPOSE
Individuals with immunoglobulin G deficiency (IgGsd) often complain of fatigue. The correlation between systemic inflammation and fatigue is unknown. In this study perceived quality of life (QoL) and fatigue in individuals with IgGsd, on and off immunoglobulin replacement therapy (IgRT) were correlated to inflammatory markers in plasma to identify the subgroup that benefits from IgRT.
METHOD
Thirty-five IgGsd-patients were sampled on three occasions: at baseline, after being on IgRT for at least 18 months, and 18 months after discontinuation of IgRT. Short form 36, EQ-5D-5L visual analogue scale and fatigue impact scale questionnaires were used for evaluation of QoL and fatigue. Furthermore, a panel of 92 inflammatory markers were analysed in plasma. Thirty-two gender- and age-matched healthy individuals were included as controls and sampled on one occasion.
RESULTS
QoL was lower and perceived fatigue higher in IgGsd compared to the controls. Severe fatigue and low QoL were associated with the need to restart IgRT (which is considered in IgGsd-individuals with a high burden of infections in Sweden). Twenty-five inflammatory factors were dysregulated in IgGsd and the plasma protein patterns were similar regardless of whether IgRT was ongoing or not. Enrichment analysis indicated IL-10 signalling as the most affected pathway. Severe fatigue was associated with decreased levels of the neurotrophic factors VEGFA and CSF-1.
CONCLUSION
Fatigue is a major contributory factor to impaired health-related QoL in IgGsd and is related to the need for IgRT. Low-grade systemic inflammation is a potential driver of fatigue. In addition to the burden of infections, we suggest the degree of fatigue should be considered when the decision to introduce IgRT is made.
Topics: Adult; Aged; Chemokine CXCL1; Chemokine CXCL5; Fatigue; Female; Humans; IgG Deficiency; Immunoglobulin G; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-10; Male; Middle Aged; Quality of Life; Surveys and Questionnaires; Sweden; Young Adult
PubMed: 35082787
DOI: 10.3389/fimmu.2021.797336 -
Medicina (Kaunas, Lithuania) Jan 2022Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA... (Review)
Review
Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA (less than 7 mg/dL but normal serum IgG and IgM) in subjects greater than 4 years of age. Intrinsic defects in the maturation of B cells and a perturbation of Th cells and/or cytokine signals have been hypothesized to contribute to SIgAD pathogenesis. The genetic basis of IgA deficiency remains to be clarified. Patients with SIgAD can be either asymptomatic or symptomatic with clinical manifestations including allergy, autoimmunity and recurrent infections mainly of the respiratory and gastrointestinal tract. Studies analyzing allergy on SIgAD patients showed prevalence up to 84%, supporting in most cases the relationship between sIgAD and allergic disease. However, the prevalence of allergic disorders may be influenced by various factors. Thus, the question of whether allergy is more common in SIgAD patients compared to healthy subjects remains to be defined. Different hypotheses support an increased susceptibility to allergy in subjects with SIgAD. Recurrent infections due to loss of secretory IgA might have a role in the pathogenesis of allergy, and vice versa. Perturbation of microbiota also plays a role. The aim of this review is to examine the association between SIgAD and atopic disease and to update readers on advances over time at this important interface between allergy and SIgAD.
Topics: Autoimmunity; B-Lymphocytes; Humans; Hypersensitivity; IgA Deficiency; Prevalence
PubMed: 35056437
DOI: 10.3390/medicina58010129