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Journal of Investigational Allergology... 2015X-linked lymphoproliferative syndrome type 2 is a rare hereditary immunodeficiency caused by mutations in the XIAP gene. This immunodeficiency frequently results in...
BACKGROUND
X-linked lymphoproliferative syndrome type 2 is a rare hereditary immunodeficiency caused by mutations in the XIAP gene. This immunodeficiency frequently results in hemophagocytic lymphohistiocytosis, although hypogammaglobulinemia and dysgammaglobulinemia are also common.
OBJECTIVE
We identified 17 patients from 12 Japanese families with mutations in XIAP. The Glu349del mutation was observed in 3 patients, each from a different family. Interestingly, these patients exhibited dysgammaglobulinemia but not hemophagocytic lymphohistiocytosis. We conducted an immunological study of patients carrying Glu349del and other mutations to elucidate the pathogenic mechanisms of dysgammaglobulinemia in patients with mutations in the XIAP gene.
PATIENTS AND METHODS
We performed an immunological study of 2 patients carrying the Glu349del mutation and 8 patients with other mutations.
RESULTS
Flow cytometry showed that the percentage of memory B cells in patients with a mutation in XIAP was lower than that observed in the healthy controls. The patients with the Glu349del mutation had a lower percentage of memory B cells than those with other mutations. Ig production was reduced in patients with the Glu349del mutation. Increased susceptibility to apoptosis was observed in the patients with other mutations. Susceptibility to apoptosis was normal in patients with Glu349del. Microarray analysis indicated that expression of Ig-related genes was reduced in patients with the Glu349del mutation and that the pattern was different from that observed in the healthy controls or patients with other mutations in XIAP.
CONCLUSIONS
Patients carrying the Glu349del mutation in the XIAP gene may have a clinically and immunologically distinct phenotype from patients with other XIAP mutations. The Glu349del mutation may be associated with dysgammaglobulinemia.
Topics: Adolescent; Apoptosis; Asian People; B-Lymphocytes; Case-Control Studies; Cells, Cultured; Child; Child, Preschool; DNA Mutational Analysis; Dysgammaglobulinemia; Female; Flow Cytometry; Gene Expression Profiling; Genetic Diseases, X-Linked; Genetic Predisposition to Disease; Humans; Immunologic Memory; Immunophenotyping; Infant; Japan; Lymphoproliferative Disorders; Male; Mutation; Oligonucleotide Array Sequence Analysis; Pedigree; Phenotype; T-Lymphocytes; X-Linked Inhibitor of Apoptosis Protein
PubMed: 26182687
DOI: No ID Found -
The Journal of Allergy and Clinical... Dec 2022X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency arising from SH2D1A mutations leading to loss of SLAM-associated protein (SAP). SAP is an...
BACKGROUND
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency arising from SH2D1A mutations leading to loss of SLAM-associated protein (SAP). SAP is an intracellular adaptor protein that binds to SLAM family receptors and is expressed in specific lymphoid lineages. In T cells, SAP relays activatory signals from the T-cell receptor but in its absence SH2 containing protein tyrosine phosphase-1 (SHP1), SH2 containing protein tyrosine phosphase-2 (SHP2), and SH2 containing inositol 5'-phosphatase proteins (SHIP) induce T-cell inhibitory signals leading to abnormal T-cell responses. This results in severe clinical manifestations including immune dysregulation, dysgammaglobulinemia, lymphoma, and hemophagocytic lymphohistiocytosis. Current treatment relies on supportive therapies including immunoglobulin replacement and symptom-directed therapy, with hematopoietic stem cell transplant offering the only curative option.
OBJECTIVES
As most XLP symptoms are due to defective T-cell function, this study investigated whether inhibition of SHP2 can restore cellular function in the absence of SAP.
METHODS
Healthy donor and XLP patient T cells were activated with anti-CD3/CD28 in T-cell media supplemented with a SHP2 inhibitor (RMC-4550 in vitro for 24 hours) and functional assays were performed to assess follicular T (T) cell function, CD8 cytotoxicity, and sensitivity to restimulation-induced cell death. Additionally, SAP-deficient (SAP) mice were treated with RMC-4550 before T-cell mediated challenge with 4-hydroxy-3-nitrophenylacetly conjugated chicken gammaglobulin and subsequent assessment of humoral immunity analyzing T cell population, germinal center formation, and antigen-dependent immunoglobulin secretion.
RESULTS
This study shows that the use of RMC-4550 restores T-cell function in XLP patient cells and a SAP model, demonstrating restoration of T cell function through immunoglobulin and cytokine secretion analysis alongside rescue of cytotoxicity and restimulation-induced cell death.
CONCLUSIONS
These data suggest that SHP2 inhibitors could offer a novel and effective targeted treatment approach for patients with XLP.
Topics: Animals; Mice; Signaling Lymphocytic Activation Molecule Associated Protein; Cell Death; T-Lymphocytes; Immunoglobulins
PubMed: 35839843
DOI: 10.1016/j.jaci.2022.06.021 -
European Journal of Haematology Apr 2021Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but... (Review)
Review
OBJECTIVES
Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but unifying guidance on immunoglobulin replacement therapy (IgRT) in these patients is lacking. We aimed to develop consensus statements for the use of IgRT in patients with HM.
METHODS
A Delphi exercise was employed to test the level of agreement on statements developed by a Task Force based on available data and their clinical experience. In Round 1, an Expert Panel, comprising specialist EU physicians caring for patients with HM, helped to refine the statements. In Round 2, experts rated their agreement with the statements. In Round 3, experts who had scored their agreement as ≤4 were invited to review their agreement based on the overall feedback.
RESULTS
Three definitions and 20 statements were formulated and tested for consensus, covering measurement of IgG levels, initiation and discontinuation of IgRT, dosing, and the use of subcutaneous IgG. Consensus (agreement ≥70% on Likert-type scale) was reached for all three definitions and 18 statements.
CONCLUSIONS
Recommendations have been developed with the aim of providing guidance for the use of IgRT to prevent severe, recurrent or persistent infections in patients with HM and SAD.
Topics: Consensus Development Conferences as Topic; Disease Management; Dysgammaglobulinemia; Europe; Hematologic Neoplasms; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Practice Guidelines as Topic; Treatment Outcome
PubMed: 33453130
DOI: 10.1111/ejh.13580 -
Pediatric Allergy and Immunology :... Feb 2020Primary B-cell immunodeficiency is the most frequent immune defect in infancy. Selective absence of serum and secretory immunoglobulin IgA is the most common, with rates...
Primary B-cell immunodeficiency is the most frequent immune defect in infancy. Selective absence of serum and secretory immunoglobulin IgA is the most common, with rates ranging from 1/333 persons to 1/16 000, among different races. By contrast, it has been estimated that hypo/agammaglobulinemia occurs with a frequency of 1/50 000 persons. Patients with antibody deficiency are usually recognized because they have recurrent infections with encapsulated bacteria or a history of failure to respond adequately to antibiotic treatment. However, some individuals, mainly those affected by IgA deficiency (SIgAD) or transient hypogammaglobulinemia of infancy , may have few or no infections.
Topics: Agammaglobulinemia; B-Lymphocytes; CD40 Ligand; Humans; Hyper-IgM Immunodeficiency Syndrome, Type 1; IgA Deficiency; Immunoglobulin A; Infant; Infant, Newborn; Infections; Lymphocyte Activation; Recurrence
PubMed: 32017208
DOI: 10.1111/pai.13166 -
JPMA. the Journal of the Pakistan... May 2022Berardinelli Seip Congenital Lipodystrophy (BSCL) or Congenital Generalized Lipodystrophy (CGL) is one of the four subgroups of lipodystrophy syndrome which is...
Berardinelli Seip Congenital Lipodystrophy (BSCL) or Congenital Generalized Lipodystrophy (CGL) is one of the four subgroups of lipodystrophy syndrome which is characterized by varying degrees of loss of adipose mass in the body. It is an extremely rare autosomal recessive disorder and commonly reported clinical presentations include muscular hypertrophy, gigantism, hepatomegaly, impaired glucose tolerance, acanthosis nigricans, hypertriglyceridaemia, cardiomyopathy, intellectual impairment, bone cysts and phlebomegaly. We present a case of a 4.5 years old male child born to consanguineous parents, presented with pneumonia. There was history of recurrent diarrhea and chest infection in the past. He had acromegaly like features, hirsutism, firm hepatomegaly, a well defined bone cyst in proximal right femur, pancytopenias with normal bone marrow biopsy report, hypertriglyceridemia and selective IgA deficiency. This is the first case of BSCL, reported in Pakistan with a bone cyst and IgA deficiency. Such patients need to be identified and monitored for complications like diabetes mellitus and hypertrophic cardiomyopathy.
Topics: Bone Cysts; Child, Preschool; Hepatomegaly; Humans; IgA Deficiency; Lipodystrophy; Lipodystrophy, Congenital Generalized; Male
PubMed: 35713067
DOI: 10.47391/JPMA.3182 -
Journal of Clinical Immunology Nov 2021Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical... (Clinical Trial)
Clinical Trial
Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).
Topics: Adolescent; Adult; Ataxia Telangiectasia; B-Lymphocytes; Child; Child, Preschool; Female; Humans; IgA Deficiency; IgG Deficiency; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Infant; Lymphocyte Count; Male; Middle Aged; T-Lymphocyte Subsets; Young Adult
PubMed: 34477998
DOI: 10.1007/s10875-021-01090-8 -
Revista Alergia Mexico (Tecamachalco,... 2017IgA deficiency is the most common primary immunodeficiency. Early diagnosis and clinical follow-up may improve the quality of life of patients with IgA deficiency. To...
BACKGROUND
IgA deficiency is the most common primary immunodeficiency. Early diagnosis and clinical follow-up may improve the quality of life of patients with IgA deficiency. To this end, IgA deficiency should be further studied and better understood on its clinical manifestations.
OBJECTIVE
To determine IgA deficiency clinical manifestations.
METHODS
Cross-sectional, retrospective, exploratory study, where the medical records of 39 patients with IgA deficiency were analyzed.
RESULTS
Among the analyzed cases, 10 patients were diagnosed with total IgA deficiency and 29 patients with partial IgA deficiency. Partial and total IgA deficiency main clinical manifestations were allergic rhinoconjunctivitis and allergic asthma. In total IgA deficiency, in addition to allergic diseases, a statistically significant number (p < 0.05) of cases of infection-related rhinosinusitis, tonsillitis and conjunctivitis were also observed.
CONCLUSION
This study showed that the main clinical manifestations in IgA deficiency were allergic rhinoconjunctivitis and allergic asthma. In addition, patients with total IgA deficiency showed a significant increase in infection-related rhinosinusitis, tonsillitis and conjunctivitis, when compared with patients with partial IgA deficiency.
Topics: Adolescent; Adult; Asthma; Child; Child, Preschool; Conjunctivitis, Allergic; Cross-Sectional Studies; Dimerization; Early Diagnosis; Female; Humans; IgA Deficiency; Immunoglobulin A; Male; Retrospective Studies; Rhinitis; Symptom Assessment; Tonsillitis; Young Adult
PubMed: 28188711
DOI: 10.29262/ram.v64i1.216 -
Frontiers in Immunology 2022IgA deficiency is the commonest immunodeficiency affecting up to 1 in 700 individuals. The effects of IgA deficiency are difficult to see in many individuals, are mild... (Review)
Review
IgA deficiency is the commonest immunodeficiency affecting up to 1 in 700 individuals. The effects of IgA deficiency are difficult to see in many individuals, are mild in many fewer and severe in fewer still. While monovalent IgA is found in serum, dimeric IgA is secreted through mucosal surfaces where it helps to maintain epithelial homeostasis. Studies with knockout mice have taught us that there are subtle inflammatory consequences of removing secretory IgA (sIgA), and the best explanation for these changes can be related by the loss of the 'excretory' immune system. The excretion of antigens is a logical process in regulating the immune system, given the long half-life of complement fixing antibodies. But the function of IgA as an immune or inflammation regulator may go beyond antigen removal.
Topics: Mice; Animals; IgA Deficiency; Immunoglobulin A, Secretory; Mucous Membrane; Biological Transport; Mice, Knockout
PubMed: 36618388
DOI: 10.3389/fimmu.2022.1076312 -
Journal of Child and Adolescent... May 2019Inflammation and immune dysregulation have been implicated in the pathogenesis of pediatric-onset obsessive-compulsive disorder (OCD) and tic disorders such as Tourette...
Inflammation and immune dysregulation have been implicated in the pathogenesis of pediatric-onset obsessive-compulsive disorder (OCD) and tic disorders such as Tourette syndrome (TS). Though few replicated studies have identified markers of immune dysfunction in this population, preliminary studies suggest that serum immunoglobulin A (IgA) concentrations may be abnormal in these children with these disorders. This observational retrospective cohort study, conducted using electronic health records (EHRs), identified 206 children with pediatric-onset OCD and 1024 adults diagnosed with OCD who also had testing for serum levels of IgA. IgA deficiency and serum IgA levels in pediatric OCD were compared with IgA levels from children diagnosed with autism spectrum disorders (ASD; = 524), tic disorders ( = 157), attention-deficit/hyperactivity disorder (ADHD; = 534), anxiety disorders ( = 1206), and celiac disease, a condition associated with IgA deficiency ( = 624). Compared with ASD and anxiety disorder cohorts, the pediatric OCD cohort displayed a significantly higher likelihood of IgA deficiency (OR = 1.93; 95% CI = 1.18-3.16, and OR = 1.98; 95% CI = 1.28-3.06, respectively), though no difference was observed between pediatric OCD and TS cohorts. Furthermore, the pediatric OCD cohort displayed similar rates of IgA deficiency and serum IgA levels when compared with the celiac disease cohort. The pediatric OCD cohort also displayed the highest percentage of IgA deficiency (15%,) when compared with TS (14%), celiac disease (14%), ADHD (13%), ASD (8%), and anxiety disorder (8%) cohorts. When segregated by sex, boys with OCD displayed a significantly higher likelihood of IgA deficiency when compared with all comparison cohorts except for celiac disease and tic disorders; no significant difference in IgA deficiency was observed between female cohorts. Pediatric OCD subjects also displayed significantly lower adjusted serum IgA levels than the ASD and anxiety disorder cohorts. Adults with OCD were also significantly less likely than children with OCD to display IgA deficiency (OR = 2.71; 95% CI = 1.71-4.28). When compared with children with celiac disease, no significant difference in IgA levels or rates of IgA deficiency were observed in the pediatric OCD cohort. We provide further evidence of IgA abnormalities in pediatric-onset OCD. These results require further investigation to determine if these abnormalities impact the clinical course of OCD in children.
Topics: Adolescent; Age Factors; Celiac Disease; Child; Cohort Studies; Dysgammaglobulinemia; Female; Humans; Immunoglobulin A; Male; Mental Disorders; Obsessive-Compulsive Disorder; Retrospective Studies; Sex Factors
PubMed: 30892924
DOI: 10.1089/cap.2018.0043 -
Harefuah Nov 2017Bronchiectasis is characterized by an abnormal dilatation of the bronchi leading to a chronic inflammatory process, airway blockage and impaired clearance of secretions.... (Review)
Review
Bronchiectasis is characterized by an abnormal dilatation of the bronchi leading to a chronic inflammatory process, airway blockage and impaired clearance of secretions. The damage to the airways is usually progressive and is the result of several pathogenic processes. In the past, healing of infections (especially pulmonary tuberculosis) was the main cause of airway dilatation and progression of chronic inflammation. Today, congenital illnesses, anatomical defects and immune deficiency play an important role in the pathogenesis of bronchiectasis formation. The immunoglobulin repertoire is vital for effective host protection against a wide variety of pathogens. Primary antibody deficiency diseases are defects of the humoral arm of the immune system and involve an absence/reduced levels of one or more immunoglobulin classes/subclasses or defects of specific antibody formation. Immunoglobulin G (IGG) subclass deficiency can occur in a healthy person and could be without clinical significance. However, in recent years there is emerging evidence that in patients with recurrent infections, early diagnosis of antibody deficiency affects the prognosis and prevention of ongoing lung damage. The use of IVIG has contributed significantly to the survival rate in primary antibody deficiencies. There is limited literature on the treatment of IVIG for patients with IGG subclass deficiency. However, all studies presented so far demonstrated that immunoglobulin therapy reduced the rate of bacterial infections, days of antibiotic usage, hospital admissions and significantly increased patients' quality of life. Therefore, in the appropriate clinical setting, ie: a patient with bronchiectasis and recurrent infections, it is justified to test whether there are humoral immune defects such as IGG subclass deficiency. In a patient with proven deficiency, we should recommend to start IVIG treatment until clinical benefit is achieved.
Topics: Bacterial Infections; Bronchiectasis; Humans; IgG Deficiency; Immunoglobulin G; Immunoglobulins, Intravenous; Quality of Life
PubMed: 29198088
DOI: No ID Found