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Immunodeficiency and disorders of immune dysregulation.

Pediatr Allergy Immunol. 2020 Feb;31 Suppl 24:8-10

Authors: Delmonte OM

Abstract
The spectrum of clinical features associated with primary immune deficiency disorders (PIDs) has broadened due to the recent identification of many novel causative genes. Patients present with increased susceptibility to infections in addition to significant immune dysregulation, often leading to multiple autoimmunity, lymphoproliferation, and malignancy. Immunosuppressive treatment is often required but has to be weighed against augmented infectious risk. Recently, the improved molecular understanding of the mechanisms underlying many loss-of-function (LOF) and gain-of-function (GOF) genetic defects leading to PIDs has set the ground for the development of mechanism-based therapeutic strategies that target a specific cell function. This article describes the clinical and laboratory features of selected recently described PIDs associated with immune dysregulation and novel precision medicine strategies aimed to control the disease burden in affected patients.

PMID: 32017223 [PubMed – in process]

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Diagnostic approach of hypogammaglobulinemia in infancy.

Pediatr Allergy Immunol. 2020 Feb;31 Suppl 24:11-12

Authors: Plebani A, Palumbo L, Dotta L, Lougaris V

Abstract
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.

PMID: 32017208 [PubMed – in process]

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Biallelic Form of a Known CD3E Mutation in a Patient with Severe Combined Immunodeficiency.

J Clin Immunol. 2020 Feb 04;:

Authors: Erman B, Fırtına S, Fışgın T, Bozkurt C, Çipe FE

PMID: 32016651 [PubMed – as supplied by publisher]

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Fluctuations of antimitochondrial antibodies and anti-gp210 antibody in a patient with primary biliary cholangitis and Sjögren syndrome with subsequent autoimmune hemolytic anemia: A case report.

Medicine (Baltimore). 2020 Jan;99(3):e18856

Authors: Zhao DT, Liu YM, Han Y, Zhang HP, Zhao Y, Yan HP

Abstract
RATIONALE: Primary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease. It is often associated with extrahepatic autoimmune disorders. However, the concurrence of PBC and Sjögren syndrome (SS) with the subsequent onset of autoimmune hemolytic anemia (AIHA) is extremely rare.
PATIENT CONCERNS: This study investigated a 60-year-old woman admitted to our hospital with complaints of xerostomia for 5 years, pruritus for 3 years, and abnormal liver function for 3 months.
DIAGNOSES: The patient was suffering from typical clinical PBC and SS, and developed decompensated liver cirrhosis after 32 months of ursodeoxycholic acid (UDCA) therapy. In May 2018, she was readmitted to the hospital with a high fever of 39 °C, coughing, and sever fatigue without remission after 3 days of cephalosporin antibiotic therapy. During the clinical course of PBC, her antimitochondrial antibodies (AMA) titers fluctuated from 1:1000 to negative and then to weakly positive, determined by indirect immunofluorescence (IIF), immunoblotting, and enzyme-linked immunosorbent assay (ELISA) based on recombinant mitochondrial antigens; furthermore, her titers of anti-gp210, an antinuclear antibody (ANA), increased sharply. Laboratory tests and imaging were performed to diagnose PBC and SS in September 2015. However, she was subsequently diagnosed with AIHA after 32 months of UDCA therapy based on the identification of pancytopenia, increased reticulocyte (RET) count, and a positive result from the direct Coombs test.
INTERVENTIONS: UDCA, hepatic protectant, albumin infusion, chest drainage, rational antibiotic use, diuretics, and methylprednisolone were used to treat the patient.
OUTCOMES: Liver cirrhosis was complicated by the development of AIHA, which became severe at 42 months of follow-up.
LESSONS: This is the first case report showing a patient with comorbid PBC and SS, as well as the sequential development of AIHA with decreased AMA and increased anti-gp210 titers; this may have been due to immunodeficiency. These findings stress the importance of the serological screening of ANA profile, as well as repeated measurement of ANA and AMA to track PBC progression and prognosis.

PMID: 32011506 [PubMed – in process]

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The role of allogeneic hematopoietic stem cell transplantation and Epstein-Barr virus infection on the treatment for child primary hemophagocytic lymphohistiocytosis patients with X-linked lymphoproliferative disease: A rare case report and family survey study.

Pediatr Transplant. 2020 Feb 03;:e13635

Authors: Cui T, Wang Y, Wang J, Zhang J, Gao Z, Wang Z

Abstract
XLP-2 is known as a rare primary immunodeficiency disease, which is characterized by the susceptibility to EBV infection and potential development into the pHLH. The existing studies believe that the dysfunction of XIAP represents one of the most significant pathogenic mechanisms of XLP-2, and allo-HSCT is regarded as a crucial treatment for the long-term survival in XLP-2 patients. In our present study, a 2-year-old male patient was diagnosed with XLP-2. After receiving chemotherapy by using HLH-2004 without allo-HSCT, he reached a complete remission, and his EBV load was brought under control. Our family survey revealed a novel frameshift mutation in the XIAP gene in this patient, as well as in his cousin and grandfather. Until now, the patient has been followed up for 22 months with no recurrence reported yet. Based on these findings, it is believed that for child pHLH patients with XLP-2, the treatment by controlling symptoms alone without allo-HSCT and with regular monitoring of EBV load could be conducive to a long-term survival.

PMID: 32011062 [PubMed – as supplied by publisher]

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Flow Cytometry for the Diagnosis of Primary Immunodeficiency Diseases: A Single Center Experience.

Allergy Asthma Immunol Res. 2020 Feb;12(2):292-305

Authors: Kwon WK, Choi S, Kim HJ, Huh HJ, Kang JM, Kim YJ, Yoo KH, Ahn K, Cho HK, Peck KR, Jang JH, Ki CS, Kang ES

Abstract
PURPOSE: While there is an urgent need for diagnosis and therapeutic intervention in patients with primary immunodeficiency diseases (PIDs), current genetic tests have drawbacks. We retrospectively reviewed the usefulness of flow cytometry (FCM) as a quick tool for immunophenotyping and functional assays in patients suspected to have PIDs at a single tertiary care institute.
METHODS: Between January 2001 and June 2018, patients suspected of having PIDs were subjected to FCM tests, including lymphocyte subset analysis, detection of surface- or intracellular-target proteins, and functional analysis of immune cells, at Samsung Medical Center, Seoul, Korea. The genetic diagnosis was performed using Sanger or diagnostic exome sequencing.
RESULTS: Of 60 patients diagnosed with definite or probable PID according to the European Society of Immune Deficiencies criteria, 24 patients were provided with useful information about immunological dysfunction after initial FCM testing. In 10 patients, the PID diagnosis was based on abnormal findings in FCM testing without genetic tests. The FCM findings provided strong evidence for the diagnosis of severe combined immunodeficiency (n = 6), X-linked chronic granulomatous diseases (CGD) (n = 6), leukocyte adhesion deficiency type 1 (n = 3), X-linked agammaglobulinemia (n = 11), autoimmune lymphoproliferative syndrome-FASLG (n = 1), and familial hemophagocytic lymphohistiocytosis type 2 (n = 1), and probable evidence for autosomal recessive-CGD (n = 2), autosomal dominant-hyper-immunoglobulin E (IgE)-syndrome (n = 1), and STAT1 gain-of-function mutation (n = 1). In PIDs derived from PIK3CD (n = 2), LRBA (n = 2), and CTLA4 mutations (n = 3), the FCM test provided useful evidence of immune abnormalities and a tool for treatment monitoring.
CONCLUSIONS: The initial application of FCM, particularly with known protein targets on immune cells, would facilitate the timely diagnosis of PIDs and thus would support clinical decisions and improve the clinical outcome.

PMID: 32009323 [PubMed]

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Human BCL10 Deficiency due to Homozygosity for a Rare Allele.

J Clin Immunol. 2020 Feb 01;:

Authors: Van Den Rym A, Taur P, Martinez-Barricarte R, Lorenzo L, Puel A, Gonzalez-Navarro P, Pandrowala A, Gowri V, Safa A, Toledano V, Cubillos-Zapata C, López-Collazo E, Vela M, Pérez-Martínez A, Sánchez-Ramón S, Recio MJ, Casanova JL, Desai MM, Perez de Diego R

Abstract
In 2014, a child with broad combined immunodeficiency (CID) who was homozygous for a private BCL10 allele was reported to have complete inherited human BCL10 deficiency. In the present study, we report a new BCL10 mutation in another child with CID who was homozygous for a BCL10 variant (R88X), previously reported as a rare allele in heterozygosis (minor allele frequency, 0.000003986). The mutant allele was a loss-of-expression and loss-of-function allele. As with the previously reported patient, this patient had complete BCL10 deficiency. The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis. Cellular and immunological phenotypes were similar to those of the previous patient. TLR4, TLR2/6, and Dectin-1 responses were found to depend on BCL10 in fibroblasts, and final maturation of T cell and B cell maturation into memory cells was affected. Autosomal-recessive BCL10 deficiency should therefore be considered in children with CID.

PMID: 32008135 [PubMed – as supplied by publisher]

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Comprehensive Assessment of Respiratory Complications in Patients with Common Variable Immunodeficiency.

Ann Allergy Asthma Immunol. 2020 Jan 30;:

Authors: Moazzami B, Mohayeji Nasrabadi MA, Abolhassani H, Olbrich P, Azizi G, Shirzadi R, Modaresi M, Sohani M, Delavari S, Shahkarami S, Yazdani R, Aghamohammadi A

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by recurrent upper and lower respiratory tract infections and some non-infectious clinical complications.
OBJECTIVE: The current study aimed to provide a detailed evaluation of respiratory presentations and complications in a cohort of Iranian patients with CVID.
METHODS: The present retrospective cohort study was conducted on 245 CVID patients who were recorded at the Iranian primary immunodeficiency disorders registry network. Respiratory manifestations were evaluated by reviewing clinical hospital records, immunologic findings, pulmonary function tests (PFT), and high-resolution computed tomography (HRCT) scans.
RESULTS: The majority of patients (n=208, 85.2%) had experienced at least one episode of acute respiratory manifestation and pneumonia was observed in 31.6 % (n=77) of cases as a first disease manifestation. During the follow-up pneumonia, sinusitis and otitis media were documented in 166 (68.6%), 125 (51.2%) and 103 (42.6%) cases, respectively. Abnormal PFT measurements were documented in 53.8 % of patients. Among these patients, 21.5% showed restrictive changes, whereas 18.4% of patients showed an obstructive pattern. Bronchiectasis was the most frequent radiological finding confirmed in 27.2 % of patients. Patients with bronchiectasis were older at the time of immunodeficiency diagnosis ( p <0.001) and had longer diagnosis delay ( p <0.001) when compared to patients without bronchiectasis.
CONCLUSION: This study highlights the importance of monitoring the respiratory tract system even in asymptomatic patients. PFT and CT scans are the most commonly used techniques aiming to identify these patients early aiming to reduce the rate of long-term respiratory complications.

PMID: 32007567 [PubMed – as supplied by publisher]

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