Research

T-cell abnormalities in common variable immunodeficiency: the hidden defect.

J Clin Pathol. 2016 May 6;

Authors: Wong GK, Huissoon AP

Abstract
This review discusses how the T-cell compartment in common variable immunodeficiency is marked by the premature arrest in thymic output, leading to T-cell exhaustion and immune dysregulation. Although B cells have been the main focus of the disorder, ample experimental data suggest that T-cell abnormalities can be seen in a large proportion of Freiburg Group 1a patients and those suffering from inflammatory complications. The reductions in T-cell receptor excision circles, naïve T cells, invariant NKT cells and regulatory T cells suggest a diminished thymic output, while CD8 T cells are driven towards exhaustion either via an antigen-dependent or an antigen-independent manner. The theoretical risk of anti-T-cell therapies is discussed, highlighting the need for an international effort in generating longitudinal data in addition to better-defined underlying molecular characterisation.

PMID: 27153873 [PubMed – as supplied by publisher]

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Successful Hematopoietic Stem Cell Transplantation in a Patient with LPS-Responsive Beige-Like Anchor (LRBA) Gene Mutation.

J Clin Immunol. 2016 May 4;

Authors: Tesi B, Priftakis P, Lindgren F, Chiang SC, Kartalis N, Löfstedt A, Lörinc E, Henter JI, Winiarski J, Bryceson YT, Meeths M

Abstract
PURPOSE: Autosomal recessive mutations in LRBA, encoding for LPS-responsive beige-like anchor protein, were described in patients with a common variable immunodeficiency (CVID)-like disease characterized by hypogammaglobulinemia, autoimmune cytopenias, and enteropathy. Here, we detail the clinical, immunological, and genetic features of a patient with severe autoimmune manifestations.
METHODS: Whole exome sequencing was performed to establish a molecular diagnosis. Evaluation of lymphocyte subsets was performed for immunological characterization. Medical files were reviewed to collect clinical and immunological data.
RESULTS: A 7-year-old boy, born to consanguineous parents, presented with autoimmune hemolytic anemia, hepatosplenomegaly, autoimmune thyroiditis, and severe autoimmune gastrointestinal manifestations. Immunological investigations revealed low immunoglobulin levels and low numbers of B and NK cells. Treatment included immunoglobulin replacement and immunosuppressive therapy. Seven years after disease onset, the patient developed severe neurological symptoms resembling acute disseminated encephalomyelitis, prompting allogeneic hematopoietic stem cell transplantation (HSCT) with the HLA-identical mother as donor. Whole exome sequencing of the patient uncovered a homozygous 1 bp deletion in LRBA (c.7162delA:p.T2388Pfs*7). Importantly, during 2 years of follow-up post-HSCT, marked clinical improvement and recovery of immune function was observed.
CONCLUSIONS: Our data suggest a beneficial effect of HSCT in patients with LRBA deficiency.

PMID: 27146671 [PubMed – as supplied by publisher]

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[Primary hypogammaglobulinemia complicated with liver cirrhosis and literature review].

Zhonghua Er Ke Za Zhi. 2016 May;54(5):379-82

Authors: Deng ZH, Jiang LR, Zhang B, Xu YZ, Shen CH, Zhou T, Xia Q, Zhang TA

Abstract
OBJECTIVE: To explore the pathogenesis, treatment and prognosis of primary hypogammaglobulinemia complicated with liver cirrhosis in a child.
METHOD: Pathogenesis, treatment and prognosis of X-linked agammaglobulinemia (XLA ) complicated with liver cirrhosis in a child were analyzed in Shanghai Children’s Medical Center.Using”primary hypogammaglobulinemia”and”liver cirrhosis”as keywords, literatures were searched from Pubmed and Chinese data of Weipu and Wanfang data from January 1988 to January 2015.
RESULT: The patient was a 12 years old boy with the chief complaint of 3 times hematemesis with diagnosis of XLA in the past 7 years. He received treatment with immunoglobulin (Ig) monthly for 6 years. He had no hepatitis C virus( HCV ) infection and serologic tests for autoantibodies were negative. Anti-HBs, anti-HBe and anti-HBc were positive, which revealed previous hepatitis B virus(HBV) infection. Gastroscopy suggested esophageal gastric varices. Liver pathology showed liver cell degeneration, necrosis, fiber tissue hyperplasia and pseudolobuli. After hospitalization the boy underwent liver transplantation (LT). He was given tacrolimus (3 mg/d), prednisone (5 mg/d), lamivudine (150 mg/d) and acyclovir (900 mg/d) by oral administration after LT. After 3 months follow-up, the boy was alive and well with stable results of liver function tests. There were no report in Weipu and Wanfang data. A total of 19 cases, including 12 cases of common variable immunodeficiency, 3 cases of XLA, 2 cases of Hyper-IgM syndrome and 2 cases of congenital hypogammaglobulinemia were obtained from Pubmed published between January 1, 1988 and January 1, 2015. Seventeen of the cases had HCV infection. Two cases had autoimmune hepatitis. Of the HCV infected patients, 15 were given intravenous gamma globulin. Seven of the 19 cases survived. Among 5 cases who received liver transplantation, 3 cases died.
CONCLUSION: In addition to HCV infection and autoimmune hepatitis as causes of liver cirrhosis in primary hypogammaglobulinemia, chronic HBV infection is another cause. Intravenous gammaglobulin is an important way of transmitting HCV and HBV infection. The effect of liver transplantation remains to be evaluated via further follow-up and studies.

PMID: 27143082 [PubMed – in process]

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Rheumatologic manifestations of primary immunodeficiency diseases: comment on the study by Dimitriades et al.

Clin Rheumatol. 2016 May 3;

Authors: Toz B, Erer B

PMID: 27142373 [PubMed – as supplied by publisher]

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Hematopoietic stem cell transplantation outcomes for 11 patients with dedicator of cytokinesis 8 deficiency.

J Allergy Clin Immunol. 2016 Apr 6;

Authors: Al-Herz W, Chu JI, van der Spek J, Raghupathy R, Massaad MJ, Keles S, Biggs CM, Cockerton L, Chou J, Dbaibo G, Elisofon SA, Hanna-Wakim R, Kim HB, Lehmann LE, McDonald DR, Notarangelo LD, Veys P, Chatila TA, Geha RS, Gaspar HB, Pai SY

Abstract
BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Reports of outcomes are still limited.
OBJECTIVE: We sought to analyze the results of HSCT in patients with DOCK8 deficiency and report whether approaches resulting in mixed chimerism result in clinically relevant immune reconstitution.
METHODS: We performed a retrospective chart review of 11 patients with DOCK8 deficiency and measured DOCK8 expression and cytokine production.
RESULTS: Of 11 patients, 7 received HSCT from related and 4 from unrelated donors; 9 patients received busulfan-based conditioning regimens. Survival was excellent (10 [91%] of 11 patients alive), including a patient who had undergone liver transplantation. Patients showed significant improvements in the frequency and severity of infections. Although eczema resolved in all, food allergies and high IgE levels persisted in some patients. Lymphopenia, eosinophilia, low numbers of naive CD8(+) T cells and switched memory B cells, and TH1/TH2 cytokine imbalance improved in most patients. Although the 8 matched related or unrelated donor recipients had full donor chimerism, all 3 recipients of mismatched unrelated donor HSCT had high levels of donor T-cell chimerism and low B-cell and myeloid cell chimerism (0% to 46%). Almost all switched memory B cells were of donor origin. All patients, including those with mixed chimerism, mounted robust antibody responses to vaccination.
CONCLUSION: Allogeneic HSCT ameliorated the infectious and atopic symptoms of patients with DOCK8 deficiency. In patients with mixed chimerism, selective advantage for donor-derived T cells and switched memory B cells promoted restoration of cellular and humoral immunity and protection against opportunistic infection.

PMID: 27130861 [PubMed – as supplied by publisher]

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Hypereosinophilia in Children and Adults: A Retrospective Comparison.

J Allergy Clin Immunol Pract. 2016 Apr 27;

Authors: Williams KW, Ware J, Abiodun A, Holland-Thomas NC, Khoury P, Klion AD

Abstract
BACKGROUND: The differential diagnosis of hypereosinophilia is broad and includes asthma, atopic disease, drug hypersensitivity, parasitic infection, connective tissue disorders, malignancy, and rare hypereosinophilic disorders. Hypereosinophilia in children has not been well characterized to date.
OBJECTIVE: The objective of this study was to identify the common causes of marked eosinophilia in children and to characterize and compare the clinical symptoms at presentation, laboratory findings, final diagnosis, and therapeutic responses between children and adults with hypereosinophilic syndromes.
METHODS: A retrospective analysis of consecutive subjects evaluated for unexplained eosinophilia ≥ 1.5 × 10(9)/L was conducted. All subjects underwent standardized clinical and laboratory evaluations with yearly follow-up. Clinical and laboratory parameters, final diagnoses, treatment responses, and outcomes were assessed. Medians and proportions were compared using Mann-Whitney U and Fisher Exact tests, respectively.
RESULTS: Of the 291 subjects evaluated, 37 (13%) were children and 254 were adults (87%). Whereas the frequencies of clinical hypereosinophilic syndrome (HES) variants were similar between children and adults, primary immunodeficiency was a more common secondary cause of HES in children (5% vs 0.4% in adults). Excluding subjects with treatable secondary causes, the median peak absolute eosinophil count was increased in pediatric subjects (9376 vs 5543/μL; P = .002), and children had more gastrointestinal complaints (62% vs 34%; P = .003) and less pulmonary involvement (34% vs 59%; P = .01) than adults. Despite these differences, corticosteroid responsiveness and overall prognosis were similar between the 2 groups.
CONCLUSIONS: Although children with HES often present with higher peak eosinophil counts than adults, the differential diagnosis, clinical characteristics, and prognosis of HES are similar in the 2 groups.

PMID: 27130711 [PubMed – as supplied by publisher]

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Hypogammaglobulinemia associated with nodular lymphoid hyperplasia of the intestine and pernicious anaemia.

Tunis Med. 2015 Nov;93(11):662-4

Authors: Ouakaa-Kchaou A, Trad D, Boussourra H, Bibani N, Elloumi H, Kochlef A, Gargouri D, Kharrat J

Abstract
BACKGROUND: Nodular lymphoid hyperplasia of the gastrointestinal tract, recurrent acute pulmonary infections and autoimmune disease are well-recognized complications of common variable immunodeficiency.
AIM: We aimed to focus on clinical presentation and differential diagnosis of diffuse nodular lymphoid and hyperplasia of the gastrointestinal tract coexisting with hypogammaglobulinemia.
CASE-REPORT: We report the case of nodular lymphoid hyperplasia associated with pernicious anaemia in a young man with hypogammaglobulinemia and a long history of pulmonary infections.
CONCLUSION: The considerable point was a mismatch primary clinical diagnosis of familial adenomatous polyposis, due to prominent polyplike endoscopic appearance of the lesions throughout the digestive tract.

PMID: 27126419 [PubMed – in process]

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