Manish Butte

Liver-Associated Immune Abnormalities.

Autoimmun Rev. 2018 Nov 05;:

Authors: Grunebaum E, Avitzur Y

Abstract
In recent years, the cross talk between the liver and the immune system is being uncovered, in part by studying liver involvement in primary immune deficiencies (PID) and in part by investigating the alterations of the immune system following orthotic liver transplantation (OLT). Here we review some of the reciprocal interactions between the liver and the immune system. Patients with PID, particularly those involving inherited defects in T and B cells or innate immunity are prone to infections and inflammatory responses that often involve the liver. Omenn’s syndrome, familial hemophagocytic lymphohistiocytosis, AIRE, FOXP3 and CD25 deficiencies, common variable immunodeficiency, CD40 ligand deficiency, chronic granulomatous disease and autoimmune lymphoproliferative syndrome are some of the notable PID associated with typical hepatobiliary abnormalities. Knowledge gained from studying these PID together with laboratory and histological evaluations can assist in managing PID-associated liver dysfunction. The liver itself also has important effects on the immune system, as evident from the growing experience with patients surviving OLT. Up to 40% of pediatric patients who receive OLT suffer from post transplantation allergy, autoimmunity, and immune-mediated disorders (PTAA). PTAA is more common after liver and heart transplantations than kidney transplantations. Potential contributing factors for the increased frequency of PTAA after OLT include the age of the patients, the prolonged use of tacrolimus and the reduced regulatory immune function with a shift towards a TH2 immune response. Better understanding of the mechanisms leading to the development of PTAA after OLT will also improve the management of these conditions.

PMID: 30408587 [PubMed – as supplied by publisher]

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The overlap between allergy and immunodeficiency.

Curr Opin Pediatr. 2018 Dec;30(6):848-854

Authors: Sokol K, Milner JD

Abstract
PURPOSE OF REVIEW: The mechanisms underlying the overlap of, and relationship between, atopy and immunodeficiency are just beginning to be recognized, through the identification of novel genetic conditions and the reexamination of well known primary immunodeficiencies. The present review seeks both to frame the topic and to highlight the most recent literature combining allergy in the context of immunodeficiency.
RECENT FINDINGS: The true prevalence of atopic disorders in the setting of primary immunodeficiency as a whole is difficult to pinpoint, however there have been recent attempts to measure prevalence. Individual immunodeficiency disorders have been more carefully dissected for atopic disease and the mechanisms underlying the atopic phenotypic, whereas several newly described immune deficiencies because of single gene mutations are highly associated with atopic phenotypes. Finally, a number of novel genetic conditions with atopy being the primary feature, even in the absence of overt immune deficiency, have been described, providing instrumental clues into the diagnostic dilemmas these syndromes create.
SUMMARY: Defining and examining diseases with primary features of atopy and infection allow for a better understanding of the interplay between the two in rare disease, and hopefully sheds light on fundamental pathways involved in atopy and host defense in the general population.

PMID: 30407976 [PubMed – in process]

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Dysregulatory syndromes: the role of signal transducers and activators of transcription.

Curr Opin Pediatr. 2018 Dec;30(6):821-828

Authors: Bezrodnik L, Gaillard MI, Caldirola MS

Abstract
PURPOSE OF REVIEW: A comparative description of dysregulatory syndromes with mutations in signal transducer and activator of transcription (STAT) genes.
RECENT FINDINGS: STAT 1, 3 and 5b loss of function (LOF) and gain of function (GOF) mutations are a heterogeneous group of genetic disorders that range from immunodeficiency (ID) to autoimmune disease (AID), depending on the underlying signalling pathway defect. Between them, there are clear overlapping and differences in clinical presentation and laboratory findings.
SUMMARY: Dysregulatory syndromes due to LOF and GOF mutations in STAT1, 3 and 5b are a particular group of primary immunodeficiencies (PIDs) in which AID may be the predominant finding in addition to infections susceptibility. STAT1 GOF mutations were described as the major cause of chronic mucocutaneous candidiasis, while activating STAT3 mutations result in early-onset multiorgan autoimmunity and ID. Human STAT5b deficiency is a rare disease that also involves ID and severe growth failure. In recent years, the identification of the genes involved in these disorders allowed to differentiate these overlapping syndromes in order to choose the most effective therapeutic options.

PMID: 30407975 [PubMed – in process]

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Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2.

Front Pediatr. 2018;6:282

Authors: Lee PY

Abstract
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of systemic vasculopathy that often presents during early childhood. Linked to biallelic mutations in ADA2 (previously CECR1), DADA2 was initially described as a syndrome of recurrent fever, livedo racemosa, early-onset strokes, and peripheral vasculopathy that resembles polyarteritis nodosum. However, the wide spectrum of clinical findings and heterogeneity of disease, even among family members with identical mutations, is increasingly recognized. Evidence of systemic inflammation and vasculopathy is not uniformly present in DADA2 patients and some can remain asymptomatic through adulthood. Humoral immunodeficiency characterized by low immunoglobulin levels and increased risk of infection is another common feature of DADA2. Variable cytopenias including pure red cell aplasia that mimics Diamond-Blackfan anemia can also be primary manifestations of DADA2. How defects in a single gene translate into these heterogeneous presentations remains to be answered. In this review, we will summarize lessons learned from the pleiotropic clinical manifestations of DADA2.

PMID: 30406060 [PubMed]

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An X-Linked Hyper-IgM Patient Followed Successfully for 23 Years without Hematopoietic Stem Cell Transplantation.

Case Reports Immunol. 2018;2018:6897935

Authors: Kutukculer N, Karaca NE, Aksu G, Aykut A, Pariltay E, Cogulu O

Abstract
When caring for patients with life-limiting diseases, improving survival and optimizing quality of life are the primary goals. For patients with X-linked hyper-IgM syndrome (XHIGM), the treatment modality has to be decided for a particular patient regarding hematopoietic stem cell transplantation or intravenous immunoglobulin replacement therapy with P. jiroveci prophylaxis. A seven-year-old male patient was admitted with recurrent upper and lower respiratory tract infections and recurrent otitis media. His initial immunologic evaluation revealed low IgG and normal IgA and IgM levels with normal lymphocyte phenotyping and inadequate specific antibody responses. He was diagnosed as common variable immunodeficiency and began to receive intravenous immunoglobulin (IVIG) (0.5 gm/kg) with four-week intervals. During follow-up for 23 years under IVIG therapy, he was extremely well and never had severe infections. In 2017, targeted next generation sequencing was performed in order to understand his molecular pathology. A previously described hemizygous c.31C>T(p.Arg11Ter) mutation was found in CD40LG gene. The mother was heterozygous carrier for this mutation and his sister did not have any mutation. Flow cytometric analysis for CD40LG expression on activated T cells showed highly decreased, but not absent, CD40LG expression. In conclusion, diagnostic delay is a clinical problem for patients with CD40LG deficiency, because of low or normal IgM levels, showing that all the hypogammaglobulinemic patients, not only with high serum IgM levels, but also with normal to low IgM levels, have to be examined for CD40LG expression on activated T lymphocytes. Secondly, type of CD40LG mutations leads to enormous interpatient variations regarding serum IgM levels, CD40LG levels on activated T cells, age at diagnosis, severity of clinical findings, and follow-up therapies with or without hematopoietic stem cell therapy.

PMID: 30405923 [PubMed]

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Expanded skin virome in DOCK8-deficient patients.

Nat Med. 2018 Nov 05;:

Authors: Tirosh O, Conlan S, Deming C, Lee-Lin SQ, Huang X, NISC Comparative Sequencing Program, Su HC, Freeman AF, Segre JA, Kong HH

Abstract
Human microbiome studies have revealed the intricate interplay of host immunity and bacterial communities to achieve homeostatic balance. Healthy skin microbial communities are dominated by bacteria with low viral representation1-3, mainly bacteriophage. Specific eukaryotic viruses have been implicated in both common and rare skin diseases, but cataloging skin viral communities has been limited. Alterations in host immunity provide an opportunity to expand our understanding of microbial-host interactions. Primary immunodeficient patients manifest with various viral, bacterial, fungal, and parasitic infections, including skin infections4. Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare primary human immunodeficiency characterized by recurrent cutaneous and systemic infections, as well as atopy and cancer susceptibility5. DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes, regulates actin cytoskeleton, which is critical for migration through collagen-dense tissues such as skin6. Analyzing deep metagenomic sequencing data from DOCK8-deficient skin samples demonstrated a notable increase in eukaryotic viral representation and diversity compared with healthy volunteers. De novo assembly approaches identified hundreds of novel human papillomavirus genomes, illuminating microbial dark matter. Expansion of the skin virome in DOCK8-deficient patients underscores the importance of immune surveillance in controlling eukaryotic viral colonization and infection.

PMID: 30397357 [PubMed – as supplied by publisher]

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Are naïve T cells and class-switched memory (IgD- CD27+) B cells not essential for establishment and maintenance of pregnancy? Insights from a case of common variable immunodeficiency with pregnancy.

Med Hypotheses. 2018 Dec;121:36-41

Authors: Shigeta N, Nakamura H, Kumasawa K, Imai K, Saito S, Sakaguchi S, Kimura T

Abstract
The disruption of adaptive immune response has adverse effects on the establishment and maintenance of pregnancy. The adaptive immune system is regulated by several types of immune cells. However, there is limited information about cell hierarchy in the adaptive immune response to the establishment and maintenance of pregnancy in women. The assessment of the outcome of pregnancy in primary immunodeficiency diseases could help in understanding the cell hierarchy in the adaptive immune system during pregnancy. Common variable immunodeficiency (CVID) is a heterogeneous adaptive immune system disorder characterized by primary hypogammaglobulinemia. A few studies have previously reported the assessment of the T and B cell subpopulations in CVID patients. However, an assessment of the subpopulations of T and B cells and the outcome of pregnancy in women with CVID has not been reported till date. Most CVID patients show a general decrease in the expression of CD27 in B cells. The assessment of pregnancy and the subpopulations of T and B cells in CVID women with severe reduction in the naïve T and switched B cells could help understand whether these cells are essential for the establishment and maintenance of pregnancy in women.

PMID: 30396484 [PubMed – in process]

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Candidiasis of the Central Nervous System in Neonates and Children with Primary Immunodeficiencies.

Curr Fungal Infect Rep. 2018 Jun;12(2):92-97

Authors: Drummond RA, Lionakis MS

Abstract
Purpose of Review: Candida infections of the central nervous system (CNS) are a life-threatening complication of invasive infections that most often affect vulnerable groups of patients, including neonates and children with primary immunodeficiency disorders (PID). Here, we review the currently known risk factors for CNS candidiasis, focusing predominantly on the PID caused by biallelic mutations in CARD9.
Recent Findings: How the CNS is protected itself against fungal invasion is poorly understood. CARD9 promotes neutrophil recruitment and function, and is the only molecule shown to be critical for protection against CNS candidiasis in humans thus far.
Summary: Fundamental insights into the pathogenesis of CNS candidiasis gained from studying rare CARD9-deficient patients has significant implications for other patients at risk for this disease, such as CARD9-sufficient neonates. These findings will be important for the development of adjunctive immune-based therapies, which are urgently needed to tackle the global burden of invasive fungal diseases.

PMID: 30393511 [PubMed]

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Hematopoietic stem cell transplantation as treatment for patients with DOCK8 deficiency.

J Allergy Clin Immunol Pract. 2018 Nov 01;:

Authors: Aydin SE, Freeman AF, Al-Herz W, Al-Mousa HA, Arnaout RK, Aydin RC, Barlogis V, Belohradsky BH, Bonfim C, Bredius RG, Chu JI, Ciocarlie OC, Doğu F, Gaspar HB, Geha RS, Gennery AR, Hauck F, Hawwari A, Hickstein DD, Hoenig M, Ikinciogullari A, Klein C, Kumar A, Ifversen MRS, Matthes S, Metin A, Neven B, Pai SY, Parikh SH, Picard C, Renner ED, Sanal Ö, Schulz AS, Schuster F, Shah NN, Shereck EB, Slatter MA, Su HC, van Montfrans J, Woessmann W, Ziegler JB, Albert MH, inborn errors working party of the European Group for Blood and Marrow Transplantation (EBMT) and the European Society for Primary Immunodeficiencies (ESID)

Abstract
BACKGROUND: Biallelic variations in the DOCK8 gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease.
OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables.
METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8 deficient patients.
RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range: 0.7-27.2) between 1995 and 2015. After median follow-up of 26 months (3-135), 68 of 81 patients are alive (84%). Severe acute (III-IV) or chronic graft versus host disease (GVHD) occurred in 11% and 10% respectively. Causes of death wereinfections (n=5), GVHD (5), multi-organ failure (2) and pre-existent lymphoma (1). Survival after matched related (n=40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared to fully myeloablative busulfan-based regimens (97% vs. 78%; p=0.049). 96% of patients aged <8 years at HSCT survived, compared to 78% of those ≥8 years (p=0.06). Of 73 patients with chimerism data available, 65 (89%) had >90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections and Mollusca resolved better than food allergies or failure to thrive.
CONCLUSION: HSCT is curative in most DOCK8 deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced toxicity regimen may offer the best chance for survival.

PMID: 30391550 [PubMed – as supplied by publisher]

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