Manish Butte

A Computational Pipeline for the Diagnosis of CVID Patients.

Front Immunol. 2019;10:2009

Authors: Emmaneel A, Bogaert DJ, Van Gassen S, Tavernier SJ, Dullaers M, Haerynck F, Saeys Y

Abstract
Common variable immunodeficiency (CVID) is one of the most frequently diagnosed primary antibody deficiencies (PADs), a group of disorders characterized by a decrease in one or more immunoglobulin (sub)classes and/or impaired antibody responses caused by inborn defects in B cells in the absence of other major immune defects. CVID patients suffer from recurrent infections and disease-related, non-infectious, complications such as autoimmune manifestations, lymphoproliferation, and malignancies. A timely diagnosis is essential for optimal follow-up and treatment. However, CVID is by definition a diagnosis of exclusion, thereby covering a heterogeneous patient population and making it difficult to establish a definite diagnosis. To aid the diagnosis of CVID patients, and distinguish them from other PADs, we developed an automated machine learning pipeline which performs automated diagnosis based on flow cytometric immunophenotyping. Using this pipeline, we analyzed the immunophenotypic profile in a pediatric and adult cohort of 28 patients with CVID, 23 patients with idiopathic primary hypogammaglobulinemia, 21 patients with IgG subclass deficiency, six patients with isolated IgA deficiency, one patient with isolated IgM deficiency, and 100 unrelated healthy controls. Flow cytometry analysis is traditionally done by manual identification of the cell populations of interest. Yet, this approach has severe limitations including subjectivity of the manual gating and bias toward known populations. To overcome these limitations, we here propose an automated computational flow cytometry pipeline that successfully distinguishes CVID phenotypes from other PADs and healthy controls. Compared to the traditional, manual analysis, our pipeline is fully automated, performing automated quality control and data pre-processing, automated population identification (gating) and deriving features from these populations to build a machine learning classifier to distinguish CVID from other PADs and healthy controls. This results in a more reproducible flow cytometry analysis, and improves the diagnosis compared to manual analysis: our pipelines achieve on average a balanced accuracy score of 0.93 (±0.07), whereas using the manually extracted populations, an averaged balanced accuracy score of 0.72 (±0.23) is achieved.

PMID: 31543876 [PubMed – in process]

Powered by WPeMatico

The Spectrum of Underlying Causes of Iatrogenic Kaposi’s Sarcoma in a Large Series: A Retrospective Study.

Indian J Dermatol. 2019 Sep-Oct;64(5):392-399

Authors: Baykal C, Atci T, Buyukbabani N, Kutlay A

Abstract
Background: The frequency of clinicoepidemiological variants of Kaposi’s sarcoma (KS) differs markedly throughout the world. The iatrogenic variant is mainly associated with the use of immunosuppressive therapy.
Aims: We aimed to investigate the distribution of KS variants in our practice and elucidate the underlying causes of iatrogenic KS.
Methods: Consecutive KS patients seen in a single tertiary center were grouped according to the tumor variants and iatrogenic KS patients were evaluated about associated conditions.
Results: Among 137 patients, classic variant was the most frequent presentation (n = 88), followed by iatrogenic (n = 37) variant. Among the iatrogenic group, ten were transplant recipients. In 16 iatrogenic KS patients, systemic corticosteroid was used, in four for myasthenia gravis (MG) and in three for rheumatoid arthritis. In three patients, KS developed under topical corticosteroid (TC) treatment. Among iatrogenic KS patients, ten of them had a second primary neoplasm and one had congenital immunodeficiency syndrome.
Conclusions: Our study revealed one of the highest rates for iatrogenic KS (27%) reported in the literature. Besides well-known causes, relatively frequent association with MG was remarkable. Usage of different forms of TCs was the cause of KS in a few cases.

PMID: 31543535 [PubMed]

Powered by WPeMatico

The architecture of the IgG anti-carbohydrate repertoire in primary antibody deficiencies (PADs).

Blood. 2019 Sep 19;:

Authors: Jandus P, Frias Boligan K, Smith DF, de Graauw E, Grimbacher B, Jandus C, Abdelhafez MM, Despont A, Bovin N, Simon D, Rieben R, Simon HU, Cummings RD, von Gunten S

Abstract
Immune system failure in primary antibody deficiencies (PADs) has been linked to recurrent infections, autoimmunity and cancer, yet clinical judgment is often based on the reactivity to a restricted panel of antigens. Previously, we demonstrated that the human repertoire of carbohydrate-specific IgG exhibits modular organization related to glycan epitope structure. The current study compares the glycan-specific IgG repertoires among different PAD entities. Distinct repertoire profiles with extensive qualitative glycan-recognition defects were observed, characterized by the common loss of Gala- and GalNAc-reactivity and disease-specific recognition of microbial, self-antigens and tumor-associated carbohydrate antigens. Antibody repertoire analysis may provide a useful tool to elucidate the dimension and clinical implications of the immune system failure in individual patients.

PMID: 31537530 [PubMed – as supplied by publisher]

Powered by WPeMatico

Approaches to patients with variants in RAG genes: from diagnosis to timely treatment.

Expert Rev Clin Immunol. 2019 Sep 19;:

Authors: Bulkhi AA, Dasso JF, Schuetz C, Walter JE

Abstract
Introduction: Patients with primary immunodeficiency (PID) secondary to abnormal recombinase activating genes (RAG) can present with broad clinical phenotypes ranging from early severe infections to autoimmune complications and inflammation. Immunological phenotype may also vary from T-B- severe combined immunodeficiency (SCID) to combined immunodeficiency (CID) or antibody deficiencies with near normal T and B cell counts and even preserved specific antibody response to pathogens. It is not uncommon that RAG variants of uncertain significance (VUS) are identified by serendipity during a broad genetic screening process and pathogenic RAG variants are increasingly recognized among all age groups, including adults. Establishing the pathogenicity and clinical relevance of novel RAG variants can be challenging since RAG genes are highly polymorphic. This review paper aims to summarize clinical phenotypes of RAG deficiencies and provide practical guidance for confirming the direct link between specific RAG variants and clinical disease. Lastly, we will review current understanding of treatment option for patients with varying severity of RAG deficiencies. Area covered: This review discusses the different phenotypes and immunological aspects of RAG deficiencies, the diagnosis dilemma facing clinicians and an overview for current and advancement in treatments. Expert opinion: A careful analysis of immunological and clinical data and their correlation with genetic findings help to determine the significance of the genetic polymorphism. Advances in functional assays, as well as anti-cytokines antibodies, make it easier to resolve the diagnostic dilemma.

PMID: 31535575 [PubMed – as supplied by publisher]

Powered by WPeMatico

Characteristics of the patients followed with the diagnosis of common variable immunodeficiency and the complications.

Cent Eur J Immunol. 2019;44(2):119-126

Authors: Erdem SB, Gulez N, Genel F, Karaman S, Nacaroglu HT

Abstract
Introduction: In this study, we aimed to retrospectively evaluate the clinical and laboratory findings and complications of 28 common variable immunodeficiency (CVID) patients.
Material and methods: The clinical features and laboratory data of 28 CVID patients were evaluated.
Results: Nineteen patients were male. In 53.5% of the cases, complications included inflammatory bowel disease, cytopenia, bronchiectasis, granulomatous lymphocytic interstitial lung disease (ILD) and asthma. In their immunological evaluations, IgG, IgM, and IgA mean values were 474.8 ±214.1 mg/dl; 56.7 ±41.9 mg/dl; 35.3 ±58.2 mg/dl, respectively, and the vaccine response was positive in 64.2% of the cases. In all age groups, absolute lymphocyte counts, naive (CD19+IgD+27-), nonswitch (CD19+IgD-27+) memory B cells were numerically higher when compared to the data of healthy children; however, although switch memory (CD19+IgD+27+) B cells were proportionally low in the 4-8 and 12-18 age groups, they were low both numerically and proportionally in the 8-12 age group. No statistically significant difference was found between the cases with complications and without complications. But the cases with pulmonary complications were compared within the group, the CD8 ratio was high but the IgA level was low in patients with bronchiectasis and CD3 was numerically and proportionally low in the cases with ILD compared to others. According to the Paris classification, 11/27 (40.7%) of the cases, 3/27 (11.1%) of them and 13/27 (48.2%) of them were evaluated as MB0, MB1, and MB2, respectively.
Conclusions: In genetic studies, TACI (trans-membrane activator and calcium-modulating cyclophilin ligand interactor – TNFRSF13B) mutation was found positive in 25% of the cases.

PMID: 31530980 [PubMed]

Powered by WPeMatico

Primary Immunodeficiency And Cancer In Children: A Systematic Review.

Curr Pediatr Rev. 2019 Sep 17;:

Authors: Kebudi R, Kiykim A, Sahin MK

Abstract
The life span of patients with primary and secondary immunodeficiency has increased due to recent advances in diagnostic and therapeutic strategies. Primary immune deficiencies (PIDs) are genetic disorders that predispose patients to frequent infections, autoimmunity and malignancies. Genomic instability due to defective DNA repair processes and other unknown mechanisms in PID patients leads to an enhanced risk of cancer. PIDs were originally described as rare, to only occur in infants and young children, and to be associated with severe clinical symptoms. However, advances in gene sequencing technologies, have revealed that they are much more common than originally appreciated and are present in older children, adolescents, and adults. After infection, malignancy is the most prevalent cause of death in both children and adults with PIDs. The overall risk for developing cancer in patients with PID is estimated to range from 4.7 to 5.7 percent. A 1.4 to 1.6-fold excess relative risk of cancer has been reported for PIDs. In this paper, we review the various categories of PIDs in children and highlight their association with various malignancies. MEDLINE was searched to identify articles for inclusion. Three authors have independently screened literature search results and abstracted data from included studies. Increasing awareness among physicians regarding the diagnosis of PID and the tendency of PID patients to develop cancer may lead to earlier diagnosis. Early diagnosis, appropriate treatment may decrease morbidity and mortality.

PMID: 31530267 [PubMed – as supplied by publisher]

Powered by WPeMatico

SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.

Nat Immunol. 2019 Sep 16;:

Authors: Burgener AV, Bantug GR, Meyer BJ, Higgins R, Ghosh A, Bignucolo O, Ma EH, Loeliger J, Unterstab G, Geigges M, Steiner R, Enamorado M, Ivanek R, Hunziker D, Schmidt A, Müller-Durovic B, Grählert J, Epple R, Dimeloe S, Lötscher J, Sauder U, Ebnöther M, Burger B, Heijnen I, Martínez-Cano S, Cantoni N, Brücker R, Kahlert CR, Sancho D, Jones RG, Navarini A, Recher M, Hess C

Abstract
Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.

PMID: 31527833 [PubMed – as supplied by publisher]

Powered by WPeMatico

Functional flow cytometry of monocytes for routine diagnosis of innate primary immunodeficiencies.

J Allergy Clin Immunol. 2019 Sep 14;:

Authors: Ammann S, Fuchs S, Martin-Martin L, Castro CN, Spielberger B, Klemann C, Elling R, Heeg M, Speckmann C, Hainmann I, Kaiser-Labusch P, Horneff G, Thalhammer J, Bredius RG, Stadt UZ, Lehmberg K, Fuchs I, von Spee-Mayer C, Henneke P, Ehl S

Abstract
The evaluation of innate primary immunodeficiency can be challenging and the impact of identified mutations on gene function is not always self-evident. We clinically validate flow cytometry assays for monocyte function as simple diagnostic tools.

PMID: 31526803 [PubMed – as supplied by publisher]

Powered by WPeMatico