Manish Butte

Severe Multisystem Involvement of Chronic Granulomatous Disease in a Pediatric Patient.

J Trop Pediatr. 2018 May 07;:

Authors: Bayramoglu Z, Adaletli I, Caliskan E, Acar M, Hancerli Torun S, Somer A

Abstract
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder identified by recurrent pyogenic and fungal infections infections secondary to defective nicotinamide adenine dinucleotide phosphate oxidase enzyme. In the present study, we demonstrated a case with a history of multiple segmental lung resections because of invasive bronchopulmonary aspergillosis, multifocal hepatic and splenic granulomas, bilateral adnexal calcific foci presumed to be related with old granulomatous infection and finally gastric outlet obstruction secondary to the involvement of the stomach wall thickening with granulomatous tissue. This is an extremely severe case of CGD with multiorgan involvement within a 10-year period after the diagnosis. Gastric antral involvement may mimic inflammatory bowel diseases in such cases, and intestinal involvement can reliably be demonstrated via ultrasonography. Spontaneous resolution of the antral involvement was observed in the follow-up.

PMID: 29741690 [PubMed – as supplied by publisher]

Powered by WPeMatico

B-cell subsets imbalance and reduced expression of CD40 in ataxia-telangiectasia patients.

Allergol Immunopathol (Madr). 2018 May 05;:

Authors: Pereira CTM, Bichuetti-Silva DC, da Mota NVF, Salomão R, Brunialti MKC, Costa-Carvalho BT

Abstract
BACKGROUND: Ataxia-telangiectasia (AT) is a well-known primary immunodeficiency with recurrent sinopulmonary infections and variable abnormalities in both the humoral and cellular immune system. Dysfunctions in immunoglobulin production, reduced number of B cells, and B-cell receptor excision circles copies have been reported. We aimed to understand the immunological mechanisms involving the humoral compartment in AT patients by analysing peripheral blood B cells subsets, B-T lymphocyte cooperation through the expression of CD40 and CD40 ligand (CD40L), and cytokines involved in class-switch recombination production.
METHODS: We compared the proportion of B-cell subsets, the expression of CD40/CD40L, and the plasma levels of IL-6 and IFN-γ of 18 AT patients and 15 healthy age-sex-matched controls using flow cytometry.
RESULTS: We found that some steps in peripheral B cell development were altered in AT with a pronounced reduction of cell-surface CD40 expression. The proportions of transitional and naïve-mature B cells were reduced, whereas CD21-low, natural effector memory, IgM-only memory, and IgG atypical memory B cells were present in a higher proportion.
CONCLUSIONS: These findings revealed a disturbed B-cell homeostasis with unconventional maturation of B lymphocyte memory cells, which can explain the consequent impairment of humoral immunity.

PMID: 29739685 [PubMed – as supplied by publisher]

Powered by WPeMatico

Molecular Classification of Primary Immunodeficiencies of T Lymphocytes.

Adv Immunol. 2018;138:99-193

Authors: Comrie WA, Lenardo MJ

Abstract
Proper regulation of the immune system is required for protection against pathogens and preventing autoimmune disorders. Inborn errors of the immune system due to inherited or de novo germline mutations can lead to the loss of protective immunity, aberrant immune homeostasis, and the development of autoimmune disease, or combinations of these. Forward genetic screens involving clinical material from patients with primary immunodeficiencies (PIDs) can vary in severity from life-threatening disease affecting multiple cell types and organs to relatively mild disease with susceptibility to a limited range of pathogens or mild autoimmune conditions. As central mediators of innate and adaptive immune responses, T cells are critical orchestrators and effectors of the immune response. As such, several PIDs result from loss of or altered T cell function. PID-associated functional defects range from complete absence of T cell development to uncontrolled effector cell activation. Furthermore, the gene products of known PID causal genes are involved in diverse molecular pathways ranging from T cell receptor signaling to regulators of protein glycosylation. Identification of the molecular and biochemical cause of PIDs can not only guide the course of treatment for patients, but also inform our understanding of the basic biology behind T cell function. In this chapter, we review PIDs with known genetic causes that intrinsically affect T cell function with particular focus on perturbations of biochemical pathways.

PMID: 29731008 [PubMed – in process]

Powered by WPeMatico

Phenotype, penetrance, and treatment of 133 CTLA-4-insufficient individuals.

J Allergy Clin Immunol. 2018 May 03;:

Authors: Schwab C, Gabrysch A, Olbrich P, Patiño V, Warnatz K, Wolff D, Hoshino A, Kobayashi M, Imai K, Takagi M, Dybedal I, Haddock JA, Sansom D, Lucena JM, Seidl M, Schmitt-Gräff A, Reiser V, Emmerich F, Frede N, Bulashevska A, Salzer U, Schubert D, Hayakawa S, Okada S, Kanariou M, Kucuk ZY, Chapdelaine H, Petruzelkova L, Sumnik Z, Sediva A, Slatter M, Arkwright PD, Cant A, Lorenz HM, Giese T, Lougaris V, Plebani A, Price C, Sullivan KE, Moutschen M, Litzman J, Freiberger T, van de Veerdonk FL, Recher M, Albert MH, Hauck F, Seneviratne S, Schmid JP, Kolios A, Unglik G, Klemann C, Speckmann C, Ehl S, Leichtner A, Blumberg R, Franke A, Snapper S, Zeissig S, Cunningham-Rundles C, Giulino-Roth L, Elemento O, Dückers G, Niehues T, Fronkova E, Kanderová V, Platt CD, Chou J, Chatila T, Geha R, McDermott E, Bunn S, Kurzai M, Schulz A, Alsina L, Casals F, Deyà-Martinez A, Hambleton S, Kanegane H, Taskén K, Neth O, Grimbacher B

Abstract
BACKGROUND: Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in humans.
OBJECTIVE: To characterize the penetrance, the clinical features and the best treatment options in 133 CTLA4 mutation carriers.
METHODS: Genetics, clinical features, laboratory values, and outcome of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers.
RESULTS: We identified 133 individuals from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting the clinical penetrance of at least 67%; median age of onset was 11 years, and mortality rate within affected mutation carriers was 16% (n=15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), respiratory- (68%), gastrointestinal- (59%), or neurological features (29%). Eight affected mutation carriers developed lymphoma, three gastric cancer. An EBV association was found in six malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and NK-cell counts. Successful targeted therapies included the application of CTLA-4-fusion-proteins, mTOR-inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in two affected mutation carriers under immunosuppression.
CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency may present in any medical specialty. Family members should be counseled, as disease manifestation may occur as late as age 50. EBV- and CMV-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.
CLINICAL IMPLICATION: This large cohort of affected CTLA4 mutation carriers gives first insights into different possible treatment options and presents available clinical information on treatment response and survival. With this knowledge, affected mutation carriers will benefit from an individualized management.

PMID: 29729943 [PubMed – as supplied by publisher]

Powered by WPeMatico

B cell differentiation and IL-21 response in IL2RG/JAK3 SCID patients after hematopoietic stem cell transplantation.

Blood. 2018 May 04;:

Authors: Miggelbrink AM, Logan BR, Buckley RH, Parrott RE, Dvorak CC, Kapoor N, Abdel-Azim H, Prockop SE, Shyr D, Decaluwe H, Hanson IC, Gillio A, Dávila Saldaña BJ, Eibel H, Hopkins G, Walter JE, Whangbo JS, Kohn DB, Puck JM, Cowan MJ, Griffith LM, Haddad E, O’Reilly RJ, Notarangelo LD, Pai SY

Abstract
Allogeneic hematopoietic stem cell transplant (HSCT) typically results in donor T cell engraftment and function in patients with severe combined immunodeficiency (SCID), but humoral immunity, particularly when using donors other than matched siblings, is variable. B cell function after HSCT for SCID depends on the genetic cause, the use of pre-HSCT conditioning and whether donor B cell chimerism is achieved. Patients with defects in IL2RG or JAK3 undergoing HSCT without conditioning often have poor B cell function post-HSCT, perhaps due to impairment of IL-21 signaling in host-derived B cells. To investigate the impact of pre-HSCT conditioning on B cell function, and the relationship of in vitro B cell function to clinical humoral immune status, we analyzed 48 patients with IL2RG/JAK3 SCID who were >2 years after HSCT with donors other than matched siblings. T follicular helper cells (TFH) developed in these patients with kinetics similar to healthy young children; thus poor B cell function could not be attributed to a failure of TFH development. In vitro differentiation of B cells into plasmablasts and immunoglobulin secretion in response to IL-21 strongly correlated with the use of conditioning, donor B cell engraftment, freedom from immunoglobulin replacement and response to tetanus vaccine. Patients on immunoglobulin replacement who had normal serum IgM showed poor response to IL-21 in vitro, similar to those with low serum IgM. In vitro response of B cells to IL-21 may predict clinically relevant humoral immune function in patients with IL2RG/JAK3 SCID after HSCT.

PMID: 29728406 [PubMed – as supplied by publisher]

Powered by WPeMatico

Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia.

Sci Rep. 2018 May 03;8(1):6956

Authors: Nemoto M, Hattori H, Maeda N, Akita N, Muramatsu H, Moritani S, Kawasaki T, Maejima M, Ode H, Hachiya A, Sugiura W, Yokomaku Y, Horibe K, Iwatani Y

Abstract
Complete tyrosine kinase 2 (TYK2) deficiency has been previously described in patients with primary immunodeficiency diseases. The patients were infected with various pathogens, including mycobacteria and/or viruses, and one of the patients developed hyper-IgE syndrome. A detailed immunological investigation of these patients revealed impaired responses to type I IFN, IL-10, IL-12 and IL-23, which are associated with increased susceptibility to mycobacterial and/or viral infections. Herein, we report a recessive partial TYK2 deficiency in two siblings who presented with T-cell lymphopenia characterized by low naïve CD4+ T-cell counts and who developed Epstein-Barr virus (EBV)-associated B-cell lymphoma. Targeted exome-sequencing of the siblings’ genomes demonstrated that both patients carried novel compound heterozygous mutations (c.209_212delGCTT/c.691C > T, p.Cys70Serfs*21/p.Arg231Trp) in the TYK2. The TYK2 protein levels were reduced by 35% in the T cells of the patient. Unlike the response under complete TYK2 deficiency, the patient’s T cells responded normally to type I IFN, IL-6, IL-10 and IL-12, whereas the cells displayed an impaired response to IL-23. Furthermore, the level of STAT1 was low in the cells of the patient. These studies reveal a new clinical entity of a primary immunodeficiency with T-cell lymphopenia that is associated with compound heterozygous TYK2 mutations in the patients.

PMID: 29725107 [PubMed – in process]

Powered by WPeMatico

Abdominal rectus muscle pyomyositis: Report of a case and review of the literature.

Infect Dis Rep. 2018 Mar 29;10(1):7522

Authors: Fountoukis T, Tsatsanidis N, Tilkeridou M, Konstantinou I, Fytas P, Skandalos I

Abstract
Pyomyositis is an uncommon primary bacterial infection of skeletal muscles, usually caused by Staphylococcus aureus. Predisposing factors for pyomyositis include immunodeficiency, trauma, injection drug use, concurrent infection and malnutrition. The diagnosis, staging of the disease and differential diagnosis are established by ultrasound, CT and MRI. Treatment involves surgical drainage and antibiotic therapy. We report a case of abdominal rectus muscle pyomyositis, which constitutes, as far as we know, the second reported in bibliography, while Prevotella disiens is firstly reported as causative agent.

PMID: 29721242 [PubMed]

Powered by WPeMatico