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Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis.

J Immunol. 2015 Nov 15;195(10):5011-24

Authors: Hainzl E, Stockinger S, Rauch I, Heider S, Berry D, Lassnig C, Schwab C, Rosebrock F, Milinovich G, Schlederer M, Wagner M, Schleper C, Loy A, Urich T, Kenner L, Han X, Decker T, Strobl B, Müller M

Abstract
In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2(-/-) mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22-STAT3 target genes is reduced in IECs from healthy and colitic Tyk2(-/-) mice. Experiments with conditional Tyk2(-/-) mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22-Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22-dependent colitis was confirmed in Citrobacter rodentium-induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3.

PMID: 26432894 [PubMed – indexed for MEDLINE]

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Quantitative Evidence of Wear-Off Effect at the End of the Intravenous IgG (IVIG) Dosing Cycle in Primary Immunodeficiency.

J Clin Immunol. 2016 Feb 24;

Authors: Rojavin MA, Hubsch A, Lawo JP

Abstract
PURPOSE: Intravenous IgG (IVIG) treatment wear-off is commonly experienced by patients, who report increased susceptibility to infection, and decreased quality of life towards the end of their 3- or 4-week dosing cycle, when serum IgG levels approach their trough. We quantified IVIG wear-off in terms of treatment efficacy and patient well-being.
METHODS: Data were collected from patients enrolled in three Phase III trials of Sandoglobulin® NF Liquid or Privigen®, treated every 3- or 4- weeks. Pooled analyses of raw patient data compared the rate of infection and other clinical outcomes during the course of the dosing cycle. Subjective symptoms of wear-off were quantified by comparing patient-reported overall well-being scores.
RESULTS: The probability of a first infection in the final week of the IVIG cycle was 1.26 (95 % confidence intervals [CI]: 0.76-2.11; p = 0.3621) and 1.55 (95 % CI: 1.04-2.32; p = 0.0314) times higher than in the first week, for patients on a 3-week cycle and 4-week dosing cycles, respectively. Wear-off, as manifested by a decrease in overall well-being, was experienced in 10 % of all cycles and reported at least once by 61 % of the patients on a 3-week cycle, and 43 % of those on a 4-week cycle.
CONCLUSIONS: These findings confirm the existence of decreased efficacy (treatment wear-off) towards the end of a 3-4 week IVIG dosing cycle, and provide a quantifiable evaluation to a phenomenon typically reported anecdotally. For patients experiencing wear-off, increasing the IgG dose or shortening the dosing interval and/or a switch to SCIG may be beneficial.

PMID: 26910102 [PubMed – as supplied by publisher]

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X-linked Agammaglobulinemia.

Indian J Pediatr. 2016 Feb 24;

Authors: Suri D, Rawat A, Singh S

Abstract
X-linked agammaglobulinemia (XLA) is one of the commonest primary immune deficiencies encountered in pediatric clinical practice. In adults, common variable immunodeficiency (CVID) is the most common primary immunodeficiency disease (PID). It is an X-linked disorder characterized by increased susceptibility to encapsulated bacteria, severe hypergammaglobulinemia and absent circulating B cells in the peripheral blood. Replacement immunoglobulin therapy is the main cornerstone of treatment. Aggressive management of intercurrent infections and prophylactic antimicrobials are needed. This review attempts to highlight varied clinical manifestations and management of XLA, especially in the context of developing country.

PMID: 26909497 [PubMed – as supplied by publisher]

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A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients with Primary Immunodeficiency Diseases: A Systematic Review and Meta-Analysis.

Expert Rev Clin Immunol. 2016 Feb 22;

Authors: Shabaninejad H, Asgharzadeh A, Rezaei N, Rezapoor A

Abstract
OBJECTIVES: subcutaneous immunoglobulin (SCIG) is a new therapeutic procedure for patients with primary immunodeficiency (PI). This research is a systematic review of studies on the efficacy and safety of intravenous immunoglobulin (IVIG) and SCIG in adult patients with PI.
METHODS: this study includes a systematic review of cohorts and randomized clinical trials (24 articles) from 5 databases with no time limits. Random effects meta-analysis was performed for outcomes such as efficacy and safety.
RESULTS: standard mean difference (SMD) of serum immunoglobulin level was equal to 0.336 (P <0.01; 0.205-0.467) and the odds ratio (OR) of side effects was 0.497 (P=0.1; 0.180-1.371). The results indicate that SCIG leads to a higher level of immunoglobulin and a reduction in side effects but shows the same infection rate as IVIG.
CONCLUSION: our analysis shows that shifting from IVIG to SCIG therapy can have clinical benefits for PI patients.

PMID: 26902306 [PubMed – as supplied by publisher]

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Common variable immunodeficiency associated with microdeletion of chromosome 1q42.1-q42.3 and inositol 1,4,5-trisphosphate kinase B (ITPKB) deficiency.

Clin Transl Immunology. 2016 Jan;5(1):e59

Authors: Louis AG, Yel L, Cao JN, Agrawal S, Gupta S

Abstract
Common variable immunodeficiency (CVID) is a heterogenous disorder characterized by hypogammaglobulinemia and impaired specific antibody response and increased susceptibility to infections, autoimmunity and malignancies. A number of gene mutations, including ICOS, TACI and BAFF-R, and CD19, CD20, CD21, CD81, MSH5 and LRBA have been described; however, they account for approximately 20-25% of total cases of CVID. In this study, we report a patient with CVID with an intrinsic microdeletion of chromosome 1q42.1-42.3, where gene for inositol 1,3,4, trisphosphate kinase β (ITPKB) is localized. ITPKB has an important role in the development, survival and function of B cells. In this subject, the expression of ITPKB mRNA as well as ITKPB protein was significantly reduced. The sequencing of ITPKB gene revealed three variants, two of them were missense variants and third was a synonymous variant; the significance of each of them in relation to CVID is discussed. This case suggests that a deficiency of ITPKB may have a role in CVID.

PMID: 26900472 [PubMed]

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Primary Immunodeficiency Diseases in Aguascalientes, Mexico: Results from an Educational Program.

J Clin Immunol. 2016 Feb 22;

Authors: Alvarez-Cardona A, Espinosa-Padilla SE, Reyes SO, Ventura-Juarez J, Lopez-Valdez JA, Martínez-Medina L, Santillan-Artolozaga A, Cajero-Avelar A, De Luna-Sosa AR, Torres-Bernal LF, Espinosa-Rosales FJ

Abstract
PURPOSE: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders characterized mainly by recurrent infections. Late diagnosis remains as one of the main issues to solve. We aimed to increase PID diagnosis in Aguascalientes, a 1.3 million inhabitants state in the center of Mexico, and to describe the clinical features of such patients.
METHODS: We developed an educational program for health personnel and general public; patients with possible PID were referred to a State University clinical center from December 2011 to December 2012. The patients were evaluated at the clinic and their definitive diagnosis pursued through laboratory, molecular and genetic assays. We describe the findings of those patients and analyze the impact of the program in terms of number of referrals.
RESULTS: After 41 talks and 12 media appearances 151patients were referred for evaluation. Fifteen (9.9 %) were diagnosed with PID: five (33 %) had antibody deficiencies, seven (47 %) Well-defined syndromes, two (13 %) Severe combined Immunodeficiency (SCID) and one case (7 %) of an innate immune deficiency. All of the 15 PID patients had been referred by physicians, as opposed to the public. We estimated a “number needed to teach” of 75 physicians to get one PID patient referral.
CONCLUSION: Educational programs are a fundamental part of the global efforts to increase PID diagnosis and care. To be successful, such programs should include public relations, reach for first-contact physicians, and aim to develop an efficient referral network with molecular diagnostic capability. Enhancing medical knowledge on PID is a successful strategy to improve early diagnosis and treatment.

PMID: 26898367 [PubMed – as supplied by publisher]

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A Boy with Relentless Pruritus: Job’s Syndrome.

Am J Case Rep. 2016;17:104-110

Authors: Khan K, Wozniak SE, Giannone AL, Abdulmassih ME

Abstract
BACKGROUND Job’s syndrome (hyper IgE syndrome) is a very rare primary immunodeficiency disease that has an annual approximate incidence of less than 1/1,000,000. This manuscript aims to provide education regarding diagnosis and management strategies of this syndrome worldwide. CASE REPORT A 6-year-old boy was seen at the clinic secondary to persistent pruritus interfering with sleep. At the age of 2 months, the patient developed diffuse eczematous and desquamating skin lesions. He was subsequently diagnosed with atopic dermatitis and managed conservatively. From 2 months to 7 years of age, intermittent exacerbations of dermatitis persisted despite an aggressive treatment regimen. The serum IgE level increased exponentially over a period of 7 years, with a peak value of 57,400 IU/ml. Molecular genetic testing revealed a dominant negative mutation within the SH2 domain of the Signal Transducer and Activator of Transcription (STAT3) gene. The patient was subsequently diagnosed with Job’s syndrome. Management included proper skin care, prophylactic antibiotics, immunomodulating agents, and psychotherapy. CONCLUSIONS Job’s syndrome can often go unrecognized and masquerade as atopic dermatitis. Therefore, genetic testing for this condition should be obtained in all patients with treatment-refractory AD. Additionally, psychotherapy can be a successful management strategy for the grating psychological impact that can be imposed on children with excessive pruritus.

PMID: 26897360 [PubMed – as supplied by publisher]

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[Nonhomologous DNA end joining pathway defect and primary immunodeficiency diseases].

Zhonghua Er Ke Za Zhi. 2015 Dec;53(12):962-6

Authors: Tang M, An Y, Jiang J, Zhao X

PMID: 26887557 [PubMed – in process]

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[Expert consensus on the clinical practice of vaccination of the immunocompromised populations (trial implementation): primary immunodeficiency].

Zhonghua Er Ke Za Zhi. 2015 Dec;53(12):898-902

Authors: Subspecialty Group of Immunology, the Society of Pediatrics, Chinese Medical Association; The Editorial Board, Chinese Journal of Pediatrics, Subspecialty Group of Immunology the Society of Pediatrics Chinese Medical Association The Editorial Board Chinese Journal of Pediatrics

PMID: 26887543 [PubMed – in process]

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[Interpretation for the expert consensus on the clinical practice of vaccination of the immunocompromised populations (trial implementation): primary immunodeficiency].

Zhonghua Er Ke Za Zhi. 2015 Dec;53(12):903-6

Authors: Song H

PMID: 26887544 [PubMed – in process]

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