Manish Butte

Neonatal screening for severe combined immunodeficiency in Brazil.

J Pediatr (Rio J). 2016 May 17;

Authors: Kanegae MP, Barreiros LA, Mazzucchelli JT, Hadachi SM, Guilhoto LM, Acquesta AL, Genov IR, Holanda SM, Di Gesu RS, Goulart AL, Dos Santos AM, Bellesi N, Costa-Carvalho BT, Condino-Neto A

Abstract
OBJECTIVE: To apply, in Brazil, the T-cell receptor excision circles (TRECs) quantification technique using real-time PCR in newborn screening for severe combined immunodeficiency (SCID) and assess the feasibility of implementing it on a large scale in Brazil.
METHODS: 8715 newborn blood samples were collected on paper filter and, after DNA elution, TRECs were quantified by real-time PCR. The cutoff value to determine whether a sample was abnormal was determined by ROC curve analysis, using SSPS.
RESULTS: The concentration of TRECs in 8682 samples ranged from 2 to 2181TRECs/μL of blood, with mean and median of 324 and 259TRECs/μL, respectively. Forty-nine (0.56%) samples were below the cutoff (30TRECs/μL) and were reanalyzed. Four (0.05%) samples had abnormal results (between 16 and 29TRECs/μL). Samples from patients previously identified as having SCID or DiGeorge syndrome were used to validate the assay and all of them showed TRECs below the cutoff. Preterm infants had lower levels of TRECs than full-term neonates. The ROC curve showed a cutoff of 26TRECs/μL, with 100% sensitivity for detecting SCID. Using this value, retest and referral rates were 0.43% (37 samples) and 0.03% (3 samples), respectively.
CONCLUSION: The technique is reliable and can be applied on a large scale after the training of technical teams throughout Brazil.

PMID: 27207231 [PubMed – as supplied by publisher]

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[Understanding primary immunodeficiencies: usefulness of a register].

Rev Med Suisse. 2016 Apr 6;12(513):708, 710-2

Authors: Jandus P, Grange E, Seebach JD

Abstract
Primary Immunodeficiency Diseases (PID) comprise inborn defects of the immune system which are and therefore difficult to study For this reason, the European Society for ImmunoDeficiencies (ESID) has set up an internet-based international patient and research database which integrates research data with more detailed clinical information. These disorders are not only found in children, but also in adults resulting in a wide range of clinical manifestations. Primary immunodeficiency adults are much less known and may remain undiagnosed.

PMID: 27197327 [PubMed – in process]

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Primary immunodeficiency and recalcitrant chronic sinusitis: a systematic review.

Int Forum Allergy Rhinol. 2016 May 17;

Authors: Mazza JM, Lin SY

Abstract
BACKGROUND: A subset of patients with chronic rhinosinusitis (CRS) has disease refractory to standard therapies. Primary immunodeficiency should be considered in this group. Past literature has demonstrated an association between immunodeficiency and chronic sinusitis.
METHODS: A systematic literature search was performed using OVID, MEDLINE, EMBASE, and Cochrane databases to identify English language papers containing original human data on subjects with primary immunodeficiency and chronic sinusitis. A total of 39 studies met inclusion criteria. Data was collected pertaining to immune dysfunction in patients with chronic sinusitis, the clinical workup for these patients, and the effectiveness of medical and surgical treatments. The studies were assessed to determine their level of evidence.
RESULTS: The majority of studies were supported by Level 4 evidence. Up to 50% of patients with recalcitrant CRS were found to have immune dysfunction. The most frequent primary immunodeficiencies studied were common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). Common collected data included measurement of serum immunoglobulins and functional antibody responses. Treatments reviewed include immunoglobulin replacement, long-term antibiotics and endoscopic sinus surgery.
CONCLUSION: Patients with recalcitrant CRS should be evaluated for primary immunodeficiency. This should include as assessment of quantitative serum immunoglobulin levels as well as functional antibody responses. Medical therapy, particularly immunoglobulin replacement therapy, appears to be most effective when administered at high doses early in the disease course. The addition of surgery is less clearly supported, but may also provide benefit if performed early.

PMID: 27187624 [PubMed – as supplied by publisher]

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Invasive meningococcal disease in three siblings with hereditary deficiency of the 8(th) component of complement: evidence for the importance of an early diagnosis.

Orphanet J Rare Dis. 2016;11(1):64

Authors: Dellepiane RM, Dell’Era L, Pavesi P, Macor P, Giordano M, De Maso L, Pietrogrande MC, Cugno M

Abstract
BACKGROUND: Deficiency of the eighth component of complement (C8) is a very rare primary immunodeficiency, associated with invasive, recurrent infections mainly caused by Neisseria species. We report functional and immunochemical C8 deficiency diagnosed in three Albanian siblings who presented with severe meningococcal infections at the age of 15 years, 4 years and 17 months, respectively. The youngest suffered serious complications (necrosis of fingers and toes requiring amputation).
METHODS: Functional activity of the classical, alternative and mannose-binding lectin complement pathways was measured in serum from the 3 siblings and their parents (37-year-old woman and 42-year-old man). Forty healthy subjects (20 males and 20 females aged 4-38 years) served as normal controls. Serum complement factors were measured by haemolytic assays and immunoblotting. Sequence DNA analysis of the C8B gene was performed.
RESULTS: Analyses of the three complement pathways revealed no haemolytic activity and also absence of C8beta in serum samples from all three siblings. The genetic analysis showed that the three siblings were homozygous for the p.Arg428* mutation in the C8B gene on chromosome 1p32 (MIM 120960). The parents were heterozygous for the mutation and presented normal complement activities. A 2-year follow-up revealed no further infective episodes in the siblings after antibiotic prophylaxis and meningococcal vaccination.
CONCLUSIONS: Complement deficiencies are rare and their occurrence is often underestimated. In presence of invasive meningococcal infection, we highlight the importance of complement screening in patients and their relatives in order to discover any genetic defects which would render necessary prophylaxis to prevent recurrent infections and severe complications.

PMID: 27183977 [PubMed – in process]

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[Basics of primary immunodeficiencies].

Rev Alerg Mex. 2016 Apr-Jun;63(2):180-189

Authors: Hernández-Martínez C, Espinosa-Rosales F, Espinosa-Padilla SE, Hernández-Martínez AR, Blancas-Galicia L

Abstract
Primary immunodeficiencies (PID) are a heterogeneous group of inherited disorders, the etiology are the defects in the development or function of the immune system. The principal PID manifestations are the infections in early age, malignancy and diseases of immune dysregulation as autoimmunity and allergy. PIDs are genetics disorders and most of them are inherited as autosomal recessive, also this group of diseases is more prevalent in males and in childhood. The antibody immunodeficiency is the PID more common in adults. The more frequent disorders are the infections in the respiratory tract, abscesses, candidiasis, diarrhea, BCGosis etc. Initial approach included a complete blood count and quantification of immunoglobulins. The delay in diagnosis could be explained due to a perception that the recurrent infections are normal process or think that they are exclusively of childhood. The early diagnosis of PID by primary care physicians is important to opportune treatment and better prognosis.

PMID: 27174761 [PubMed – as supplied by publisher]

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[Cancer as secondary immunodeficiency. Review].

Rev Alerg Mex. 2016 Apr-Jun;63(2):169-179

Authors: Vargas-Camaño ME, Guido-Bayardo RL, Martínez-Aguilar NE, Castrejón-Vázquez MI

Abstract
Secondary immunodeficiencys, previously presented in immunocompetent individuals. The lack of primary or secondary response to the presence of a foreign antigen, in the case of infections is a sentinel data in the diagnosis of immunodeficiency (can be primary or secondary), in the case of a self antigen may generate the presence of Cancer. Cancer has shown an increase in the prevalence and incidence globally. Most current medical treatments in cancer are focused primarily on immunomodulatory actions (immunosuppression / immune stimulation or both). Knowledge of key concepts from the perspective of innate and acquired immunity lead to cancer development, engaging immune surveillance and escape mechanisms of this that contribute to better understand the origin, behavior and treatment of neoplasm’s. These treatments can cause immunological disorders such as allergy, anaphylaxis, lack of response immunogenicity care fields specialist in allergy and clinical immunology.

PMID: 27174760 [PubMed – as supplied by publisher]

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Analysis of subsets of B cells, Breg, CD4Treg and CD8Treg cells in adult patients with primary selective IgM deficiency.

Am J Clin Exp Immunol. 2016;5(1):21-32

Authors: Louis AG, Agrawal S, Gupta S

Abstract
Primary selective IgM deficiency (SIGMD) is a rare and recently IUIS-recognized primary immunodeficiency disease with increased susceptibility to infections, allergy, and autoimmune diseases. The pathogenesis of selective IgM remains unclear. The objective of the study was to understand the pathogenesis of selective IgM deficiency via a comprehensive analysis of subsets of B cells, naïve and memory subsets of CD4+ and CD8+ T cells, and Breg, CD4Treg, and CD8Treg cells. Twenty adult patients with SIGMD (serum IgM 4 mg/dl-32 mg/dl) and age-and gender-matched healthy controls were studied. Naïve B cells, transitional B cells, marginal zone B cells, germinal center B cells, IgM memory B cells, switched memory B cells, plasmablasts, CD21(low) B cells, B1 cells, CXCR3+ naive and memory B cells; naïve, central memory, and effector memory subsets of CD4+ and CD8+ T cells, and CD4Treg, CD8Treg and Breg were phenotypically analyzed using multicolor flow cytometry. A significant increase in CD21(low), IgM memory B cells, Breg and CD8Treg, and a significant decreased in germinal center B cells, and CXCR3+ naïve and memory B cells were observed in SIGMD. These alterations in subsets of B cells, and Breg and CD8Treg cells may play a role in the pathogenesis of SIGMD.

PMID: 27168952 [PubMed – as supplied by publisher]

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Mucosal-Associated Invariant T (MAIT) Cells Are Impaired in Th17 Associated Primary and Secondary Immunodeficiencies.

PLoS One. 2016;11(5):e0155059

Authors: Gao Y, Rae W, Ramakrishnan KA, Barcenas-Morales G, Döffinger R, Eren E, Faust SN, Ottensmeier CH, Williams AP

Abstract
The recently described Mucosal Associated Invariant T (MAIT) cells mediate specific recognition of bacterial and fungal vitamin B2 metabolites. As innate T cells, they possess broad effector responses, including IFN- including Iproduction, that are comparable to conventional T cell responses. Immunodeficiencies associated with systemic Th17 deficiency may also be compounded by defects in MAIT immunity. We evaluated Th17 immunity in this innate T cell compartment in primary (AD-HIES) and secondary immunodeficiency (thymoma) patients with conventional Th17 deficiency and susceptibility to fungal and bacterial disease. Our results suggest that MAIT cells are both reduced and functional deficient in STAT3 deficiency and thymoma patients with IL-12/23 autoantibodies. In contrast, thymoma patients without autoantibodies preserved the normal number and functional MAIT cells.

PMID: 27167980 [PubMed – as supplied by publisher]

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Treatment options for chronic mucocutaneous candidiasis.

J Infect. 2016 May 6;

Authors: van de Veerdonk FL, Netea MG

Abstract
Autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) is a rare and severe primary immunodeficiency that is characterized by mucocutaneous fungal infection, autoimmunity, cerebral aneurysms, and oropharyngeal and esophageal cancer. Recently, it was discovered that STAT1 mutations are responsible for AD-CMC. These mutations lead to the inability of STAT1 to be dephosphorylated, resulting in hyperphosphorylation, increased binding to the DNA, and gain of function (GOF) effects on STAT1 signaling. Furthermore, a characteristic feature of AD-CMC patients is deficiency in the T-helper 17 (Th17) responses, which is believed to be the immunological cause of the mucocutaneous fungal infection. No targeted treatment other than lifelong antifungal prophylaxis exists for AD-CMC. However, the discovery of the genetic and immunological defects makes it now possible to explore new treatment strategies. This review will discuss immunomodulatory treatment options that can be explored in patients with STAT1 GOF mutations.

PMID: 27161991 [PubMed – as supplied by publisher]

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