Manish Butte

Periodontitis in Chédiak-Higashi Syndrome: An Altered Immunoinflammatory Response.

JDR Clin Trans Res. 2018 Jan;3(1):35-46

Authors: Thumbigere Math V, Rebouças P, Giovani PA, Puppin-Rontani RM, Casarin R, Martins L, Wang L, Krzewski K, Introne WJ, Somerman MJ, Nociti FH, Kantovitz KR

Abstract
Chédiak-Higashi syndrome (CHS), a rare autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator gene (LYST), is associated with aggressive periodontitis. It is suggested that LYST mutations affect the toll-like receptor (TLR)-mediated immunoinflammatory response, leading to frequent infections. This study sought to determine the periodontal status of patients with classic (severe) and atypical (milder) forms of CHS and the immunoregulatory functions of gingival fibroblasts in CHS patients. In contrast to aged-matched healthy controls, atypical (n = 4) and classic (n = 3) CHS patients presented with mild chronic periodontitis with no evidence of gingival ulceration, severe tooth mobility, or premature exfoliation of teeth. As a standard of care, all classic CHS patients had undergone bone marrow transplantation (BMT). Primary gingival fibroblasts obtained from atypical and BMT classic CHS patients displayed higher protein expression of TLR-2 (1.81-fold and 1.56-fold, respectively) and decreased expression of TLR-4 (-2.5-fold and -3.85-fold, respectively) at baseline when compared with healthy control gingival fibroblasts. When challenged with whole bacterial extract of Fusobacterium nucleatum, both atypical and classic CHS gingival fibroblasts failed to up-regulate TLR-2 and TLR-4 expression when compared with their respective untreated groups and control cells. Cytokine multiplex analysis following F. nucleatum challenge showed that atypical CHS gingival fibroblasts featured significantly increased cytokine expression (interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, IL-12, interferon-γ, tumor necrosis factor-α), whereas classic CHS cells featured similar/decreased cytokine expression when compared with treated control cells. Collectively, these results suggest that LYST mutations in CHS patients affect TLR-2 and TLR-4 expression/function, leading to dysregulated immunoinflammatory response, which in turn may influence the periodontal phenotype noted in CHS patients. Furthermore, our results suggest that atypical CHS patients and classic CHS patients who undergo BMT early in life are less susceptible to aggressive periodontitis and that hematopoietic cells play a critical role in mitigating the risk of aggressive periodontitis in CHS. Knowledge Transfer Statement: Results from this study can be used to create awareness among clinicians and researchers that not all CHS patients exhibit historically reported aggressive periodontitis, especially if they have atypical CHS disease or have received bone marrow transplantation. LYST mutations in CHS patients may affect TLR-2 and TLR-4 expression/function leading to dysregulated immunoinflammatory response, which in turn may influence the periodontal phenotype noted in CHS patients.

PMID: 29276776 [PubMed]

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Are Circulating Type 2 Vaccine-derived Polioviruses (VDPVs) Genetically Distinguishable from Immunodeficiency-associated VDPVs?

Comput Struct Biotechnol J. 2017;15:456-462

Authors: Zhao K, Jorba J, Shaw J, Iber J, Chen Q, Bullard K, Kew OM, Burns CC

Abstract
Public health response to vaccine-derived poliovirus (VDPV) that is transmitted from person to person (circulating VDPV [cVDPV]) differs significantly from response to virus that replicates in individuals with primary immunodeficiency (immunodeficiency-associated VDPV [iVDPV]). cVDPV outbreaks require a community immunization response, whereas iVDPV chronic infections require careful patient monitoring and appropriate individual treatment. To support poliovirus outbreak response, particularly for type 2 VDPV, we investigated the genetic distinctions between cVDPV2 and iVDPV2 sequences. We observed that simple genetic measurements of nucleotide and amino acid substitutions are sufficient for distinguishing highly divergent iVDPV2 from cVDPV2 sequences, but are insufficient to make a clear distinction between the two categories among less divergent sequences. We presented quantitative approaches using genetic information as a surveillance tool for early detection of VDPV outbreaks. This work suggests that genetic variations between cVDPV2 and iVDPV2 may reflect differences in viral micro-environments, host-virus interactions, and selective pressures during person-to-person transmission compared with chronic infections in immunodeficient patients.

PMID: 29276577 [PubMed]

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Should Antibiotic Prophylaxis Be Routinely Used in Patients with Antibody-Mediated Primary Immunodeficiency?

J Allergy Clin Immunol Pract. 2017 Dec 21;:

Authors: Ballow M, Paris K, de la Morena M

PMID: 29274825 [PubMed – as supplied by publisher]

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Conventional and single-molecule targeted sequencing method for specific variant detection in IKBKG whilst bypassing the IKBKGP1 pseudogene.

J Mol Diagn. 2017 Dec 18;:

Authors: Frans G, Meert W, Van der Werff Ten Bosch J, Meyts I, Bossuyt X, Vermeesch JR, Hestand MS

Abstract
In addition to Sanger sequencing, next-generation sequencing of gene panels and exomes has emerged as a standard diagnostic tool in many laboratories. However, these captures can miss regions, have poor efficiency, or capture pseudogenes which hamper proper diagnoses. One such example is the primary immunodeficiency-associated gene IKBKG. Its pseudogene IKBKGP1 makes traditional capture methods aspecific. We therefore developed a long-range PCR method to efficiently target IKBKG, as well as two associated genes (IRAK4 and MYD88), whilst bypassing the IKBKGP1 pseudogene. Sequencing accuracy was evaluated using both conventional short read technology and a newer long read single molecule sequencer. Different mapping and variant calling options were evaluated in their capability to bypass the pseudogene using both sequencing platforms. Based on these evaluations, we determined a robust diagnostic application for unambiguous sequencing and variant calling in IKBKG, IRAK4, and MYD88. This method allows rapid identification of selected primary immunodeficiency diseases in patients suffering from life-threatening invasive pyogenic bacterial infections.

PMID: 29269280 [PubMed – as supplied by publisher]

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Classic Kaposi Sarcoma: An Exceptional Cause of Adrenal Incidentaloma.

J Endocr Soc. 2017 Jun 01;1(6):737-741

Authors: de Risi-Pugliese T, Genc S, Bertherat J, Larousserie F, Bollet M, Bassi C, Dupin N

Abstract
Context: Classic Kaposi sarcoma (KS), also known as Mediterranean KS, affects immunocompetent patients and is usually limited to the skin, without profound organ involvement. We report an exceptional case of a primary adrenal classic KS.
Case Description: A left adrenal incidentaloma was fortuitously discovered on a computed tomography scan performed for chest pain in a 60-year-old man. Magnetic resonance imaging showed a heterogeneous left adrenal nodule enhanced by gadolinium injection. Adrenalectomy revealed a massive spindle cell infiltrate of the adrenal gland that was positive for CD31, CD34, and herpes virus 8 (HHV8) on immunohistochemistry, allowing for the diagnosis of KS. The explorations revealed no immunodeficiency or other involvement of KS. Four months later, another nodular lesion appeared on the right adrenal gland, and 2.5 years later, two nodular angiomatous KS lesions had appeared on the right foot. The evolution was indolent, and no complementary treatment of KS was required at 3 years after the diagnosis.
Conclusions: Adrenal involvement of KS is rare, eventually observed in AIDS-KS. The present case is, to the best of our knowledge, the first report of primary isolated adrenal classic KS. KS should be considered in the etiology of adrenal incidentaloma, especially if the patient has epidemiological risk factors for HHV8 infection, mainly, but not exclusively, in the context of immunodeficiency.

PMID: 29264526 [PubMed]

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A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome.

NPJ Genom Med. 2017;2:23

Authors: Dinur Schejter Y, Ovadia A, Alexandrova R, Thiruvahindrapuram B, Pereira SL, Manson DE, Vincent A, Merico D, Roifman CM

Abstract
Roifman syndrome (OMIM# 616651) is a complex syndrome encompassing skeletal dysplasia, immunodeficiency, retinal dystrophy and developmental delay, and is caused by compound heterozygous mutations involving the Stem II region and one of the other domains of the RNU4ATAC gene. This small nuclear RNA gene is essential for minor intron splicing. The Canadian Centre for Primary Immunodeficiency Registry and Repository were used to derive patient information as well as tissues. Utilising RNA sequencing methodologies, we analysed samples from patients with Roifman syndrome and assessed intron retention. We demonstrate that a homozygous mutation in Stem II is sufficient to cause the full spectrum of features associated with typical Roifman syndrome. Further, we demonstrate the same pattern of aberration in minor intron retention as found in cases with compound heterozygous mutations.

PMID: 29263834 [PubMed]

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Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings.

Front Immunol. 2017;8:1683

Authors: Pietrucha B, Heropolitańska-Pliszka E, Geffers R, Enßen J, Wieland B, Bogdanova NV, Dörk T

Abstract
Germline mutations in the RING finger protein gene RNF168 have been identified in a combined immunodeficiency disorder called RIDDLE syndrome. Since only two patients have been described with somewhat different phenotypes, there is need to identify further patients. Here, we report on two Polish siblings with RNF168 deficiency due to homozygosity for a novel frameshift mutation, c.295delG, that was identified through exome sequencing. Both patients presented with immunoglobulin deficiency, telangiectasia, cellular radiosensitivity, and increased alpha-fetoprotein (AFP) levels. The younger sibling had a more pronounced neurological and morphological phenotype, and she also carried an ATM gene mutation in the heterozygous state. Immunoblot analyses showed absence of RNF168 protein, whereas ATM levels and function were proficient in lymphoblastoid cells from both patients. Consistent with the absence of RNF168 protein, 53BP1 recruitment to DNA double-strand breaks (DSBs) after irradiation was undetectable in lymphoblasts or primary fibroblasts from either of the two patients. γH2AX foci accumulated normally but they disappeared with significant delay, indicating a severe defect in DSB repair. A comparison with the two previously identified patients indicates immunoglobulin deficiency, cellular radiosensitivity, and increased AFP levels as hallmarks of RNF168 deficiency. The variability in its clinical expression despite similar cellular phenotypes suggests that some manifestations of RNF168 deficiency may be modified by additional genetic or epidemiological factors.

PMID: 29255463 [PubMed]

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Autoimmunity and primary immunodeficiency: two sides of the same coin?

Nat Rev Rheumatol. 2017 Dec 19;14(1):7-18

Authors: Schmidt RE, Grimbacher B, Witte T

Abstract
Autoimmunity and immunodeficiency were previously considered to be mutually exclusive conditions; however, increased understanding of the complex immune regulatory and signalling mechanisms involved, coupled with the application of genetic analysis, is revealing the complex relationships between primary immunodeficiency syndromes and autoimmune diseases. Single-gene defects can cause rare diseases that predominantly present with autoimmune symptoms. Such genetic defects also predispose individuals to recurrent infections (a hallmark of immunodeficiency) and can cause primary immunodeficiencies, which can also lead to immune dysregulation and autoimmunity. Moreover, risk factors for polygenic rheumatic diseases often exist in the same genes as the mutations that give rise to primary immunodeficiency syndromes. In this Review, various primary immunodeficiency syndromes are presented, along with their pathogenetic mechanisms and relationship to autoimmune diseases, in an effort to increase awareness of immunodeficiencies that occur concurrently with autoimmune diseases and to highlight the need to initiate appropriate genetic tests. The growing knowledge of various genetically determined pathologic mechanisms in patients with immunodeficiencies who have autoimmune symptoms opens up new avenues for personalized molecular therapies that could potentially treat immunodeficiency and autoimmunity at the same time, and that could be further explored in the context of autoimmune rheumatic diseases.

PMID: 29255211 [PubMed – in process]

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[Disseminated infection by M. tuberculosis complex in patient with IFN-γ receptor 1 complete deficiency].

Rev Alerg Mex. 2017 Oct-Dec;64(4):499-504

Authors: Martínez-Morales MC, Deswarte C, Castañeda-Casimiro J, Bustamante J, Blancas-Galicia L, Scheffler-Mendoza S

Abstract
BACKGROUND: Several mutations have been described leading to impaired immunity in the IL-12/IFN-γ axis and, they confer susceptibility to mycobacterial infections. One of the more serious clinical phenotypes is secondary to mutations at IFN-γ receptor 1 gene, characterized by an early onset and more severe disease.
CLINICAL REPORT: We present a 3-month-old female patient with systemic M. tuberculosis complex who has a homozygous mutation, it affects the splicing site at IFNGR1 c.201-1G> T. At time of this report, she is with antimycobacterial treatment in the protocol of pluripotent hematopoietic cell transplantation (TCHP).
CONCLUSION: It has been reported that antiphimic treatment should be maintained until the immune system is restored by the TCHP. If patients receive THCP before the age of 1 year old, they have a better prognosis. Diminish the levels of IFN-γ in plasma before the procedure is associated to better results.

PMID: 29249112 [PubMed – in process]

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[Common immunodeficiency variable in adults].

Rev Alerg Mex. 2017 Oct-Dec;64(4):452-462

Authors: O’Farrill-Romanillos PM, Herrera-Sánchez DA, Hernández-Fernández C, López-Rocha EG

Abstract
Primary immunodeficiencies (PIDs) are low-incidence diseases caused by defects in genes involved in the development, maintenance, and regulation of the immune system. Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency of adulthood. It has an approximate prevalence of 1 in 25 000-50 000 in the general population, with a delay in diagnosis between 6-7 years. The clinical manifestations of CVID constitute six main categories: infections, pulmonary complications, granulomatous or polyclonal lymphocytic disease, autoimmunity, gastrointestinal diseases and malignancy Most patients must have at least one of the following clinical manifestations (infection, autoimmunity, lymphoproliferation). However, the diagnosis of CVID can be conferred in asymptomatic patients, especially in familial cases. Secondary causes of hypogammaglobulinemia should be ruled out in any patient meeting the diagnostic criteria for CVID, as the treatment may be totally different from that required for CVID. Because CVID comprises a heterogeneous group of syndromes with poor primary antibody production, the potential number of entities within this group is unknown. Patients with CVID suffer from various complications that are considered prognostic. In the absence of clear guidelines for their search, it is recommended that lymphoproliferative disease, lung disease, liver disease and autoimmunity be investigated intentionally during the initial evaluation. The intervals in which they should be performed are not clear, but several evaluations may be required per year, according to the clinical evolution of the patient.

PMID: 29249107 [PubMed – in process]

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