5

Early-onset autoimmune disease as a manifestation of primary immunodeficiency.

May 23, 2015 By Manish Butte

Early-onset autoimmune disease as a manifestation of primary immunodeficiency.

Front Immunol. 2015;6:185

Authors: Carneiro-Sampaio M, Coutinho A

Abstract
Autoimmune disorders (AID) have been increasingly observed in association with primary immunodeficiencies (PIDs). Here, we discuss the interface between PID and AID, focusing on autoimmune manifestations early in life, which can be diagnostic clues for underlying PIDs. Inflammatory bowel disease in infants and children has been associated with IL-10 and IL-10R deficiencies, chronic granulomatous disease, immunedysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (IPEX), autoinflammatory disorders, and others. Some PIDs have been identified as underlying defects in juvenile systemic lupus erythematosus: C1q-, IgA-, IgM deficiencies, alterations of the IFN-α pathway (in Aicardi-Goutières syndrome due to TREX1 mutation). IPEX (due to FOXP3 mutation leading to Treg cell deficiency), usually appearing in the first months of life, was recently observed in miscarried fetuses with hydrops who presented with CD3+ infiltrating lymphocytes in the pancreas. Hemophagocytic lymphohistiocytosis due to perforin deficiency was also identified as a cause of fetal hydrops. In conclusion, PID should be suspected in any infant with signs of autoimmunity after excluding transferred maternal effects, or in children with multiple and/or severe AID.

PMID: 25999944 [PubMed]

Autoimmunity in patients with selective IgA deficiency.

May 23, 2015 By Manish Butte

Autoimmunity in patients with selective IgA deficiency.

J Investig Allergol Clin Immunol. 2015;25(2):112-9

Authors: Abolhassani H, Gharib B, Shahinpour S, Masoom SN, Havaei A, Mirminachi B, Arandi N, Torabi-Sagvand B, Khazaei HA, Mohammadi J, Rezaei N, Aghamohammadi A

Abstract
BACKGROUND AND OBJECTIVE: Selective immunoglobulin A deficiency (SIgAD) is the most common primary antibody deticiency. Patients with SIgAD have a greater risk of concomitant autoimmune disorders than healthy individuals. The exact mechanism underlying the relationship between autoimmunity and SIgAD is not fully understood. The aim of this study was to evaluate potential associations between autoimmunity and specific clinical or immunological findings in patients with SIgAD.
METHODS: The study population comprised 57 symptomatic patients (65% males) with confirmed SIgAD who were referred to our center. Demographic data and history of autoimmunity were recorded both for patients and for their relatives. Comprehensive clinical and laboratory examinations were performed to investigate autoimmune complications in all the patients.
RESULTS: Autoimmune disorders were documented in 17 cases (29.8%; 9 males and 8 females). The most common manifestations were thyroiditis, vitiligo, and hemolytic anemia (3 cases each). Ten patients (17.5%) had a family history of autoimmunity. Significant associations were detected between autoimmunity and increased duration of follow-up (P = .003), serum level of IgM (P = .01), regulatory T-cell count (P = .03), and class-switched memory B-cell count (P = .01). Four cases of autoimmune SIgAD (23.5%) progressed to common variable immunodeficiency during the follow-up period (P = .006).
CONCLUSIONS: Autoimmune disorders, autoimmune cytopenia, and Ig subclass deficiency can lead to severe clinical manifestations in patients with SIgAD. Therefore, immunologists and pediatricians should be aware of these conditions.

PMID: 25997304 [PubMed – in process]

Primary hepatic leiomyoma: unusual cause of an intrahepatic mass.

May 21, 2015 By Manish Butte

Primary hepatic leiomyoma: unusual cause of an intrahepatic mass.

Ann Transl Med. 2015 Apr;3(5):73

Authors: Vyas S, Psica A, Watkins J, Yu D, Davidson B

Abstract
Leiomyomas are benign lesions arising from the smooth muscle layer. They are most commonly detected either within the gastrointestinal or genitourinary tracts. Primary hepatic leiomyoma (PHL) is a rare pathology. It is an isolated pathology within the liver, without evidence of any other coexisting leiomyomas. Very few cases have been described in literature. PHL may occur in healthy individuals although an association with immunodeficiency and Epstein-Barr virus (EBV) infection has been observed. Majority of the reported cases have been in females. A 20-year-old female patient presented with abdominal symptoms. MRI confirmed an 8 cm mass, with very low signal intensity on T2 images and peripheral rim enhancement on gadolinium. A laparoscopic left lateral sectorectomy was performed. Final histopathology confirmed the presence of benign lesion with spindle cell and smooth muscle proliferation and a fibro-vascular stroma compatible with a leiomyoma. There was no evidence of any leiomyomatous lesion elsewhere in the body. A rare diagnosis of PHL was therefore established. Acknowledging the rare incidence of this lesion, we report the same and review the relevant literature. PHL is usually a retrospective diagnosis, confirmed on histo-pathology assessment of the resected specimen. Liver resection is required in these patients due to the presence of symptoms, in the presence of a solid mass lesion within the liver. Surgery is thus definitive, diagnostic cum therapeutic.

PMID: 25992372 [PubMed]

Developmental trajectories in 22q11.2 deletion syndrome.

May 20, 2015 By Manish Butte

Developmental trajectories in 22q11.2 deletion syndrome.

Am J Med Genet C Semin Med Genet. 2015 May 18;

Authors: Swillen A, McDonald-McGinn D

Abstract
Chromosome 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic condition, is the most common microdeletion syndrome affecting 1 in 2,000-4,000 live births and involving haploinsufficiency of ∼50 genes resulting in a multisystem disorder. Phenotypic expression is highly variable and ranges from severe life-threatening conditions to only a few associated features. Most common medical problems include: congenital heart disease, in particular conotruncal anomalies; palatal abnormalities, most frequently velopharyngeal incompetence (VPI); immunodeficiency; hypocalcemia due to hypoparathyroidism; genitourinary anomalies; severe feeding/gastrointestinal differences; and subtle dysmorphic facial features. The neurocognitive profile is also highly variable, both between individuals and during the course of development. From infancy onward, motor delays (often with hypotonia) and speech/language deficits are commonly observed. During the preschool and primary school ages, learning difficulties are very common. The majority of patients with 22q11.2DS have an intellectual level that falls in the borderline range (IQ 70-84), and about one-third have mild to moderate intellectual disability. More severe levels of intellectual disability are uncommon in children and adolescents but are more frequent in adults. Individuals with 22q11.2DS are at an increased risk for developing several psychiatric disorders including attention deficit with hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety and mood disorders, and psychotic disorders and schizophrenia. In this review, we will focus on the developmental phenotypic transitions regarding cognitive development in 22q11.2DS from early preschool to adulthood, and on the changing behavioral/psychiatric phenotype across age, on a background of frequently complex medical conditions. © 2015 Wiley Periodicals, Inc.

PMID: 25989227 [PubMed – as supplied by publisher]

Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation.

May 20, 2015 By Manish Butte

Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation.

Clin Immunol. 2015 May 16;

Authors: Tallmadge RL, Shen L, Tseng CT, Miller SC, Barry J, Felippe MJ

Abstract
Common variable immunodeficiency (CVID) is a late-onset humoral deficiency characterized by B lymphocyte dysfunction or loss, decreased immunoglobulin production, and recurrent bacterial infections. CVID is the most frequent human primary immunodeficiency but still presents challenges in the understanding of its etiology and treatment. CVID in equine patients manifests with a natural impairment of B lymphocyte differentiation, and is a unique model to identify genetic and epigenetic mechanisms of disease. Bone marrow transcriptome analyses revealed decreased expression of genes indicative of the pro-B cell differentiation stage, importantly PAX5 (p≤0.023). We hypothesized that aberrant epigenetic regulation caused PAX5 gene silencing, resulting in the late-onset and non-familial manifestation of CVID. A significant increase in PAX5 enhancer region methylation was identified in equine CVID patients by genome-wide reduced-representation bisulfite sequencing and bisulfite PCR sequencing (p=0.000). Thus, we demonstrate that integrating transcriptomics and epigenetics in CVID enlightens potential mechanisms of dysfunctional B lymphopoiesis or function.

PMID: 25988861 [PubMed – as supplied by publisher]

Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return.

May 20, 2015 By Manish Butte

Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return.

Ann Rheum Dis. 2015 May 18;

Authors: Störch H, Zimmermann B, Resch B, Tykocinski LO, Moradi B, Horn P, Kaya Z, Blank N, Rehart S, Thomsen M, Lorenz HM, Neumann E, Tretter T

Abstract
BACKGROUND: Cross-talk between synovial fibroblasts (SF) and immune cells is suggested to play a crucial role in inflammation and chronification of rheumatoid arthritis (RA). The contribution of B cells in this process is poorly defined.
METHODS: Here, primary B cells from healthy donors were polyclonally activated and cocultured with SF of non-synovitic origin from patients with osteoarthritis.
RESULTS: In B-SF cocultures the concentrations of interleukin 6 (IL-6) and IL-8 increased manifold compared with single cultures even under physical separation and remained stable for several days after B-cell removal. Intracellular staining confirmed SF as key producers of IL-6 and IL-8, and B cells as main producers of tumour necrosis factor alpha (TNFα) and IL-1ß. Blocking experiments with a combination of anti-TNFα-antibodies and rIL-1RA significantly reduced SF cytokine production by up to 90%, suggesting that B-cell-derived TNFα and IL-1ß were crucial mediators of SF activation. Interestingly, B-cell cytokine production, CD25 expression and proliferation decreased in cocultures by at least 50%, demonstrating a negative regulatory loop towards the activated B cells. Inhibition of activin receptor-like kinase 5, a crucial component of the tumour growth factor ß (TGFß) signalling pathway, partly restored B-cell proliferation, suggesting a contribution of SF-derived TGFß in B-cell suppression. Besides cytokines, B-cell-activated SF also upregulated secretion of matrix metalloproteases such as MMP-3, thereby acquiring potential tissue destructive properties. This was confirmed by their invasion into human cartilage in the severe combined immunodeficiency mouse fibroblast invasion model in vivo.
CONCLUSIONS: Interaction with activated B cells leads to conversion of non-arthritic SF into SF with a proinflammatory and aggressive RA-like phenotype, thereby suggesting a new, so far unrecognised role for B cells in RA pathogenesis.

PMID: 25985971 [PubMed – as supplied by publisher]

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.

May 20, 2015 By Manish Butte

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.

Nat Genet. 2015 May 18;

Authors: Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Németh AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sørensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SR, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AO, Bentley D, Donnelly P, McVean G

Abstract
To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

PMID: 25985138 [PubMed – as supplied by publisher]

Clinical application of whole-genome sequencing in patients with primary immunodeficiency.

May 20, 2015 By Manish Butte

Clinical application of whole-genome sequencing in patients with primary immunodeficiency.

J Allergy Clin Immunol. 2015 May 13;

Authors: Mousallem T, Urban TJ, McSweeney KM, Kleinstein SE, Zhu M, Adeli M, Parrott RE, Roberts JL, Krueger B, Buckley RH, Goldstein DB

PMID: 25981738 [PubMed – as supplied by publisher]