Manish Butte

Mendelian susceptibility to mycobacterial disease: Clinical and immunological findings of patients suspected for IL12Rβ1 deficiency.

July 28, 2019 By Manish Butte

Mendelian susceptibility to mycobacterial disease: Clinical and immunological findings of patients suspected for IL12Rβ1 deficiency.

Allergol Immunopathol (Madr). 2019 Jul 23;:

Authors: Moradi L, Cheraghi T, Yazdani R, Azizi G, Rasouli S, Zavareh FT, Parvaneh L, Parvaneh N, Sohani M, Delavari S, Abolhassani H, Rezaei N, Aghamohammadi A

Abstract
BACKGROUND: Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by increased susceptibility to weakly virulent mycobacteria (Bacillus Calmette-Guérin [BCG] vaccines and environmental mycobacteria), Mycobacterium tuberculosis, Candida spp. and Salmonella spp. The aim of this study is to evaluate clinical features and immunological findings of MSMD patients with interleukin 12 receptor beta 1 (IL12Rβ1) deficiency.
METHODS: Among 117 screened patients with BCG infection following vaccination, 23 suspected MSMD subjects were recruited to this study by the exclusion of severe combined immunodeficiencies and chronic granulomatous diseases. Flow cytometric assessment for surface expression of IL12Rβ1 was performed. Moreover, the clinical and immunological data from the patients was evaluated.
RESULTS: A significant decrease (less than 1%) in the surface expression of IL12Rβ1 was reported in six cases which showed a significant increase in the count of lymphocytes (p=0.009) and CD8+ T cells (p=0.008) as compared to MSMD subjects with normal expression of surface IL12Rβ1. The frequency of disseminated BCGosis (50% vs. 20%, p=0.29), recurrent infection (83.3% vs. 40%, p=0.14) and salmonellosis (33.3% vs. 0.0%, p=0.07) was higher in IL12Rβ1 deficient subjects than IL12Rβ1 sufficient individuals.
CONCLUSION: MSMD patients with childhood onset of mycobacteriosis (mostly after BCG vaccination) and recurrent salmonellosis could be evaluated for IL12Rβ1 expression with flow cytometry for punctual diagnosis.

PMID: 31350062 [PubMed – as supplied by publisher]

Autoimmunity in Common Variable Immunodeficiency.

July 28, 2019 By Manish Butte

Autoimmunity in Common Variable Immunodeficiency.

Ann Allergy Asthma Immunol. 2019 Jul 23;:

Authors: Agarwal S, Cunningham-Rundles C

Abstract
OBJECTIVE: Common variable immunodeficiency (CVID) is a primary immunodeficiency that is clinically heterogeneous, characterized by both infectious and non-infectious complications. While the hallmark of disease presentation is commonly a history of recurrent sinopulmonary infections, autoimmunity and non-infectious inflammatory conditions are increasing associated with CVID.
DATA SOURCES: A comprehensive literature search using PubMed of basic science and clinical articles was performed.
STUDY: Selections: Articles discussing the association of autoimmunity with primary immunodeficiency, specifically CVID, were selected.
RESULTS: The most common autoimmune conditions are cytopenias, including immune thrombocytopenia purpura and hemolytic anemia, but organ specific autoimmune/inflammatory complications involving the gastrointestinal, skin, joints, connective tissue, and respiratory tract. In most cases immunoglobulin replacement therapy does not ameliorate or treat these inflammatory complications, and additional immunomodulatory treatments are needed.
CONCLUSION: Mechanisms producing these conditions are poorly understood but include cytokine and cellular inflammatory pathways, and loss of tolerance to self-antigens through the multiple signaling molecules and pathways common to tolerance and immune deficiency.

PMID: 31349011 [PubMed – as supplied by publisher]

A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance.

July 28, 2019 By Manish Butte

A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance.

Proc Natl Acad Sci U S A. 2019 Jul 25;:

Authors: Khourieh J, Rao G, Habib T, Avery DT, Lefèvre-Utile A, Chandesris MO, Belkadi A, Chrabieh M, Alwaseem H, Grandin V, Sarrot-Reynauld F, Sénéchal A, Lortholary O, Kong XF, Boisson-Dupuis S, Picard C, Puel A, Béziat V, Zhang Q, Abel L, Molina H, Marr N, Tangye SG, Casanova JL, Boisson B

Abstract
Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients’ primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

PMID: 31346092 [PubMed – as supplied by publisher]

New Ocular Findings in a Case of Chronic Granulomatous Disease in a Child.

July 26, 2019 By Manish Butte

New Ocular Findings in a Case of Chronic Granulomatous Disease in a Child.

Ophthalmic Surg Lasers Imaging Retina. 2019 Jul 01;50(7):459-461

Authors: Khundkar T, Panarelli J, Shulman J

Abstract
The authors report a case of a 2-year-old male with chronic granulomatous disease (CGD). On examination, the patient had chorioretinal lesions, peripheral avascular retina, and unilateral glaucoma. CGD is a primary immunodeficiency that leaves the host susceptible to infections and granuloma formation. Chorioretinal lesions are a well-documented finding of CGD. The advent of widefield angiography allowed the authors to detect peripheral retinal nonperfusion in this case. Glaucoma, which by itself has been associated with peripheral avascular retina, has not been previously reported in a case of CGD. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:459-461.].

PMID: 31344247 [PubMed – in process]

Primary Immunodeficiency Disorders: Where Do We Stand?

July 26, 2019 By Manish Butte

Primary Immunodeficiency Disorders: Where Do We Stand?

Indian J Pediatr. 2019 Jul 24;:

Authors: Gupta A

PMID: 31342413 [PubMed – as supplied by publisher]

Aberrant X chromosome skewing and acquired clonal hematopoiesis in adult-onset common variable immunodeficiency.

July 26, 2019 By Manish Butte

Aberrant X chromosome skewing and acquired clonal hematopoiesis in adult-onset common variable immunodeficiency.

JCI Insight. 2019 Jul 25;4(14):

Authors: Wong GK, Barmettler S, Heather JM, Millar D, Penny SA, Huissoon A, Richter A, Cobbold M

Abstract
Advances in genomic medicine have elucidated an increasing number of genetic etiologies for patients with common variable immunodeficiency (CVID). However, there is heterogeneity in clinical and immunophenotypic presentations and a limited understanding of the underlying pathophysiology of many cases. The primary defects in CVID may extend beyond the adaptive immune system, and the combined defect in both the myeloid and lymphoid compartments suggests the mechanism may involve bone marrow output and earlier progenitors. Using the methylation profile of the human androgen receptor (AR) gene as a surrogate epigenetic marker for bone marrow clonality, we examined the hematopoietic compartments of patients with CVID. Our data show that clonal hematopoiesis is common among patients with adult-onset CVID who do not have associated noninfectious complications. Nonblood tissues did not show a skewed AR methylation status, supporting a model of an acquired clonal hematopoietic event. Attenuation of memory B cell differentiation into long-lived plasma cells (CD20-CD27+CD38+CD138+) was associated with marked changes in the postdifferentiation methylation profile, demonstrating the functional consequence of clonal hematopoiesis on humoral immunity in these patients. This study sheds light on a potential etiology of a subset of patients with CVID, and the findings suggest that it is a stage of an acquired lymphocyte maturation disorder.

PMID: 31341110 [PubMed – in process]

Community-based care of children affected by AIDS in Swaziland: a gender-aware analysis.

July 26, 2019 By Manish Butte

Community-based care of children affected by AIDS in Swaziland: a gender-aware analysis.

Prim Health Care Res Dev. 2019 01;20:e15

Authors: Brear MR, Shabangu PN, Hammarberg K, Fisher J, Keleher H

Abstract
BACKGROUND: Care of children affected by AIDS in Swaziland is predominately provided by families, with support from ‘community-based responses’. This approach is consistent with United Nations International Children’s Fund’s (UNICEF) framework for the protection, care and support of children affected by AIDS. However, the framework relies heavily on voluntary caregiving which is highly gendered. It pays limited attention to caregivers’ well-being or sustainable community development which enables more effective caregiving. As a result, the framework is incompatible with the social justice principles of primary health care, and the sustainable development goals (SDGs).AimOur aim was to examine the effects and gender dimensions of providing voluntary, community-based, care-related labour for children affected by AIDS.
METHODS: We conducted multiple-methods research involving an ethnography and participatory health research, in a rural Swazi community. We analysed data related to community-based responses using an abductive, mixed-methods technique, informed by the capabilities approach to human development and a gender analysis framework.FindingsTwo community-based responses, ‘neighbourhood care points’ (facilities that provide children meals) and the ‘lihlombe lekukhalela’ (child protector) program were being implemented. The unpaid women workers at neighbourhood care points reported working in challenging conditions (eg, lacking labour-saving technologies), insufficient and diminishing material support (eg, no food), and receiving limited support from the broader community. Child protectors indicated their effectiveness was limited by lack of social power, relative to the perpetrators of child abuse. The results indicate that support for community-based responses will be enhanced by acknowledging and addressing the highly gendered nature of care-related labour and social power, and that increasing access to material resources including food, caregiver stipends and labour-saving technologies, is essential. These strategies will simultaneously contribute to the social and economic development of communities central to primary health care, and achieving the poverty, hunger, gender and work-related SDGs.

PMID: 30444211 [PubMed – indexed for MEDLINE]

Advances in site-specific gene editing for primary immune deficiencies.

July 26, 2019 By Manish Butte

Advances in site-specific gene editing for primary immune deficiencies.

Curr Opin Allergy Clin Immunol. 2018 12;18(6):453-458

Authors: Kuo CY

Abstract
PURPOSE OF REVIEW: Conventional gene therapy has been a successful, curative treatment modality for many primary immune deficiencies with significant improvements in the last decade. However, the risk of leukemic transformation with viral-mediated gene addition still remains, and unregulated gene addition is not an option for certain diseases in which the target gene is closely controlled. The recent bloom in genome modification platforms has created the opportunity to site-specifically correct mutated DNA base pairs or insert a corrective cDNA minigene while maintaining gene expression under control of endogenous regulatory elements.
RECENT FINDINGS: There is an abundance of ongoing research utilizing programmable nucleases to facilitate site-specific gene correction of many primary immune deficiencies including X-linked severe combined immune deficiency, X-linked chronic granulomatous disease, Wiskott-Aldrich syndrome, X-linked hyper-IgM syndrome, X-linked agammaglobulinemia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked. In all, these studies have demonstrated the ability to integrate corrective DNA sequences at a precise location in the genome at rates likely to either cure or ameliorate disease.
SUMMARY: Gene editing for primary immune deficiency (PID) has advanced to the point to that translation to clinical trials is likely to occur in the next several years. At the current pace of research in DNA repair mechanisms, stem cell biology, and genome-editing technology, targeted genome modification represents the next chapter of gene therapy for PID.

PMID: 30299399 [PubMed – indexed for MEDLINE]

Very early onset IBD: novel genetic aetiologies.

July 26, 2019 By Manish Butte

Very early onset IBD: novel genetic aetiologies.

Curr Opin Allergy Clin Immunol. 2018 12;18(6):470-480

Authors: Batura V, Muise AM

Abstract
PURPOSE OF REVIEW: To summarize the current understanding and recent advances on the genetic aetiology in the pathogenesis of very early onset inflammatory bowel disease (VEO-IBD).
RECENT FINDINGS: IBD is a chronic disorder of the gastrointestinal tract whose manifestation is a result of complex interactions between genetics, environment, immune system and microbial flora. Over 230 IBD risk loci have been reported in genome wide association studies but the genetic contribution of the majority of these loci in the manifestation of IBD is very low. Patients with VEO-IBD present with a more severe disease than older patients, characterized by poor prognosis and failure of conventional therapy. Recent studies have reported several monogenic diseases with high penetrance that present with IBD and IBD-like intestinal manifestations and overlap with primary immunodeficiencies. Increasing body of evidence supports a prominent role of genetics in the onset of VEO-IBD. New genetic variants and diagnoses in VEO-IBD are reviewed and current challenges in therapy with potential strategy to manage the disease are discussed.
SUMMARY: Functional analysis of the genes implicated in monogenic IBD has increased the understanding of the underlying pathobiological mechanism of the disease. This knowledge can be used to personalize medicine for specific patients, improving the standard of care and quality of life.

PMID: 30299396 [PubMed – indexed for MEDLINE]

Non-CF Bronchiectasis as a Possible Indicator of a Primary Immunodeficiency: Diagnosis, Clinical Course, and Quality of Life in a Pediatric Cohort.

July 25, 2019 By Manish Butte

Non-CF Bronchiectasis as a Possible Indicator of a Primary Immunodeficiency: Diagnosis, Clinical Course, and Quality of Life in a Pediatric Cohort.

Klin Padiatr. 2019 Jul 24;:

Authors: Klemann C, Kellermann KB, Ehl S, Stenzel M, Mueller C, Heinzmann A, Bode SFN

Abstract
BACKGROUND: Non cystic fibrosis bronchiectasis (NCBE) is an increasingly recognized chronic, progressive respiratory disorder with significant morbidity also in children and adolescents.
METHODS: We longitudinally assessed a cohort of 35 pediatric patients with NCBE and investigated underlying diagnosis, symptoms, clinical course, treatment, and quality of life.
RESULTS: NCBE were diagnosed at a mean age of 9.5 (±5.3) years. In half of the children NCBE were found prior to identification of the causative diagnosis. Primary immunodeficiency (PID) was identified as the underlying diagnosis in 24/35 (68%) cases, of which two-thirds showed antibody deficiency. In the 11 non-PID cases ciliopathies were most common (n=7). Clinical aspects such as manifestation age, cough or dyspnea symptoms, and exacerbation frequency did not differ significantly between PID and non-PID patients. Likewise, quality of life (QoL) was equally reduced in both groups. Lung function test parameters were stable under appropriate therapy in all children. The majority in both groups was insufficiently vaccinated against influenza and pneumococci.
CONCLUSION: Our data indicates that NCBE need to be especially appreciated as a presenting sign of PID in pediatric patients. Thus, occurrence of NCBE should warrant rigorous diagnostics to identify the underlying condition. In our cohort NCBE themselves rather than the causative diagnoses seem to dictate the clinical course of disease and reduce QoL in children. More intensive efforts have to be undertaken to vaccinate patients according to recommendations.

PMID: 31340404 [PubMed – as supplied by publisher]