Manish Butte

Vici syndrome: a review.

March 2, 2016 By Manish Butte

Vici syndrome: a review.

Orphanet J Rare Dis. 2016;11(1):21

Authors: Byrne S, Dionisi-Vici C, Smith L, Gautel M, Jungbluth H

Abstract
Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency. Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal, suggesting an evolving (neuro) degenerative component. In most patients there is additional variable multisystem involvement that may affect virtually any organ system, including lungs, thyroid, liver and kidneys. A skeletal myopathy is consistently associated, and characterized by marked fibre type disproportion, increase in internal nuclei, numerous vacuoles, abnormal mitochondria and glycogen storage. Life expectancy is markedly reduced.Vici syndrome is due to recessive mutations in EPG5 on chromosome 18q12.3, encoding ectopic P granules protein 5 (EPG5), a key autophagy regulator in higher organisms. Autophagy is a fundamental cellular degradative pathway conserved throughout evolution with important roles in the removal of defective proteins and organelles, defence against infections and adaptation to changing metabolic demands. Almost 40 EPG mutations have been identified to date, most of them truncating and private to individual families.The differential diagnosis of Vici syndrome includes a number of syndromes with overlapping clinical features, neurological and metabolic disorders with shared CNS abnormalities (in particular callosal agenesis), and primary neuromuscular disorders with a similar muscle biopsy appearance. Vici syndrome is also the most typical example of a novel group of inherited neurometabolic conditions, congenital disorders of autophagy.Management is currently largely supportive and symptomatic but better understanding of the underlying autophagy defect will hopefully inform the development of targeted therapies in future.

PMID: 26927810 [PubMed – as supplied by publisher]

Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium.

March 2, 2016 By Manish Butte

Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium.

Immunity. 2015 Nov 17;43(5):987-97

Authors: Maltez VI, Tubbs AL, Cook KD, Aachoui Y, Falcone EL, Holland SM, Whitmire JK, Miao EA

Abstract
Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Pyroptosis was the primary bacterial clearance mechanism in the spleen, but both pyroptosis and interleukin-18 (IL-18)-driven natural killer (NK) cell responses were required for liver defense. NK cells cleared hepatocyte replication niches via perforin-dependent cytotoxicity, whereas interferon-γ was not required. These insights suggested a therapeutic approach: exogenous IL-18 restored perforin-dependent cytotoxicity during infection by the inflammasome-evasive bacterium Listeria monocytogenes. Therefore, inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens.

PMID: 26572063 [PubMed – indexed for MEDLINE]

CD21 and CD19 deficiency: Two defects in the same complex leading to different disease modalities.

March 2, 2016 By Manish Butte

CD21 and CD19 deficiency: Two defects in the same complex leading to different disease modalities.

Clin Immunol. 2015 Dec;161(2):120-7

Authors: Wentink MW, Lambeck AJ, van Zelm MC, Simons E, van Dongen JJ, IJspeert H, Schölvinck EH, van der Burg M

Abstract
PURPOSE: Deficiencies in CD19 and CD81 (forming the CD19-complex with CD21 and CD225) cause a severe clinical phenotype. One CD21 deficient patient has been described. We present a second CD21 deficient patient, with a mild clinical phenotype and compared the immunobiological characteristics of CD21 and CD19 deficiency.
METHODS: CD21 deficiency was characterized by flowcytometric immunophenotyping and sequencing. Real-time PCR, in vitro stimulation and next generation sequencing were used to characterize B-cell responses and affinity maturation in CD21(-/-) and CD19(-/-) B cells.
RESULTS: A compound heterozygous mutation in CD21 caused CD21 deficiency. CD21(-/-) B cells responded normally to in vitro stimulation and AID was transcribed. Affinity maturation was less affected by CD21 than by CD19 deficiency.
CONCLUSIONS: Both CD21 and CD19 deficiencies cause hypogammaglobulinemia and reduced memory B cells. CD19 deficiency causes a more severe clinical phenotype. B-cell characteristics reflect this, both after in vitro stimulation as in affinity maturation.

PMID: 26325596 [PubMed – indexed for MEDLINE]

Insights into primary immune deficiency from quantitative microscopy.

March 2, 2016 By Manish Butte

Insights into primary immune deficiency from quantitative microscopy.

J Allergy Clin Immunol. 2015 Nov;136(5):1150-62

Authors: Mace EM, Orange JS

Abstract
Recent advances in genomics-based technology have resulted in an increase in our understanding of the molecular basis of many primary immune deficiencies. Along with this increased knowledge comes an increased responsibility to understand the underlying mechanism of disease, and thus increasingly sophisticated technologies are being used to investigate the cell biology of human immune deficiencies. One such technology, which has itself undergone a recent explosion in innovation, is that of high-resolution microscopy and image analysis. These advances complement innovative studies that have previously shed light on critical cell biological processes that are perturbed by single-gene mutations in primary immune deficiency. Here we highlight advances made specifically in the following cell biological processes: (1) cytoskeletal-related processes; (2) cell signaling; (3) intercellular trafficking; and (4) cellular host defense.

PMID: 26078103 [PubMed – indexed for MEDLINE]

Primary Immunodeficiency Diseases: Need for Awareness and Advocacy in India.

March 1, 2016 By Manish Butte

Primary Immunodeficiency Diseases: Need for Awareness and Advocacy in India.

Indian J Pediatr. 2016 Feb 29;

Authors: Singh S, Gupta S

PMID: 26924652 [PubMed – as supplied by publisher]

Systemic lupus erythematosus: Is it one disease?

February 29, 2016 By Manish Butte

Systemic lupus erythematosus: Is it one disease?

Reumatol Clin. 2016 Feb 24;

Authors: Rivas-Larrauri F, Yamazaki-Nakashimada MA

Abstract
Systemic lupus erythematosus (SLE) is a multisystemic disease with a variety of clinical presentations. Monogenic predisposing conditions to the development of this disease have been described. As examples, an impaired expression of interferon-α regulated genes or complement deficiencies have been reported in patients with SLE, with particular clinical presentations. Those defects present particular presentations and a different severity, making an argument that lupus is not a single disease but many. Treatment could be individualized depending on the underlying defect generating the subtype of the disease.

PMID: 26922326 [PubMed – as supplied by publisher]

Deficiency of Adenosine Deaminase 2 Causes Antibody Deficiency.

February 29, 2016 By Manish Butte

Deficiency of Adenosine Deaminase 2 Causes Antibody Deficiency.

J Clin Immunol. 2016 Feb 27;

Authors: Schepp J, Bulashevska A, Mannhardt-Laakmann W, Cao H, Yang F, Seidl M, Kelly S, Hershfield M, Grimbacher B

Abstract
PURPOSE: Determining the monogenic cause of antibody deficiency and immune dysregulation in a non-consanguineous family with healthy parents, two affected children, and one unaffected child.
METHODS: Whole Exome Sequencing (WES) was performed in the index family. WES results were confirmed by Sanger Sequencing. Dried plasma spots of the male patient and his mother were analyzed for ADA2 enzymatic activity.
RESULTS: Following data analysis of WES, we found a compound heterozygous mutation in CECR1 (encoding adenosine deaminase 2, ADA2) that segregated in the two affected children. Enzyme activity measurement confirmed a severely diminished ADA2 activity in our patient. The 32 year old index patient was suffering from recurrent respiratory infections and was previously diagnosed with common variable immunodeficiency (CVID), showing no signs of vasculitis. His sister had a systemic lupus erythematosus (SLE)-like phenotype and died at age 17.
CONCLUSIONS: Deficiency of ADA2 (DADA2) has been reported to cause vasculopathy and early-onset stroke. Our case suggests that it should also be considered when evaluating patients with antibody deficiencies and immune dysregulation syndromes.

PMID: 26922074 [PubMed – as supplied by publisher]

SAPI Lego Day

February 28, 2016 By Manish Butte

SAPI sponsored a Lego day! Kids had fun playing with Legos and playing with each other.

Guidelines for Screening, Early Diagnosis and Management of Severe Combined Immunodeficiency (SCID) in India.

February 28, 2016 By Manish Butte

Guidelines for Screening, Early Diagnosis and Management of Severe Combined Immunodeficiency (SCID) in India.

Indian J Pediatr. 2016 Feb 27;

Authors: Madkaikar M, Aluri J, Gupta S

Abstract
Severe combined immunodeficiency (SCID) is one of the most severe and fatal forms of inherited primary immunodeficiency. Early diagnosis of SCID improves the outcome of life before and after hematopoietic stem cell transplant (HSCT). SCID fulfills the internationally-established criteria for a condition to be screened for at birth. T cell receptor excision circle (TREC) assay is commonly used in western countries as part of newborn blood spot screening (NBS) program as the assay has high sensitivity and specificity to identify SCID infants, allowing early intervention and curative bone marrow (BM) transplantation. In India, the blood spot based screening programs are yet to mature into a full-fledged national program. Moreover, TREC assay, a PCR based test, is not widely available and may cost USD 5-7 per test; thus limiting its applicability for screening newborns in Indian scenario. Most of the SCID patients have lymphopenia at birth and routine evaluation for absolute lymphocyte count (ALC) on cord blood samples can help in pre-symptomatic detection and early intervention for neonates with SCID. Although ALC count lacks the sensitivity and specificity of TREC assay; its lower cost and widespread availability makes it an attractive option for identifying newborns with lymphopenia during the post-partum hospital stay. BCG vaccine and other live attenuated vaccines (e.g., oral polio vaccine) should be withheld in lymphopenic infants until SCID is excluded by clinical and/or immunological work-up. A diagnosis of SCID warrants immediate care to prevent and treat infections and wherever feasible, early stem cell transplantation for disease free survival.

PMID: 26920398 [PubMed – as supplied by publisher]

From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation.

February 27, 2016 By Manish Butte

From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation.

Ann N Y Acad Sci. 2016 Feb 25;

Authors: Bacchetta R, Barzaghi F, Roncarolo MG

Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder that increasingly has gained attention as a model of genetic autoimmunity. Numerous papers documenting the key clinical and molecular characteristics of IPEX have provided a detailed understanding of this devastating disease. IPEX is a primary immunodeficiency caused by mutations in the gene FOXP3, which encodes an essential transcription factor required for maintenance of thymus-derived regulatory T (tTreg ) cells. tTreg cell dysfunction is the main pathogenic event leading to multiorgan autoimmunity in IPEX. In addition to the traditional clinical presentation (i.e., severe enteropathy, type 1 diabetes, and eczema), IPEX may encompass other variable and distinct clinical manifestations. As IPEX awareness and characterization have increased, so has identification of FOXP3 mutations, with at least 70 to date. Thus, while FOXP3 is the unifying gene, IPEX is a complex and diverse clinical continuum of disorders. Despite understanding IPEX pathogenesis, new treatment options have remained elusive, although early diagnosis led to hematopoietic stem cell transplantation (HSCT) and immunosuppression treatment and improved patient outcomes. Here, we review current knowledge about IPEX syndrome and highlight findings that could lead to novel targeted treatments.

PMID: 26918796 [PubMed – as supplied by publisher]