Research

Single-institution Experience of Unrelated Cord Blood Transplantation for Primary Immunodeficiency.

J Pediatr Hematol Oncol. 2014 Aug 1;

Authors: Chang TY, Jaing TH, Lee WI, Chen SH, Yang CP, Hung IJ

Abstract
Pediatric patients with primary immunodeficiencies (PID) constitute life-threatening medical emergencies. In the absence of an HLA-identical hematopoietic stem cell donor, unrelated donor cord blood transplantation (CBT) is another treatment option. There are little data regarding the outcome of unrelated CBT for PID in Taiwan. We report the results of CBT performed in 8 patients with PID between 2004 and 2013 at Chang Gung Memorial Hospital. The cases included severe combined immunodeficiency (n=4), chronic granulomatous disease (n=2), Wiskott-Aldrich syndrome (n=1), and T-cell immunodeficiency (n=1). Median follow-up time was 73 months. Most UCB recipients received a myeloablative conditioning regimen. There were 7 boys and 1 girl with a median age of 2.5 months at diagnosis (range, antenatal to 17 mo). Median age at transplant was 5.5 months (range, 2 to 74 mo). All but 1 patients engrafted at a median time of 14 days. One developed significant grade III graft-versus-host disease after transplant. Our data show that unrelated CBT in PID is possible. However, no definite conclusions can be drawn from this small number of patients, and more studies are needed to further investigate and confirm these findings.

PMID: 25089606 [PubMed – as supplied by publisher]

Powered by WPeMatico

XLP: Clinical Features and Molecular Etiology due to Mutations in SH2D1A Encoding SAP.

J Clin Immunol. 2014 Aug 2;

Authors: Tangye SG

Abstract
X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency affecting approximately 1-2 per 1 million males. A key feature of XLP is the exquisite sensitivity of affected individuals to disease induced following EBV infection. However, patients can also develop hypogammaglobulinemia and B-cell lymphoma independently of exposure to EBV. XLP is caused by loss-of function mutations in SH2D1A, which encodes the intracellular adaptor molecule SAP. SAP is predominantly expressed in T cells and NK cells, and functions to regulate signal transduction pathways downstream of the SLAM family of surface receptors to control CD4+ T cell (and by extension B cells), CD8+ T cell and NK cell function, as well as the development of NKT cells. The study of XLP had shed substantial light on the requirements for lymphocyte differentiation and immune regulation, which in turn have the potential to be translated into novel treatments for not only XLP patients but individuals affected by EBV-induced disease, impaired humoral immunity and malignancy.

PMID: 25085526 [PubMed – as supplied by publisher]

Powered by WPeMatico

Primary intramedullary non-Hodgkin’s lymphoma in an immunocompetent child.

Spinal Cord. 2014 Aug;52 Suppl 2:S21-3

Authors: Bhushanam TV, Rajesh A, Linga VG, Uppin MS, Malik M

Abstract
STUDY DESIGN: Case report.
OBJECTIVES: Primary intramedullary spinal cord lymphoma is a rare entity. Studies have shown that there is a recent increase in the number of patients regardless of the status of the immunity. High index of suspicion should be kept in all patients with intramedullary tumors. Multidisciplinary approach at the earliest is required for best outcomes.
SETTING: Department of Neurosurgery, Medical Oncology, Pathology and Radiation oncology. Nizam’s Institute of Medical Sciences, Hyderabad, India.
METHODS: We describe the case of an 11-year-old boy who presented with paraparesis and sensory loss below T10 level. On imaging, the dorsal spine showed intramedullary lesion mimicking an astrocytoma.
RESULTS: Surgical decompression of the tumor was done and histopathology showed non-Hodgkin’s lymphoma, diffuse large B-cell type. There were no findings suggestive of congenital or acquired immunodeficiency. After complete staging evaluation, we instituted chemotherapy with modified DeAngelis protocol. At 2 years post treatment, he is in complete remission with near normal neurological status.
CONCLUSIONS: Intramedullary spinal cord diffuse B-cell lymphoma in a pediatric age group is very rare and hence requires a high index of suspicion in patients presented with myelopathy. The outcomes are encouraging with current multidisciplinary approach.

PMID: 25082378 [PubMed – in process]

Powered by WPeMatico

Transplantation Outcomes for Severe Combined Immunodeficiency, 2000-2009.

N Engl J Med. 2014 Jul 31;371(5):434-446

Authors: Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, Kapoor N, Hanson IC, Filipovich AH, Jyonouchi S, Sullivan KE, Small TN, Burroughs L, Skoda-Smith S, Haight AE, Grizzle A, Pulsipher MA, Chan KW, Fuleihan RL, Haddad E, Loechelt B, Aquino VM, Gillio A, Davis J, Knutsen A, Smith AR, Moore TB, Schroeder ML, Goldman FD, Connelly JA, Porteus MH, Xiang Q, Shearer WT, Fleisher TA, Kohn DB, Puck JM, Notarangelo LD, Cowan MJ, O’Reilly RJ

Abstract
Background The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. Methods We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). Results Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. Conclusions Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

PMID: 25075835 [PubMed – as supplied by publisher]

Powered by WPeMatico

[Working together to improve the quality of life for people with primary immunodeficiencies: World PI Week 2013].

Rev Alerg Mex. 2013 Jan-Mar;60(1):1-4

Authors: Sorensen R, Etzioni A, Aziz A, Zeiger JB

PMID: 24008062 [PubMed – indexed for MEDLINE]

Powered by WPeMatico

Novel NLRP12 mutations associated with intestinal amyloidosis in a patient diagnosed with common variable immunodeficiency.

Clin Immunol. 2014 Jul 23;

Authors: Borte S, Celiksoy MH, Menzel V, Ozkaya O, Ozen FZ, Hammarström L, Yildiran A

Abstract
Heterozygous mutations in the NLRP12 gene have been found in patients with systemic auto-inflammatory diseases. However, the NLRP12-associated periodic fever syndromes show a wide clinical spectrum, including patients without classical diagnostic symptoms. Here, we report on a 20-year-old female patient diagnosed with common variable immunodeficiency (CVID), who developed intestinal amyloidosis and carried novel compound heterozygous mutations in NLRP12, identified by whole exome and transcriptome sequencing. CVID is not only a primary immunodeficiency characterized by low serum immunoglobulins, recurrent bacterial infections and development of malignancy, but it also presents with a magnitude of autoimmune features. Because of the unspecific heterogeneous clinical features of the disease, a delay in diagnosis is common. Secondary, inflammatory (AA type) amyloidosis has infrequently been observed in CVID patients. Based on our case observation and a critical review of the literature, we suggest that NLRP12 mutations might account for a small fraction of CVID patients with severe auto-inflammatory complications.

PMID: 25064839 [PubMed – as supplied by publisher]

Powered by WPeMatico

Intact IL-12 signaling is necessary for the generation of human natural killer cells with enhanced effector function after restimulation.

J Allergy Clin Immunol. 2014 Jul 24;

Authors: Simhadri VR, Mariano JL, Zenarruzabeitia O, Seroogy CM, Holland SM, Kuehn HS, Rosenzweig SD, Borrego F

PMID: 25065718 [PubMed – as supplied by publisher]

Powered by WPeMatico

The possible implication of the S250C variant of the autoimmune regulator protein in a patient with autoimmunity and immunodeficiency: in silico analysis suggests a molecular pathogenic mechanism for the variant.

Gene. 2014 Jul 25;

Authors: Bellacchio E, Palma A, Corrente S, Di Girolamo F, Helen Kemp E, Di Matteo G, Comelli L, Carsetti R, Cascioli S, Cancrini C, Fierabracci A

Abstract
Autoimmunity can develop from an often undetermined interplay of genetic and environmental factors. Rare forms of autoimmune conditions may also result from single gene mutations as for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, an autosomal recessive disease associated with mutated forms of the autoimmune regulator gene. It was proposed that genetic variability in the autoimmune regulator locus, in particular heterozygous loss-of-function mutations, might favor the development of organ-specific autoimmunity by affecting the presentation of self-antigens in the thymus. Indeed, heterozygous mutations of the autoimmune regulator gene were reported in patients with organ-specific autoimmunity. Also, in primary immunodeficiencies, a breakdown in central/peripheral tolerance frequently produces association with autoimmunity. The causative link may involve a common genetic background and several gene defects have been identified as putative culprits. We report a unique patient, a 14year old male from Lazio region, affected by common variable immunodeficiency associated with autoimmune manifestations (alopecia, onychodystrophy) and heterozygote for the S250C variant located in the SAND domain of the autoimmune regulator gene protein. To our knowledge this is the first report of the S250C variant in a patient bearing this unusual combination of autoimmunity and immunodeficiency. To obtain insights into the possible molecular effects of the S250C variant, we have carried out an in silico analysis of the SAND domain structure of the autoimmune regulator protein. In particular, homology modeling has allowed us to observe that the cysteine introduced by the S250C variant is surrounded by cationic residues, and by means of molecular dynamics simulations together with pKa calculations, we have shown that these residues remain stably proximal to cysteine-250 lowering its pKa and thus conferring high chemical reactivity to the mutated residue. We propose that the enhanced reactivity of cysteine-250, which is likely to impair the protein function but probably insufficient to produce alone a phenotype as a heterozygous S250C variant due to compensation mechanisms, might become manifest when combined with other genetic/environmental factors. These results can provide the rationale for the patient’s unusual phenotype, shedding new light into the pathogenesis of the clinical association of autoimmunity and immunodeficiency.

PMID: 25068407 [PubMed – as supplied by publisher]

Powered by WPeMatico

Three difficult cases: the challenge of autoimmunity, immunodeficiency and recurrent infections in patients with Good’s syndrome.

Br J Dermatol. 2014 Jul 24;

Authors: Arnold SJ, Hodgson T, Misbah SA, Patel SY, Cooper SM, Venning VA

Abstract
Good’s syndrome is a rare, adult-acquired primary combined immunodeficiency syndrome arising in the context of previous or current thymoma. Patients with Good’s syndrome frequently develop recurrent sinopulmonary infections and are also at high risk of autoimmune manifestations including skin conditions such as lichen planus. We report three cases of middle-aged patients with Good’s syndrome complicated by multiple autoimmune and infectious manifestations. The combination of immunodeficiency, autoimmunity and recurrent infections seen in patients with Good’s syndrome continues to present a management challenge, particularly in patients with oral mucosal disease and recurrent candidiasis. Clinicians should be prompted to investigate an underlying immunodeficiency in patients with multiple autoimmune conditions and recurrent sinopulmonary infections. This article is protected by copyright. All rights reserved.

PMID: 25059810 [PubMed – as supplied by publisher]

Powered by WPeMatico

Consanguinity and polygenic diseases: a model for antibody deficiencies.

Hum Hered. 2014;77(1-4):144-9

Authors: Di Pierro V, Zuntini R, Cancrini C, Finocchi A, Angelino G, Rossi P, Ferrari S

Abstract
Primary immunodeficiencies represent a heterogeneous group of disorders of the immune system, predisposing to various types of infections. Among them, common variable immunodeficiency is the most common symptomatic antibody deficiency. It includes several different forms characterized by defects in the terminal stage of B lymphocyte differentiation, leading to markedly reduced immunoglobulin serum levels and increased susceptibility to bacterial infections. The clinical phenotype is complex, including autoimmunity, granulomatous inflammation, lymphoproliferative disorders and malignancies. Rare autosomal recessive mutations in a number of single genes have recently been reported. However, the underlying genetic defects remain unknown in the majority of cases. In order to seek new genes responsible for the disease, we studied a consanguineous Italian family through exome sequencing combined with homozygosity mapping. Six missense homozygous variants passed our filtering selection and at least two of them were associated with some aspects of the pathological phenotype. Our data remark the complexity of immune system disorders and emphasize the difficulty to understand the significance of genetic results and their correlation with the disease phenotype. © 2014 S. Karger AG, Basel.

PMID: 25060277 [PubMed – in process]

Powered by WPeMatico