Background Profound combined immunodeficiency can present with normal numbers of T and B cells, and therefore the functional defect of the cellular and humoral immune response is often not recognized ...until the first severe clinical manifestation. Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history. Objective We sought to identify the genetic alteration in a patient with combined immunodeficiency and characterize human caspase recruitment domain family, member 11 (CARD11), deficiency. Methods Molecular, immunologic, and functional assays were performed. Results The immunologic characterization revealed only subtle changes in the T-cell and natural killer cell compartment, whereas B-cell differentiation, although normal in number, was distinctively blocked at the transitional stage. Genetic evaluation revealed a homozygous deletion of exon 21 in CARD11 as the underlying defect. This deletion abrogated protein expression and activation of the canonical nuclear factor κB (NF-κB) pathway in lymphocytes after antigen receptor or phorbol 12-myristate 13-acetate stimulation, whereas CD40 signaling in B cells was preserved. The abrogated activation of the canonical NF-κB pathway was associated with severely impaired upregulation of inducible T-cell costimulator, OX40, cytokine production, proliferation of T cells, and B cell–activating factor receptor expression on B cells. Conclusion Thus in patients with CARD11 deficiency, the combination of impaired activation and especially upregulation of inducible T-cell costimulator on T cells, together with severely disturbed peripheral B-cell differentiation, apparently leads to a defective T-cell/B-cell cooperation and probably germinal center formation and clinically results in severe immunodeficiency. This report discloses the crucial and nonredundant role of canonical NF-κB activation and specifically CARD11 in the antigen-specific immune response in human subjects.
Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (
SDHB, SDHC, and
SDHD) of the four genes that encode mitochondrial succinate ...dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were
SDHB mutation positive, one family with germline
SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline
SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline
SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.
Early diagnosis of primary immunodeficiencies is crucial for timely treatment and preventing unwanted complications. Next-generation sequencing (NGS) and detailed clinical and immunological ...evaluation can help early detect such disorders. This study aimed to confirm the diagnosis of two cases of autosomal recessive hyper-immunoglobulin E (IgE) syndrome (AR-HIES), presenting with irreversible eye involvement.
Two unrelated patients with suspected AR-HIES were referred to the Immunology, Asthma and Allergy Research Institute (IAARI), Tehran, Iran. Immunological screening tests were performed for AR-HIES, which showed elevated serum IgE levels, eosinophilia, and low T-lymphocyte responses. NGS was performed, and the results were confirmed by Sanger sequencing.
Sequence analysis showed a mutation in intron 17 of the dedicator of cytokinesis 8 (DOCK8) gene in the first patient, and a homozygous three base-pair deletion in exon 45 of DOCK8 in the second
patient. This is the first time such mutations are reported and these variants are predicted to be damaging. Both patients suffered from persistent viral infections along with cytomegalovirus (CMV) retinitis.
Suspicion of these two novel DOCK8 mutations can benefit patients presenting with recalcitrant ophthalmic viral involvements and relevant immunological test results. This would lead to earlier referrals for immunologic and genetic confirmation and thus, a more timely intervention with hematopoietic stem cell transplantation (HSCT).
Objective
We aimed to test the relevance of deficiency of adenosine deaminase 2 (DADA2) in patients with antibody deficiency and describe the clinical picture of the disease in adulthood.
Methods
We ...screened for DADA2 in a cohort of 181 patients with antibody deficiency with or without vascular lesions using next‐generation sequencing and targeted Sanger sequencing. All mutations were confirmed by determining the ADA2 enzymatic activity levels in dried plasma spots. Clinical data and laboratory values were collected in a standardized format.
Results
Following the diagnosis of 2 siblings in the index family, we identified 9 additional affected patients with compound heterozygous or homozygous CECR1 mutations, containing 6 novel and 4 previously published mutations. The patients' age at evaluation ranged from 13 to 51 years, with a median age of 22 years. Clinically, we saw a broad phenotype, ranging from isolated antibody deficiency to recurrent strokes. All but 1 patient had low numbers of memory B cells. Moreover, B cell function seemed to correlate with inflammation.
Conclusion
Taken together, our findings indicate that DADA2 presents not only with vasculopathy but also with an immunodeficiency of the B cell compartment. Therefore, patients with antibody deficiency should be screened for DADA2. Anti–tumor necrosis factor treatment might improve immunologic features over time and might be considered in patients without vascular manifestations but with elevated inflammation markers. Conservative management has so far proven to be the choice for our less severely affected adolescent and adult DADA2 patients; however, in patients with severe cytopenias and bone marrow failure, hematopoietic stem cell transplantation should be considered.
CONTEXT Germline mutations of the genes encoding succinate dehydrogenase subunits
B (SDHB) and D (SDHD) predispose
to paraganglioma syndromes type 4 (PGL-4) and type 1 (PGL-1), respectively.
In both ...syndromes, pheochromocytomas as well as head and neck paragangliomas
occur; however, details for individual risks and other clinical characteristics
are unknown. OBJECTIVE To determine the differences in clinical features in carriers of SDHB mutations and SDHD mutations. DESIGN, SETTING, AND PATIENTS Population-based genetic screening for SDHB and SDHD germline mutations in 417 unrelated patients with
adrenal or extra-adrenal abdominal or thoracic pheochromocytomas (n = 334)
or head and neck paragangliomas (n = 83), but without syndromic features,
from 2 registries based in Germany and central Poland, conducted from April
1, 2000, until May 15, 2004. MAIN OUTCOME MEASURES Demographic and clinical findings with respect to gene mutation in SDHB vs SDHD compared with nonmutation
carriers. RESULTS A total of 49 (12%) of 417 registrants carried SDHB or SDHD mutations. In addition, 28 SDHB and 23 SDHD mutation carriers
were newly detected among relatives of these carriers. Comparison of 53 SDHB and 47 SDHD total mutation
carriers showed similar ages at diagnosis but differences in penetrance and
of tumor manifestations. Head and neck paragangliomas (10/32 vs 27/34, respectively, P<.001) and multifocal (9/32 vs 25/34, respectively, P<.001) tumors were more frequent in carriers of SDHD mutations. In contrast, SDHB mutation
carriers have an increased frequency of malignant disease (11/32 vs 0/34, P<.001). Renal cell cancer was observed in 2 SDHB mutation carriers and papillary thyroid cancer in 1 SDHB mutation carrier and 1 SDHD mutation
carrier. CONCLUSIONS In contrast with SDHD mutation carriers (PGL-1)
who have more frequent multifocal paragangliomas, SDHB mutation
carriers (PGL-4) are more likely to develop malignant disease and possibly
extraparaganglial neoplasias, including renal cell and thyroid carcinomas.
Appropriate and timely clinical screening is recommended in all patients with
PGL-1 and PGL-4.
CONTEXT Paraganglioma syndrome includes inherited head and neck paragangliomas
(HNPs) and adrenal or extra-adrenal pheochromocytomas and are classified according
to the susceptibility genes SDHB, ...SDHC, and SDHD. In contrast with those with
germline mutations of the SDHB and SDHD genes, clinical and genetic data on patients with mutations of SDHC are scarce. OBJECTIVE To determine the prevalence and clinical characteristics of SDHC mutation carriers compared with patients with SDHB and SDHD mutations and with sporadic
cases. DESIGN, SETTING, AND PATIENTS Genetic screening for SDHC mutations in an
international HNP registry of 121 unrelated index cases and in 371 sporadic
cases from a pheochromocytoma registry, conducted January 1, 2001, until December
31, 2004. Identified index cases and affected relatives were clinically evaluated. MAIN OUTCOME MEASURES Prevalence of and clinical findings for SDHC mutation–associated
HNPs vs those with SDHB and SDHD mutations. RESULTS The prevalence of SDHC carriers was 4% in HNP
but 0% in pheochromocytoma index cases. None of the SDHC mutation carriers had signs of pheochromocytoma. We compared HNPs
in 22 SDHC mutation carriers with the HNPs of SDHB (n = 15) and SDHD (n = 42)
mutation carriers and with 90 patients with sporadic HNPs. Location, number
of tumors, malignancy, and age were different: more carotid body tumors were
found in SDHC (13/22 59%) than in sporadic HNPs
(29/90 32%, P = .03), as well as fewer
instances of multiple tumors in SDHC (2/22) than
in SDHD (24/42; P<.001),
0 malignant tumors in SDHC vs 6/15 in SDHB (P = .002), and younger age
at diagnosis in SDHC than in sporadic HNPs (45 vs
52 years; P = .03). CONCLUSIONS Patients with HNP, but not those with pheochromocytoma, harbor SDHC mutations in addition to those in SDHB and SDHD. In total, more than one quarter
of HNP patients carry a mutation in 1 of these 3 genes. Head and neck paragangliomas
associated with SDHC mutations are virtually exclusively
benign and seldom multifocal. Analysis for germline mutations of SDHC is recommended in apparently sporadic HNP to identify risk of
inheritance.
In 2012 the School of Nursing, Midwifery and Indigenous Health, Charles Sturt University introduced guest lectures from consumers of mental health services and their carers. These lectures were ...placed within the introductory mental health subjects of both the Mental Health Nursing and Paramedic undergraduate programs. This paper describes this experience by combining the recollections of six key stakeholders: the NGO carer support organisation CentaCare Wilcannia-Forbes, a consumer, two carers, a student and the academic involved. Each provided responses to five aspects: the background to the project, the gains from the experience, the personal hopes and concerns when the project was proposed, the perceived value of the project and finally thoughts about the future of the project.
Risks are recognised at an individual level for students, carers and consumers of a re-traumatising nature, and of inadvertent reinforcement of pre-existing stereotyping or stigmatising positions. However, overall, the project was well regarded and is considered worthy of continuing, supported by some research to identify the germane elements.
Abstract
Patients with primary immunodeficiency present an excellent opportunity to understand the role of specific molecules in the human immune system. Recently we had the chance to investigate a ...young girl with a complete CARD11 deficiency due to a homozygous deletion of exon 21. Clinically the child presented with increased susceptibility to respiratory tract infections at 6 months, before she was diagnosed at 13 months with Pneumocystis jirovecii revealing her combined immunodeficiency. The immunological characterization showed severe hypogammaglobulinemia, but normal T-, B- and NK-cell numbers. While there were only subtle changes in the T cell compartment, B-cell differentiation was blocked at the transitional stage. In the absence of CARD11 protein expression activation of the canonical NF-κB pathway after antigen receptor or PMA stimulation was abrogated, while CD40 signaling in B cells was preserved. CARD11 deficient T cells were severely impaired in the up-regulation of ICOS, OX40, cytokine production and proliferation after TCR stimulation. On B cells BAFF receptor expression was reduced and after activation ICAM1 and CD25 were not induced while CD86 induction was comparable to control cells. Immunoglobulin production was intact after anti-IL-21/CD40L stimulation, demonstrating that plasma cell differentiation was not dependent on intact CARD11. Thus CARD11 plays a crucial, non-redundant role in the antigen specific immune response in humans.
Background: Profound combined immunodeficiency can present with normal numbers of T and B cells, and therefore the functional defect of the cellular and humoral immune response is often not ...recognized until the first severe clinical manifestation. Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history. Objective: We sought to identify the genetic alteration in a patient with combined immunodeficiency and characterize human caspase recruitment domain family, member 11 (CARD11), deficiency. Methods: Molecular, immunologic, and functional assays were performed. Results: The immunologic characterization revealed only subtle changes in the T-cell and natural killer cell compartment, whereas B-cell differentiation, although normal in number, was distinctively blocked at the transitional stage. Genetic evaluation revealed a homozygous deletion of exon 21 in CARD11 as the underlying defect. This deletion abrogated protein expression and activation of the canonical nuclear factor kappaB (NF-kappaB) pathway in lymphocytes after antigen receptor or phorbol 12-myristate 13-acetate stimulation, whereas CD40 signaling in B cells was preserved. The abrogated activation of the canonical NF-kappaB pathway was associated with severely impaired upregulation of inducible T-cell costimulator, OX40, cytokine production, proliferation of T cells, and B cellaactivating factor receptor expression on B cells. Conclusions: Thus in patients with CARD11 deficiency, the combination of impaired activation and especially upregulation of inducible T-cell costimulator on T cells, together with severely disturbed peripheral B-cell differentiation, apparently leads to a defective T-cell/B-cell cooperation and probably germinal center formation and clinically results in severe immunodeficiency. This report discloses the crucial and nonredundant role of canonical NF-kappaB activation and specifically CARD11 in the antigen-specific immune response in human subjects.
Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID ...patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10, 999 controls across 123, 127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P = 2.0 x 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P = 4.8 x 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.
PDF
