Immunosuppressive agents (corticosteroids and azathioprine) are associated with significant adverse effects, mostly infections. ...in a series of 5 patients treated with anti-TNF- agents,3 infections ...were more frequent, and 2 deaths occurred despite effectiveness in severe colitis, thus raising concerns regarding their safety in such patients. Because patients 3 and 6 experienced improvement in their pseudomass lesions after 6 and 12 months (see Figs E2 and E3), patients 4 and 5 did not show any improvement in their interstitial pattern, fibrotic pattern, or both (see Fig E4).
Background The inclusion of severe combined immunodeficiency (SCID) in a Europe-wide screening program is currently debated. Objective In making a case for inclusion in the French newborn screening ...program, we explored the costs incurred and potentially saved by early management of SCID. Methods For test costs, a microcosting study documented the resources used in a laboratory piloting a newborn screening test on Guthrie cards using the T-cell receptor excision circle quantification method. For treatment costs, patients with SCID admitted to the national reference center for primary immunodeficiency in France between 2006 and 2010 were included. Costs of admission were estimated from actual national production costs. We estimated the costs for patients who underwent early versus delayed hematopoietic stem cell transplantation (HSCT; age, ≤3 vs >3 months, respectively). Results The unit cost of the test varied between €4.69 and €6.79 for 33,800 samples per year, depending on equipment use and saturation. Of the 30 patients included, 27 underwent HSCT after age 3 months. At 1 year after HSCT, 10 of these had died, and all 3 patients undergoing early transplantation survived. The medical costs for HSCT after 3 months were €195,776 (interquartile range, €165,884-€257,160) versus €86,179 (range, €59,014-€272,577) when performed before 3 months of age. In patients undergoing late transplantation, active infection contributed to high cost and poor outcome. Conclusion Early detection of SCID could reduce the cost of treatment by €50,000-100,000 per case. Assuming a €5 unit cost per test, the incidence required to break even is 1:20,000; however, if the survival advantage of HSCT before 3 months is confirmed, universal screening is likely to be cost-effective.
Background Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or ...elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level. Objective This study's objective was to delineate new causes of immunoglobulin CSR-Ds and thus gain further insights into the process of immunoglobulin class-switch recombination (CSR). Methods Exome sequencing in 2 immunoglobulin CSR-D patients identified variations in the INO80 gene. Functional experiments were performed to assess the function of INO80 on immunoglobulin CSR. Results We identified recessive, nonsynonymous coding variations in the INO80 gene in 2 patients affected by defective immunoglobulin CSR. Expression of wild-type INO80 in patients' fibroblastic cells corrected their hypersensitivity to high doses of γ-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Sα and Eμ regions of the IgH locus, and downregulation of INO80 as well as its partners Reptin and Pontin impaired CSR. In addition, Reptin and Pontin were shown to interact with activation-induced cytidine deaminase. Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity. Conclusion INO80 deficiency appears to be associated with defective immunoglobulin CSR. We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis.
Background Blau syndrome (BS) and Crohn disease (CD) are both characterized by granulomatous inflammation and related to nucleotide oligomerization domain 2 (NOD2) mutations. Objective This study ...aimed to define the morphologic and immunohistochemical characteristics of granulomas in patients with NOD2 -related BS and CD. Methods Granuloma-containing biopsy specimens from 6 patients with BS and 7 pediatric patients with CD carrying NOD2 mutations or single nucleotide polymorphisms were studied for morphology, cellular composition, and cytokine expression by using hematoxylin and eosin staining and immunohistochemistry. Results Biopsy specimens from patients with BS typically showed polycyclic granulomas with large lymphocytic coronas, extensive emperipolesis of lymphocytes within multinucleated giant cells (MGCs), MGC death, and fibrinoid necrosis and fibrosis. In contrast, biopsy specimens from patients with CD showed simple granulomas with subtle/absent lymphocytic coronas, sclerosis of the surrounding tissue, and polymorphonuclear cells. Findings found to be similar in all granulomas were as follows: CD68 and HLA-DR expression by epithelioid cells, monocyte-macrophage lineage cells and MGCs, increased lymphocytic HLA-DR expression, increased CD4+ /CD8+ T-cell ratio, and CD20+ B lymphocytes evenly distributed within and around granulomas. In both patient groups prominent IFN-γ expression was found in and around granulomas, and TNF-α and IL-23 receptor expression was moderate. IL-6, IL-17, and TGF-β expression was prominent in granulomas from patients with BS but sporadic in granulomas from patients with CD. IL-10 expression was absent. Conclusion Granulomas from patients with BS and granulomas from patients with NOD2 -associated CD show distinct morphologic features and cytokine expression patterns, suggesting that the TH 17 axis might be involved in the pathogenesis of BS, whereas TH 1 is important in both patients with BS and patients with CD.
BENTA disease is genetically linked to germline-encoded, gain-of-function mutations in caspase recruitment domain 11 (CARD11), a scaffolding protein largely expressed in lymphocytes and required for ...antigen receptor (AgR)-induced NF-κB activation.3,4 Like somatic mutations found in approximately 10% of diffuse large B-cell lymphomas, CARD11 mutations in patients with BENTA fall within or immediately adjacent to the coiled-coil (CC) domain.5 CC mutations likely abrogate the requirement for AgR-triggered phosphorylation of the inhibitory linker domain, which supports the "open" conformational change necessary for BCL10-MALT1 recruitment and downstream signal transduction via the IκB kinase complex.6 We recently encountered 3 new patients with disease symptoms suggesting BENTA, including moderate, polyclonal B-cell lymphocytosis with a markedly diminished memory B-cell compartment (Table I). The CARD domain is critical for BCL10 interaction and downstream TCR signaling, as well as regulatory T-cell development.7 This mutation was previously reported in 1 case of diffuse large B-cell lymphoma,8 and identified in an unbiased screen for gain-of-function CARD11 mutants capable of activating NF-κB and promoting human diffuse large B-cell lymphoma tumor growth in vitro.6 Indeed, we confirmed that transfection of the C49Y CARD11 mutant into the CARD11-deficient Jurkat T-cell line JPM50.6 resulted in spontaneous protein aggregation, colocalization with MALT1 and active IκB kinase,9 and constitutive NF-κB activation in the absence of AgR stimulation, comparable to other BENTA mutants described (Fig 1, C and D).
The CEC count was persistently higher at day 30 in patients with VE (median = 98/mL; range: 1-548) as compared to patients without VE (median = 4/mL; range: 2-52; P = .002) (Fig 1, A). ...the ...increase of CEC counts was significantly higher in patients with VE during the first month post-transplant (median δD0-D30 = 92; range: 16.5-547; P = .007) as compared to patients without (Fig 1, B).  No vascular event (n = 23) Vascular event (n = 11) Total patients (n = 34) Sex ratio female/male 9/14 3/8 12/22 Age: median (range) 3 y (0.5-14 y) 0.9 y (0.25-9 y) 3 and 5 y (0.25-14 y) Diagnosis    SCID 6 2 8 CID 8 5 13 HLH 5 3 8 Neutrophil disorders 3 1 5 Donor    Matched sibling donor 7 0 7 MUD 7 5 12 MMUD 4 2 6 Haploidentical donor 5 4 9 Defibrotide conditioning regimen 8 9 17 Bu/Flu/ATG 16 6 22 Bu/Flu/ThioTEPA/ATG 6 5 11 Mel/Flu/Alemtuzumab 1 0 1 Graft characteristics    In vitro T-depletion 5 6 11 No in vitro T-depletion 18 5 23 CD34 cell dose (106/kg) 8.2 (1.4-24.2) 13 (5-24.2) 10.5 (1.4-24.2) Engraftment day 19 (9-49) 18.5 (13-31) 19 (9-49) Rejection 2 1 3 GVHD 8 3 11 Grade 1-2 6 1 7 Grade 3-4 2 2 4 Time onset (days) 16.5 (2-60) 27 (10-47) 17 (2-60) CMV systemic replication 4 3 7 Severe sepsis 2 1 3 Duration of hospitalization post-HSCT (days) 78 (38-212) 92 (56-155) 83 (38-212) Death 3 5 8 Table I Hematopoietic transplantation characteristics For CD34 number, engraftment, time of onset of GVHD, and duration of post-HSCT hospitalization, median time is indicated with range in brackets.ATG, Antithymocyte globulin; Bu, busulfan; CID, combined immunodeficiency; CMV, cytomegalovirus; Flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; Mel, Melphalan; MMUD, mismatched unrelated donor; MUD, matched unrelated donor; SCID, severe combined immunodeficiency.
Background Telomeres represent the tips of linear chromosomes. In human subjects telomere maintenance deficiency leads to dyskeratosis congenita (DC), a rare genetic disorder characterized by ...progressive bone marrow failure, accelerated aging, and cancer predisposition. Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an early onset of bone marrow failure leading to combined immunodeficiency is associated with microcephaly, cerebellar hypoplasia, and growth retardation. Objectives Limited information is available on the cellular and molecular phenotypes of cells from patients with HH. We analyzed fibroblasts and whole blood cells from 5 patients with HH, 3 of them of unknown molecular origin. Methods Telomere length, cellular senescence rate, telomerase activity, telomeric aberration, and DNA repair pathways were investigated. Results Although patients’ cells exhibit dysfunctional telomeres, sharp differences in the telomeric aberrations and telomere lengths were noted among these patients. In some patients the dysfunctional telomere phenotype was unprecedented and associated with either normal telomere length or with telomeric aberrations akin to fragile telomeres. This result is of particular importance because the molecular diagnosis of these patients is primarily based on telomere length, which therefore misses a subset of patients with telomere dysfunction. Conclusion These observations provide the notions that (1) various telomere defects can lead to similar clinical features, (2) telomere dysfunction in cells from patients with DC/HH is not always associated with short telomeres, and (3) additional factors, likely involved in telomere protection rather than in length regulation, are responsible for a subset of DC/HH.
Background Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also have defects in cell-mediated immunity and ...antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but has not been reported in patients with CHH. Objective We sought to describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency, and evaluate treatment options. Methods In a retrospective observational study we collected clinical data on 21 patients with CHH to identify and further characterize patients with granulomatous inflammation. Results Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) had epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti–TNF-α mAb therapy in 3 of these patients led to significant regression of granulomas. However, 1 treated patient had fatal progressive multifocal leukoencephalopathy caused by the JC polyomavirus. In 2 patients immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas. Conclusion To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although TNF-α antagonists can effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients.
Background Primary immunoglobulin deficiencies lead to recurrent bacterial infections of the respiratory tract and bronchiectasis, even with adequate immunoglobulin replacement therapy. It is not ...known whether patients able to secrete IgM (eg, those with hyper-IgM HIgM syndrome) are as susceptible to these infections as patients who lack IgM production (eg, those with panhypogammaglobulinemia PHG). Objective This study is aimed at identifying specific microbiological and clinical (infections) characteristics that distinguish immunoglobulin-substituted patients with PHG from patients with HIgM syndrome. Methods A cohort of patients with HIgM syndrome (n = 25) and a cohort of patients with PHG (n = 86) were monitored prospectively for 2 years while receiving similar polyvalent immunoglobulin replacement therapies. Regular bacterial analyses of nasal swabs and sputum were performed, and clinical events were recorded. In parallel, serum and saliva IgM antibody concentrations were measured. Results When compared with patients with PHG, patients with HIgM syndrome were found to have a significantly lower risk of nontypeable Haemophilus influenzae carriage in particular (relative risk, 0.39; 95% CI, 0.21-0.63). Moreover, patients with HIgM syndrome (including those unable to generate somatic hypermutations of immunoglobulin genes) displayed anti–nontypeable H influenzae IgM antibodies in their serum and saliva. Also, patients with HIgM syndrome had a lower incidence of acute respiratory tract infections. Conclusions IgM antibodies appear to be microbiologically and clinically protective and might thus attenuate the infectious consequences of a lack of production of other immunoglobulin isotypes in patients with HIgM syndrome. Polyvalent IgG replacement therapy might not fully compensate for IgM deficiency. It might thus be worth adapting long-term antimicrobial prophylactic regimens according to the underlying B-cell immunodeficiency phenotype.
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