Immunodeficiency, auto-inflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic auto-inflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1, a component the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin-1β (IL-1β) was compromised in the patients’ fibroblasts. By contrast, the patients’ mononuclear leukocytes, particularly monocytes, were hyperresponsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of auto-inflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1β responses differently in different cell types

Expansion of Regulatory T Cells in Patients with Langerhans Cell Histiocytosis

Frederic Geissmann and colleagues find that Langerhans cell accumulation in Langerhans cell histiocytosis results from survival rather than uncontrolled proliferation, and is associated with the expansion of regulatory T cells

Invasive mold infections in chronic granulomatous disease: A 25-year retrospective survey

Background. Invasive fungal infection (IFI) represents a life-threatening condition for patients with chronic granulomatous disease (CGD) and causes one-third of deaths in this population. This study offers a descriptive review of invasive mold infection (mIFI) in children with CGD over an extended period of time. Methods. In a cohort of patients with CGD registered in the French National database for Primary Immunodeficiency, we performed a retrospective review of proven mIFI episodes (European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group 2008 criteria) occurring from 1984 through 2009. Results. Twenty-nine proven mIFIs were identified in 24 patients. Thirteen (54%) of 24 children were receiving itraconazole prophylaxis. Seven episodes were caused by Aspergillus fumigatus, 10 by Aspergillus nidulans, 2 by Aspergillus species, and 6 by other opportunistic molds (4 patients only had positive pathological examination findings). First proven mIFI occurred later in the group that received itraconazole than in the group without (median time to mIFI, 10 vs 4 years; P <. 01), with a higher proportion of infections due to A. nidulans and other opportunistic molds (P <. 05). Course of IFI was complex, with the median duration of therapy and hospitalization reaching 446 and 153 days, respectively. Combined antifungal therapy was commonly used. Four patients received geno-identical hematopoietic stem cell transplantation as salvage therapy. Global cure rate among the cohort reached 75%, but sequelae were frequent. Prognosis has improved over time (43% mortality during 1985-1990 vs 6% thereafter; P =. 06). Mortality tended to be lower in the group that recieved itraconazole prophylaxis but at the cost of a longer duration of therapy among cured patients. Conclusions. Management of mIFI remains challenging in patients with CGD, but significant improvements have been made over the past decade. © 2011 The Author.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency

International audienceAllogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for severe combined immunodeficiency (SCID). Detailed assessment of the long-term outcome of HSCT, ie, the occurrence of clinical events and the quality and stability of immune reconstitution, is now required. We performed a single-center retrospective analysis of the long-term outcome of HSCT in 90-patient cohort followed for between 2 and 34 years (median, 14 years). Clinical events and immune reconstitution data were collected. Almost half the patients have experienced one or more significant clinical events, including persistent chronic graft-versus-host disease (GVHD), autoimmune and inflammatory manifestations, opportunistic and nonopportunistic infections, chronic human papilloma virus (HPV) infections, and a requirement for nutritional support. With the notable exception of severe HPV infection, these complications tend to become less common 15 years later after HSCT. A multivariate analysis showed that the occurrence of these events correlated with non-genoidentical donors, diagnosis of Artemis SCID, and quality of immune reconstitution. In most cases, HSCT enables long-term survival with infrequent sequelae. However, the occurrence of relatively late-onset complications is a concern that requires specific means of prevention and justifies careful patient follow-up

Inherited MST1 Deficiency Underlies Susceptibility to EV-HPV Infections

<div><p>Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare <em>ERCC3</em> variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.</p> </div