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.

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Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency, the first genetic disorder treated by gene therapy. Two different retroviral vectors were used to transfer ex vivo the human ADA minigene into bone marrow cells and peripheral blood lymphocytes from two patients undergoing exogenous enzyme replacement therapy. After 2 years of treatment, long-term survival of T and B lymphocytes, marrow cells, and granulocytes expressing the transferred ADA gene was demonstrated and resulted in normalization of the immune repertoire and restoration of cellular and humoral immunity. After discontinuation of treatment, T lymphocytes, derived from transduced peripheral blood lymphocytes, were progressively replaced by marrow-derived T cells in both patients. These results indicate successful gene transfer into long-lasting progenitor cells, producing a functional multilineage progeny.

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Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency with microthrombocytopenia, eczema, recurrent infections, autoimmune disorders, and malignancies that are life-threatening in the majority of patients. In this long-term, retrospective, multicenter study, we analyzed events that occurred in 96 WAS patients who received transplants between 1979 and 2001 who survived at least 2 years following hematopoietic stem-cell transplantation (HSCT). Events included chronic graft-versus-host disease (cGVHD), autoimmunity, infections, and sequelae of before or after HSCT complications. Three patients (3%) died 2.1 to 21 years following HSCT. Overall 7-year event-free survival rate was 75%. It was lower in recipients of mismatched related donors, also in relation with an older age at HSCT and disease severity. The most striking finding was the observation of cGVHD-independent autoimmunity in 20% of patients strongly associated with a mixed/split chimerism status (P < .001), suggesting that residual-host lymphocytes can mediate autoimmune disease despite the coexistence of donor lymphocytes. Infectious complications (6%) related to splenectomy were also significant and may warrant a more restrictive approach to performing splenectomy in WAS patients. Overall, this study provides the basis for a prospective, standardized, and more in-depth detailed analysis of chimerism and events in longterm follow-up of WAS patients who receive transplants to design better-adapted therapeutic strategies. (Blood. 2008;111: 439-445)

The chemokine receptor CXCR4 and its functional ligand, CXCL12, are essential regulators of development and homeostasis of hematopoietic and lymphoid organs. Heterozygous truncating mutations in the CXCR4 intracellular tail cause a rare genetic disease known as WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis), whose pathophysiology remains unclear. We report CXCR4 function in 3 patients with WHIM syndrome carrying heterozygous truncating mutations of CXCR4. We show that CXCR4 gene mutations in WHIM patients do not affect cell surface expression of the chemokine receptor and its internalization upon stimulation with CXCL12. Moreover, no significant differences in calcium mobilization in response to CXCL12 are found. However, the chemotactic response of both polymorphonuclear cells and T lymphocytes in response to CXCL12 is increased. IntroductionWHIM syndrome is a rare disease characterized by warts, hypogammaglobulinemia, recurrent respiratory bacterial infections, and myelokathexis, defined as the presence of an increased proportion of mature myeloid cells with degenerative changes in the bone marrow, associated with severe neutropenia in the peripheral blood. [1][2][3] This condition, most often inherited as an autosomal dominant trait, is caused by heterozygous truncating mutations in the C-terminus tail of the chemokine receptor CXCR4. 4 CXCR4 is the only cognate receptor for the CXC-chemokine L12 (CXCL12, or stromal-derived factor-1␣ ). 5 CXCL12 is constitutively produced by stromal and endothelial cells (ECs) ubiquitously; the highest concentrations of CXCL12 are found in bone marrow, spleen red pulp, and lymph node medulla. CXCR4-CXCL12 interaction plays a key role in regulating bone marrow homeostasis [6][7][8][9] and is involved in lymphocyte trafficking. 10,11 Chemotaxis and integrin-mediated adhesion are the main cellular responses to CXCL12 9,12-16 ; in addition, CXCR4 signaling participates in several cellular activation and proliferation processes. 17,18 Both CXCR4-and CXCL12-deficient mice display a lethal phenotype, with severe impairment of myeloid and B-cell generation, reduced proliferation of both triple-negative and doublepositive thymocytes, and developmental defects in cerebellum, heart, and gut vascularization. These abnormalities illustrate that this pair of molecules plays an indispensable role in controlling cell migration and influences (either directly or indirectly) survival/ proliferation of different cell types during embryogenesis. [19][20][21] Mice reconstituted with progenitor cells infected with CXCL12 intrakine (which prevents surface CXCR4 expression) suffer from impaired hematopoiesis that involves both myeloid and lymphoid cell lineages. 22 AMD3100, a pharmacologic CXCR4 antagonist, induces a rapid mobilization of hematopoietic progenitors and mature cells in a dose-dependent manner. 23 In contrast, overexpression of CXCR4 in transgenic T lymphocytes induces their accumulation in the bone marrow and causes a reduction of these cells in peripheral...

Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.