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.
Background Recent identification of STAT3 mutations in autosomal dominant (AD) hyper-IgE syndrome (HIES) has improved the clinical, genetic, and molecular classification of the HIES. Objective We ...sought to characterize the cutaneous signs observed in molecularly diagnosed AD-HIES. Methods We conducted a retrospective study of 21 patients with AD-HIES and confirmed STAT3 mutations, treated at Necker-Enfants Malades Hospital, Paris, France. Results A papulopustular rash on the face and scalp before the age of 2 months was observed in 67% of patients. This “early rash” was distinguished from other neonatal pustular eruptions by crusted papules and pustules, rash intensity, and a continuum with chronic dermatitis. An eczematous dermatitis was almost always present before the age of 18 months (95% of patients) and was mainly confined to the face, scalp, chest, and buttocks. All patients presented with infected dermatitis ( Staphylococcus aureus ) and 59% had chronic candidiasis of the oral mucosa and nails. Cutaneous herpes virus infections were not unusually severe. Coarse facial skin at puberty, and sometimes at a younger age, with prominent follicular ostia resembling atrophoderma vermiculatum was not related to severe acne or facial abscesses. Limitations This was a retrospective study with a small number of patients. Conclusion When associated with serum IgE levels 10 times the age-appropriate level, a neonatal papulopustular rash progressing to a chronic impetiginized eczematous dermatitis that differs from classic atopic dermatitis is highly suggestive of AD-HIES. Early recognition is important for initiation of prophylactic antistaphylococcal and antifungal treatment.
...long after treatment, patients with HL exhibit a persistent and dramatic alteration in CD4+ T-cell homeostasis and in thymic function, evidenced by a decrease in naive thymic CD4+ CD45RA+ CD31+ ...T-cell numbers and TREC levels, while memory CD4+ T-cell counts remained unaffected.
...little is known about the mechanisms by which homozygous JAK3 R117C missense mutations impair JAK3 signaling in lymphocyte ontogeny to result in the persistence of dysfunctional NK cells, although ...a hypomorphic mutation could be possible. ...the present study describes a case of T-B+NK+ SCID caused by a homozygous JAK3 missense mutation, resulting in leaky SCID.
Background Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphoproliferation, accumulation of double-negative T cells, hypergammaglobulinemia G and A, and ...autoimmune cytopenia. Objectives Although mostly associated with FAS mutations, different genetic defects leading to impaired apoptosis have been described in patients with ALPS, including the FAS ligand gene (FASLG) in rare cases. Here we report on the first case of complete FAS ligand deficiency caused by a homozygous null mutant. Methods Double-negative T-cell counts and plasma IL-10 and FAS ligand concentrations were determined as ALPS markers. The FASLG gene was sequenced, and its expression was analyzed by means of Western blotting. FAS ligand function was assessed based on reactivation-induced cell death. Results We describe a patient born to consanguineous parents who presented with a severe form of ALPS caused by FASLG deficiency. Although the clinical presentation was compatible with a homozygous FAS mutation, FAS-induced apoptosis was normal, and plasma FAS ligand levels were not detectable. This patient carries a homozygous, germline, single-base-pair deletion in FASLG exon 1, leading to a premature stop codon (F87fs x95) and a complete defect in FASLG expression. The healthy parents were each heterozygous for the mutation, confirming its recessive trait. Conclusion FAS ligand deficiency should be screened in patients presenting with ALPS features but lacking the usual markers, including plasma soluble FAS ligand and an in vitro apoptotic defect. An activation-induced cell death test could help in discrimination.
Next-generation DNA sequencing has accelerated the genetic characterization of many human primary immunodeficiency diseases (PIDs). These discoveries can be lifesaving for the affected patients and ...also provide a unique opportunity to study the effect of specific genes on human immune function. In the past 18 months, a number of independent groups have begun to define novel PIDs caused by defects in the caspase recruitment domain family, member 11 (CARD11) –B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10) –mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1 CBM) signalosome complex. The CBM complex forms an essential molecular link between the triggering of cell-surface antigen receptors and nuclear factor κB activation. Germline mutations affecting the CBM complex are now recognized as the cause of novel combined immunodeficiency phenotypes, which all share abnormal nuclear factor κB activation and dysregulated B-cell development as defining features. For this “Current perspectives” article, we have engaged experts in both basic biology and clinical immunology to capture the worldwide experience in recognizing and managing patients with PIDs caused by CBM complex mutations.
Background Defects in the development or activation of T cells result in immunodeficiency associated with severe infections early in life. T-cell activation requires Ca2+ influx through Ca2+ -release ...activated Ca2+ (CRAC) channels encoded by the gene ORAI1. Objective Investigation of the genetic causes and the clinical phenotype of immunodeficiency in patients with impaired Ca2+ influx and CRAC channel function. Methods DNA sequence analysis for mutations in the genes ORAI1 , ORAI2 , ORAI3 , and stromal interaction molecule (STIM) 1 and 2, as well as mRNA and protein expression analysis of ORAI1 in immunodeficient patients. Immunohistochemical analysis of ORAI1 tissue distribution in healthy human donors. Results We identified mutations in ORAI1 in patients from 2 unrelated families. One patient is homozygous for a frameshift nonsense mutation in ORAI1 (ORAI1-A88SfsX25), and a second patient is compound heterozygous for 2 missense mutations in ORAI1 (ORAI1-A103E/L194P). All 3 mutations abolish ORAI1 expression and impair Ca2+ influx and CRAC channel function. The clinical syndrome associated with ORAI1 deficiency is characterized by immunodeficiency with a defect in the function but not in the development of lymphocytes, congenital myopathy, and anhydrotic ectodermal dysplasia with a defect in dental enamel calcification. In contrast with the limited clinical phenotype, we found ORAI1 protein expression in a wide variety of cell types and organs. Conclusion Ca2+ influx through ORAI1 is crucial for lymphocyte function in vivo . Despite almost ubiquitous ORAI1 expression, the channel has a nonredundant role in only a few cell types judging from the limited clinical phenotype in ORAI1-deficient patients.
Primary immunodeficiencies: 2009 update Notarangelo, Luigi D., MD; Fischer, Alain, MD; Geha, Raif S., MD ...
Journal of allergy and clinical immunology,
12/2009, Letnik:
124, Številka:
6
Journal Article
Recenzirano
Odprti dostop
More than 50 years after Ogdeon Bruton's discovery of congenital agammaglobulinemia, human primary immunodeficiencies (PIDs) continue to unravel novel molecular and cellular mechanisms that govern ...development and function of the human immune system. This report provides the updated classification of PIDs that has been compiled by the International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies after its biannual meeting in Dublin, Ireland, in June 2009. Since the appearance of the last classification in 2007, novel forms of PID have been discovered, and additional pathophysiology mechanisms that account for PID in human beings have been unraveled. Careful analysis and prompt recognition of these disorders is essential to prompt effective forms of treatment and thus to improve survival and quality of life in patients affected with PIDs.
...she developed septicemia and severe lung infections poorly responsive to antimicrobial therapy with the deterioration of respiratory functions and bronchiectasis. Because of the chronic pulmonary ...inflammation with alveolar involvement and because of the lung biopsy revealing a PAP-like picture, corticosteroid therapy was started followed by rapid clinical improvement. ...we describe the first early-onset case of agammaglobulinemia with the complete absence of B, NK, monocyte, and dendritic cell precursors.
Background The generation of high-affinity antibodies requires the presence of a population of CD4+ T cells (follicular TH TFH cells) in the lymph node follicles. These cells differ from TH 1, TH 2, ...and TH 17 effector cells in that they strongly express activation markers and the chemokine receptor CXCR5 and secrete large amounts of IL-21 and CXCL13. Small numbers of nonactivated CD4+ CD45RO+ CXCR5+ T cells are also found in the blood. Objective We sought to obtain in vitro a population close to the TFH cells and to study the presence of this cell population among patients with autosomal dominant hyper-IgE syndrome carrying heterozygous signal transducer and activator of transcription 3 (STAT3) mutations that impair the IL-21 signaling required for B-cell differentiation. Methods CD4+ CD45RO+ CXCR5+ T cells were isolated from blood and activated by CD3/T-cell receptor. Results We found that CD4+ CD45RO+ CXCR5+ activated T cells corresponding to circulating bona fide memory TFH cells and that STAT3-deficient patients have abnormally low numbers of “TFH -like” blood T cells. However, STAT3-deficient TFH cells have much the same phenotypic and functional characteristics as TFH cells from healthy control subjects. The ability of STAT3-deficient TFH cells to produce IL-21 on CD28/T-cell receptor activation and to proliferate did not differ from that observed for control TFH cells in vitro . Although the STAT3-deficient TFH cells were also able to help control B cells to produce IgG and IgA, induction of IgG production by naive B cells was impaired. Conclusion Heterozygous mutations in STAT3 lead to reduced numbers of circulating TFH -like cells, a finding that might account (at least in part) for the observed defect in antibody production.
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