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Biomedical subjects

Francisco A Bonilla

Publications and source records attributed to Francisco A Bonilla.

17 recordsLinked to original sources
PubMed2006

Interleukin receptor-associated kinase-4 deficiency impairs Toll-like receptor-dependent innate antiviral immune responses.

BACKGROUND: Engagement of all known Toll-like receptors (TLRs) causes the production of inflammatory cytokines, including TNF-alpha, whereas in humans, engagement of TLRs 3, 7, 8, and 9 also induces type I IFNs. IRAK-4 is a critical effector in signaling by TLRs and the IL-1 receptor, which share homology in their intracellular domain and recruit IRAK-4 via the adaptor myeloid differentiation factor 88 (MyD88). Patients with IRAK-4 deficiency are susceptible to invasive bacterial infections but have so far not been reported to be susceptible to viral infection. Blood cells from these patients are impaired in their ability to make TNF-alpha in response to activation by TLRs. A recent report has described concomitant impairment of type I IFN production after activation of TLRs 7, 8, and 9, but not TLR3. OBJECTIVES: We sought to evaluate the role of IRAK-4 in TLR-induced production of the type I IFN, IFN-alpha, in humans. METHODS: We examined TLR-induced production of TNF-alpha and IFN-alpha in PBMCs from an IRAK-4-deficient patient, his heterozygous carrier parents, and normal controls. RESULTS: TNF-alpha production in response to TLR agonists was severely impaired in the patient. IFN-alpha production induced by TLR7, TLR8, and TLR9, as well as TLR3 agonists, was low or absent. CONCLUSIONS: IRAK-4 plays an important role in the production of type I IFN, as well as TNF-alpha, induced by all TLRs, including TLR3. CLINICAL IMPLICATIONS: IRAK-4 may play a broader role in human innate antiviral immunity than previously appreciated.

Cells, Cultured↗
PubMed2006

TACI mutation in common variable immunodeficiency and IgA deficiency.

Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disease. Immunoglobulin A deficiency (IGAD) shares some clinical, laboratory, and genetic features with CVID and occurs with relatively greater frequency in first-degree relatives of individuals with CVID. Recently, patients with CVID and IGAD have been found to have mutations of the gene TNFRSF13B encoding the TACI (transmembrane activator and calcium-modulator and cyclophilin-ligand interactor), a member of the tumor necrosis factor-receptor superfamily. In this article, we review the various TACI mutations that have been identified so far. Although six mutations have been reported, no clear genotype-phenotype association has been shown to date. This suggests that the phenotypic expression of TACI mutation is affected by additional genetic and environmental factors. Analysis of a larger sample of patients will be needed to determine if the specific mutations are associated with a particular phenotype or predisposition to the common features of CVID and IGAD: autoimmunity, lymphoproliferation, or malignancy.

Animals↗
PubMed2006

2. Update on primary immunodeficiency diseases.

The pace of discovery in primary immunodeficiency continues to accelerate. In particular, lymphocyte defects have been the source of the most impressive expansion in recent years. Novel forms of agammaglobulinemia, class-switch defects, and T-B(+) severe combined immunodeficiency have been described. Little by little, the genetic heterogeneity of the common variable immunodeficiency and IgA deficiency phenotypes continues to be unraveled as new molecular defects have been reported in these patients as well. The phenotypic spectrum of DiGeorge syndrome has been further developed, along with promising advances in therapy. Defects of nuclear factor kappaB regulation and Toll-like receptor signaling have been described, along with defects of chemokine receptors and cytoplasmic proteases. Clinically defined immunodeficiencies, such as hyper-IgE syndrome and idiopathic CD4 lymphocytopenia, are also discussed. Finally, significant adverse effects in some patients have tempered initial enthusiasm for gene therapy.

Agammaglobulinemia↗
PubMed2006

Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.

Human immunoglobulin prepared for intravenous administration (IGIV) has a number of important uses in the treatment of disease. Some of these are in diseases for which acceptable treatment alternatives do not exist. In this review we have evaluated the evidence underlying a wide variety of IGIV uses and make specific recommendations on the basis of these data. Given the potential risks and inherent scarcity of IGIV, careful consideration of the indications for and administration of IGIV is warranted.

Asthma↗
PubMed2004

Characteristics of mycobacterial infection in patients with immunodeficiency and nuclear factor-kappaB essential modulator mutation, with or without ectodermal dysplasia.

Hypomorphic mutations of the nuclear factor kappaB essential modulator gene cause ectodermal dysplasia and immunodeficiency. Affected patients have increased susceptibility to mycobacterial disease including cutaneous manifestations. We describe clinical and histopathologic characteristics of 5 patients with nuclear factor kappaB essential modulator gene mutations and mycobacterial infections, two of whom had mycobacterial cutaneous infections.

Adolescent↗
PubMed2004

The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation.

BACKGROUND: An increasing number of rare genetic defects are associated with immunodeficiency and impaired ability to activate gene transcription through nuclear factor (NF) kappaB. Hypomorphic mutations in the NFkappaB essential modulator (NEMO) impair NFkappaB function and are linked to both immunodeficiency and ectodermal dysplasia (ED), as well as susceptibility to atypical mycobacterial infections. OBJECTIVE: We sought to investigate the clinical and immunologic natural history of patients with NEMO mutation with immunodeficiency (NEMO-ID). METHODS: Patients with severe bacterial infection and ED or unexplained mycobacterial sensitivity were evaluated for NEMO mutation. Laboratory investigations and clinical data were retrospectively and prospectively accumulated and reviewed. RESULTS: We have given a diagnosis of NEMO-ID to 7 boys; 6 had ED, and 5 had gene mutations in the 10th exon of NEMO. Our resulting estimated incidence of NEMO-ID is 1:250,000 live male births. All patients had serious pyogenic bacterial illnesses early in life, and the median age of first infection was 8.1 months. Most boys had mycobacterial disease (median age, 84 months), and a minority had herpesviral infections. Initial immunologic assessments showed hypogammaglobulinemia (median IgG, 170 mg/dL) with variable IgM (median, 41 mg/dL) and IgA (median, 143 mg/dL) levels. Two patients had increased IgM levels, and 5 had increased IgA levels. All patients evaluated had normal lymphocyte subsets with impaired proliferative responses, specific antibody production, and natural killer cell function. Two patients died from complications of mycobacterial disease (ages 21 and 33 months). CONCLUSION: NEMO-ID is a combined immunodeficiency with early susceptibility to pyogenic bacteria and later susceptibility to mycobacterial infection. Specific features of particular NEMO mutations in these patients provide insight into the role of this gene in immune function.

Agammaglobulinemia↗
PubMed2004

Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia.

BACKGROUND: Many receptors rely on the appropriate activation of nuclear factor (NF) kappa B to induce cellular function. This process depends critically on the phosphorylation of the inhibitor of NF-kappa B (I kappa B) by the I kappa B kinase. This targets I kappa B for ubiquitination and degradation, allowing NF-kappa B to translocate to the nucleus, where it can direct transcription. Hypomorphic human mutations affecting one I kappa B kinase component, the NF-kappa B essential modulator (NEMO), result in impaired signaling from receptors required for ectodermal development and immune function. Male subjects with these mutant NEMO molecules have an X-linked syndrome known as ectodermal dysplasia with immunodeficiency, which is characterized by severe infections, with herpesviruses, bacteria, and mycobacterial susceptibility. OBJECTIVE: We sought to genetically and biochemically characterize a patient with a mutant NEMO molecule without ectodermal abnormalities. METHODS: We evaluated NEMO in a patient who had immunodeficiency and atypical mycobacterial infection but normal ectoderm. RESULTS: We identified a novel NEMO mutant causing immunodeficiency without ectodermal dysplasia. The mutation, which altered the exon 9 splice site, was present in cells of ectodermal and hematopoetic origin and resulted in a heterogeneous mixture of mutant and wild-type cDNA species. Immunologic function was variably impaired, with reduced CD40-induced B-cell proliferation, partially reduced NF-kappa B p65 nuclear translocation, and variable Toll-like receptor-induced TNF production. This variability might be explained by an inconsistent ratio of mutant to wild-type NEMO. The lack of any ectodermal phenotype, however, suggested a separation in the hematopoetic and ectodermal function of NEMO that leads to NF-kappa B activation. CONCLUSION: Mutation of the gene encoding NEMO can result in immunodeficiency without ectodermal dysplasia.

Adolescent↗
PubMed2003

Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells.

An 11-year-old girl presented with a papulovesicular rash and severe respiratory distress 5 weeks after receiving varicella vaccine. Restriction fragment length-polymorphism analysis of virus isolated from an endotracheal-tube aspirate and from bronchoalveolar lavage revealed that this patient's illness was due to the Oka vaccine strain of varicella. An extensive immunologic analysis failed to identify a known diagnostic entity to explain her susceptibility to this attenuated vaccine strain. Analysis of her lymphocytes on separate occasions, months after recovery from her illness, revealed a profound deficiency of natural killer T (NKT) cells and of NKT-cell activity, suggesting that NKT cells contribute to host defense against varicella virus.

Antigens, Viral↗
PubMed2003

Management of an anaphylactoid reaction to methotrexate with a stepwise graded challenge.

We report the management of a 15-year-old boy with an anaphylactic or anaphylactoid response to his first dose of methotrexate during induction therapy for acute lymphoblastic leukemia (ALL). Because weekly methotrexate therapy is an important component of continuation chemotherapy for pediatric ALL, a stepwise graded challenge was employed to achieve drug tolerance.

Adolescent↗
PubMed2003

IgG Fc receptor polymorphisms in human disease: implications for intravenous immunoglobulin therapy.

Polymorphisms of human Fc receptors (FcRs) have been described that are associated with the development or progression of autoimmune diseases. The FcR polymorphisms affect the affinity with which FcRs interact with immunoglobulin molecules. Intravenous immunoglobulin is administered as therapy for many autoimmune diseases and might exert its effects by interacting with FcRs. Thus, FcR polymorphisms might influence the efficacy of intravenous immunoglobulin therapy for patients with certain autoimmune diseases. In this article we review FcR polymorphisms in relation to autoimmune diseases for which intravenous immunoglobulin is used therapeutically.

Autoimmune Diseases↗
PubMed2003

12. Primary immunodeficiency diseases.

Although primary immunodeficiency disorders are relatively rare, intensive investigation of these disorders has yielded a great wealth of understanding of basic immunologic mechanisms in host defense, inflammation, and autoimmunity. These advances have led to important developments for the treatment not only of the primary immunodeficiencies but also for patients with secondary immunocompromised states, autoimmune disorders, hypersensitivity, graft rejection, and graft versus host disease. Correction of a form of severe combined immunodeficiency represents the first true success of human gene therapy. This review introduces the major clinical manifestations of primary immunodeficiency disorders, along with descriptions of essential elements of the pathophysiology of those disorders that have been defined at the molecular level. Key concepts in treatment are also presented. It is critical for the practicing primary care provider and allergist to maintain an index of suspicion for immunodeficiency. Early diagnosis offers the best opportunity for reduced morbidity and survival and is critical for accurate genetic counseling.

Antibodies↗
PubMed2003

Acute chylothorax in children: selective retention of memory T cells and natural killer cells.

OBJECTIVE: To assess for immunodeficiency in patients with hypogammaglobulinemia in the setting of draining acute chylothorax. STUDY DESIGN: Humoral and cellular immunity was evaluated in 8 patients with chylothorax. Chylous fluid was also analyzed to document cellular losses. Data regarding clinical course and immunologic characteristics were reviewed retrospectively. RESULTS: All patients had hypogammaglobulinemia (IgG=179+/-35 mg/dL) as well as lymphopenia (985+/-636 cells/mm(3)). T cells were decreased and natural killer cells increased in peripheral blood. The converse was found in chylous fluid. The ratio of CD3+/CD45RA+ naive: CD3+/CD45RO+ memory T cells was greater in chyle than in peripheral blood. In vitro proliferative responses to antigens and mitogens were similar to control subjects, and previously immunized patients maintained evidence of protective vaccine-specific humoral immunity. To treat hypogammaglobulinemia, patients received intravenous immunoglobulin (IVIG) to maintain IgG within normal range; 6 of 8 patients had serious infections before receiving IVIG compared with 4 of 8 patients during the period of IVIG administration. CONCLUSION: Draining chylothorax resulted in IgG and lymphocyte depletion with preferential retention of memory T cells and natural killer cells in the circulation. Overall, protective-specific antibody levels and T cell function were maintained. IVIG administration did not lead to discernible protection from infectious complications in this small group of patients.

Acute Disease↗
PubMed2002

Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses.

The Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder caused by a mutation in WAS protein (WASp) that results in defective actin polymerization. Although the function of many hematopoietic cells requires WASp, the specific expression and function of this molecule in natural killer (NK) cells is unknown. Here, we report that WAS patients have increased percentages of peripheral blood NK cells and that fresh enriched NK cells from two patients with a WASp mutation have defective cytolytic function. In normal NK cells, WASp was expressed and localized to the activating immunologic synapse (IS) with filamentous actin (F-actin). Perforin also localized to the NK cell-activating IS but at a lesser frequency than F-actin and WASp. The accumulation of F-actin and WASp at the activating IS was decreased significantly in NK cells that had been treated with the inhibitor of actin polymerization, cytochalasin D. NK cells from WAS patients lacked expression of WASp and accumulated F-actin at the activating IS infrequently. Thus, WASp has an important function in NK cells. In patients with WASp mutations, the resulting NK cell defects are likely to contribute to their disease.

Actins↗
PubMed2002

Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations.

NF-kappaB essential modifier (NEMO), also known as IKK-gamma, is a member of the I-kappaB kinase complex responsible for phosphorylating I-kappaB, allowing the release and activation of NF-kappaB. Boys with an expressed NEMO mutation have an X-linked syndrome characterized by hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID). The immunophenotype resulting from NEMO mutation is highly variable, with deficits in both T and B cell responses. We evaluated three patients with NEMO mutations (L153R, Q403X, and C417R) and HED-ID who had evidence of defective CD40 signaling. All three patients had normal percentages of peripheral blood NK cells, but impaired NK cell cytotoxic activity. This was not due to a generalized defect in cytotoxicity because antibody-dependent cellular cytotoxicity was intact. This abnormality was partially reversed by in vitro addition of IL-2, which was also able to induce NF-kappaB activation. In one patient with recurrent cytomegalovirus infections, administration of IL-2 partially corrected the NK cell killing deficit. These data suggest that NEMO participates in signaling pathways leading to NK cell cytotoxicity and that IL-2 can activate NF-kappaB and partially overcome the NK cell defect in patients with NEMO mutations.

Adolescent↗