[Show abstract][Hide abstract] ABSTRACT: Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.
Journal of Clinical Immunology 01/2014; · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with primary immunodeficiency diseases (PIDD) may present with recurrent infections affecting different organs, organ-specific inflammation/autoimmunity, and also increased cancer risk, particularly hematopoietic malignancies. The diversity of PIDD and the wide age range over which these clinical occurrences become apparent often make the identification of patients difficult for physicians other than immunologists. The aim of this report is to develop a tool for educative programs targeted to specialists and applied by clinical immunologists.
Considering the data from national surveys and clinical reports of experiences with specific PIDD patients, an evidence-based list of symptoms, signs, and corresponding laboratory tests were elaborated to help physicians other than immunologists look for PIDD.
Tables including main clinical manifestations, restricted immunological evaluation, and possible related diagnosis were organized for general practitioners and 5 specialties. Tables include information on specific warning signs of PIDD for pulmonologists, gastroenterologists, dermatologists, hematologists, and infectious disease specialists.
This report provides clinical immunologists with an instrument they can use to introduce specialists in other areas of medicine to the warning signs of PIDD and increase early diagnosis. Educational programs should be developed attending the needs of each specialty.
Journal of Clinical Immunology 11/2013; · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antibodies are an essential component of the adaptative immune response and hold long-term memory of the immunological experiences throughout life. Antibody defects represent approximately half of the well-known primary immunodeficiencies requiring immunoglobulin replacement therapy. In this article, the authors review the current indications and therapeutic protocols in the Latin American environment. Immunoglobulin replacement therapy has been a safe procedure that induces dramatic positive changes in the clinical outcome of patients who carry antibody defects.
Allergologia et Immunopathologia 01/2013; · 1.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: To investigate the immunological phenotypes detected in children with recurrent upper and lower respiratory infections that have normal total immunoglobulin concentrations. METHODS: A cohort of over 60 children with recurrent respiration infections was evaluated for specific antibody deficiencies (SAD) and for memory B-cell abnormalities. A control group of children without recurrent infections was also evaluated. Evaluation included a detailed history of immunizations with pneumococcal vaccines; determination of IgM, IgG, IgA, and IgE concentrations; measurement of anti-pneumococcal polysaccharide antibody levels by ELISA and expression of CD27, IgD, and IgM on peripheral CD19(+)B cells by flow cytometry to determine the proportions of naive, IgM-memory B cells, and class-switched memory B cells. RESULTS: Patients were classified as having a SAD to either pure polysaccharides (PPV-SAD) or to conjugate polysaccharides (PCV-SAD) based on the number of polysaccharides to which they developed an adequate antibody response. A normal response to only 2 or fewer of 7 PCV or PPV serotypes was considered as evidence of SAD. Forty-one patients without SAD and 26 with SAD were identified. IgM-memory B cells were low in 3 of 41 patients without SAD; in 3 of 5 PPV-SAD patients; and in 10 of 21 PCV-SAD patients. Class-switched memory B cells were low in 19 of 41 patients without SAD; in all 5 patients with PPV-SAD; and in 11 of 21PCV-SAD patients. CONCLUSIONS: Patients with recurrent infection with or without SAD may have low IgM- and/or class-switched memory B cells. Ongoing research aims to determine the prognostic implications of these differences in patients with SAD.
Journal of Clinical Immunology 10/2012; · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.
The Journal of allergy and clinical immunology 09/2012; 130(3 Suppl):S1-24. · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary immunodeficiency diseases (PIDD) are associated with significant morbidity and mortality and result in a significant public health burden. This is in part due to the lack of appropriate diagnosis and treatment of these patients. It is critical that governments become aware of this problem and provide necessary resources to reduce this impact on health care systems. Leading physicians in their respective countries must be supported by their own governments in order to implement tools and provide education and thus improve the diagnosis and treatment of PIDD. The Latin American Society of Primary Immunodeficiencies (LASID) has initiated a large number of activities aimed at achieving these goals, including the establishment of a PIDD registry, development of educational programmes and guidelines, and the introduction of a PIDD fellowship programme. These initiatives are positively impacting the identification and appropriate treatment of patients with PIDD in Latin America. Nevertheless, much remains to be done to ensure that every person with PIDD receives proper therapy.
Allergologia et Immunopathologia 03/2012; 40(3):187-93. · 1.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary immunodeficiencies (PIDs) are genetic disorders of the immune system comprising many different phenotypes. Although previously considered rare, recent advances in their clinical, epidemiological, and molecular definitions are revealing how much we still need to learn about them. For example, geographical and ethnic variations as well as the impact of certain practices influence their frequency and presentation, making it necessary to consider their study in terms of regions. The Latin American Society for Immunodeficiencies was established as an organization dedicated to provide scientific support for basic and clinical research and to develop tools and educational resources to promote awareness in the medical community. Initiatives such as these are positively influencing the way PIDs are tackled in these countries, as shown by recent reports and publications. This paper provides a historical compilation and a current view of the many issues faced by scientists studying these diseases in these countries, highlighting the diverse scientific contributions and offering a promising perspective for the further developments in this field in Latin America.
Annals of the New York Academy of Sciences 02/2012; 1250:62-72. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A large population of patients with recurring infections are undiagnosed or under diagnosed and Primary Immunodeficiency (PI) is more common than had been previously estimated. The results strongly indicate the measurable impact of Physician Education and Public Awareness in identifying patients with an underlying PI. The Jeffrey Modell Centers Network (JMCN) provides the infrastructure for referral, diagnosis and appropriate treatment. All disease classifications and identified defects increased significantly over the study period. Quality of Life for referred and diagnosed patients dramatically improved compared to undiagnosed patients. There is a substantial cost savings for diagnosed patients compared to undiagnosed, even if regular IgG is required. The SPIRIT(®) Software successfully identified patients with PI in a large database and at three pilot sites. The Software was successfully tested for specificity and sensitivity.
Immunologic Research 09/2011; 51(1):61-70. · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypomorphic mutations in the nuclear factor-κB (NF-κB) essential modulator (NEMO) gene result in a variable syndrome of somatic and immunologic abnormalities. Clinically relevant genotype-phenotype associations are essential to understanding this complex disease.
To study 2 unrelated boys with novel NEMO mutations altering codon 223 for similarity in phenotype in consideration of potential genotype-phenotype associations.
Clinical and laboratory features, including cell counts, immunoglobulin quantity and quality, natural killer cell cytotoxicity, and Toll-like and tumor necrosis factor receptor signaling, were evaluated. Because both mutations affected NEMO codon 223 and were novel, consideration was given to new potential genotype-phenotype associations.
Both patients were diagnosed as having hypohidrotic ectodermal dysplasia and had severe or recurrent infections. One had recurrent sinopulmonary infections and the other necrotizing soft tissue methicillin-resistant Staphylococcus aureus infection and Streptococcus anginosus subdural empyema with bacteremia. NEMO gene sequence demonstrated a 3-nucleotide deletion (c.667_669delGAG) in one patient and a substitution (667G>A) in the other. These findings predict either the deletion of NEMO glutamic acid 223 or it being replaced with lysine, respectively. Both patients had normal serum IgG levels but poor specific antibodies. Natural killer cell cytotoxicity and Toll-like and tumor necrosis factor receptor signaling were also impaired. Serious bacterial infection did not occur in both patients after immunoglobulin replacement therapy.
Two different novel mutations affecting NEMO glutamic acid 223 resulted in clinically relevant similar phenotypes, providing further evidence to support genotype-phenotype correlations in this disease. They suggest NEMO residue 223 is required for ectodermal development and immunity and is apparently dispensable for quantitative IgG production but may be required for specific antibody production.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 07/2011; 107(1):50-6. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Early diagnosis and appropriate therapy are essential for the best prognosis and quality of life in patients with primary immunodeficiency diseases (PIDDs). Experts from several Latin American countries have been meeting on a regular basis as part of an ongoing effort to improve the diagnosis and treatment of PIDD in this region. Three programmes are in development that will expand education and training and improve access to testing facilities throughout Latin America. These programmes are: an educational outreach programme (The L-Project); an immunology fellowship programme; and the establishment of a laboratory network to expand access to testing facilities. This report provides the status of these programmes based on the most recent discussions and describes the next steps toward full implementation of these programmes.
Allergologia et Immunopathologia 02/2011; 39(2):106-10. · 1.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Experts from six Latin American countries met to discuss critical issues and needs in the diagnosis and management of primary immunodeficiency diseases (PIDD). The diagnosis of PIDD is generally made following referral to an immunology centre located in a major city, but many paediatricians and general practitioners are not sufficiently trained to suspect PIDD in the first place. Access to laboratory testing is generally limited, and only some screening tests are typically covered by government health programmes. Specialised diagnostic tests are generally not reimbursed. Access to treatment varies by country reflecting differences in healthcare systems and reimbursement policies. An online PIDD Registry Programme for Latin America has been available since 2009, which will provide information about PIDD epidemiology in the region. Additional collaboration across countries appears feasible in at least two areas: a laboratory network to facilitate the diagnosis of PIDD, and educational programmes to improve PIDD awareness. In total, these collaborations should make it possible to advance the diagnosis and management of PIDD in Latin America.
Allergologia et Immunopathologia 01/2011; 39(1):45-51. · 1.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc) is metabolically incorporated into human tissues from certain mammalian-derived foods, and this occurs in the face of an anti-Neu5Gc "xeno-autoantibody" response. Given evidence that this process contributes to chronic inflammation in some diseases, it is important to understand when and how these antibodies are generated in humans. We show here that human anti-Neu5Gc antibodies appear during infancy and correlate with weaning and exposure to dietary Neu5Gc. However, dietary Neu5Gc alone cannot elicit anti-Neu5Gc antibodies in mice with a humanlike Neu5Gc deficiency. Other postnatally appearing anti-carbohydrate antibodies are likely induced by bacteria expressing these epitopes; however, no microbe is known to synthesize Neu5Gc. Here, we show that trace exogenous Neu5Gc can be incorporated into cell surface lipooligosaccharides (LOS) of nontypeable Haemophilus influenzae (NTHi), a human-specific commensal/pathogen. Indeed, infant anti-Neu5Gc antibodies appear coincident with antibodies against NTHi. Furthermore, NTHi that express Neu5Gc-containing LOS induce anti-Neu5Gc antibodies in Neu5Gc-deficient mice, without added adjuvant. Finally, Neu5Gc from baby food is taken up and expressed by NTHi. As the flora residing in the nasopharynx of infants can be in contact with ingested food, we propose a novel model for how NTHi and dietary Neu5Gc cooperate to generate anti-Neu5Gc antibodies in humans.
Journal of Experimental Medicine 08/2010; 207(8):1637-46. · 13.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Defects causing severe combined immunodeficiency (SCID) have been reported in pathways mediating antigen receptor rearrangement, antigen receptor and cytokine signaling, and purine metabolism. Recognizing that the actin regulator Coronin-1A is essential for development of a normal peripheral T cell compartment in mouse models, we identified absence of Coronin-1A in a girl with T−B+NK+ SCID who suffered recurrent infections including severe post-vaccination varicella at age 13 months. Murine Coronin-1A is essential for the release of T cells from the thymus, consistent with the paradoxically detectable thymus in our patient. Molecular analysis revealed a 2 bp deletion in the paternal CORO1A coding sequence paired with a 600 kb de novo deletion encompassing CORO1A on the maternal allele. This genomic region at 16p11.2 is subject to recurrent copy number variations associated with autism spectrum disorders, including attention deficit and hyperactivity, present in our patient. This case highlights the first link between actin cytoskeleton regulation and SCID.
[Show abstract][Hide abstract] ABSTRACT: The identification of the molecular bases of more than 130 primary immunodeficiency diseases has prompted the use of mutation analysis in the diagnostic approach to these patients. Here we discuss the importance of and the limitations associated with molecular diagnosis of these disorders and emphasize the need that mutation analysis be accompanied by appropriate evidence that the identified genetic defect has pathologic consequences on RNA/protein expression and function.
The Journal of allergy and clinical immunology 12/2008; 122(6):1069-73. · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mice carrying the recessive locus for peripheral T cell deficiency (Ptcd) have a block in thymic egress, but the mechanism responsible is undefined. Here we found that Ptcd T cells had an intrinsic migration defect, impaired lymphoid tissue trafficking and irregularly shaped protrusions. Characterization of the Ptcd locus showed a point substitution of lysine for glutamic acid at position 26 in the actin regulator coronin 1A that enhanced its inhibition of the actin regulator Arp2/3 and resulted in its mislocalization from the leading edge of migrating T cells. The discovery of another coronin 1A mutant during an N-ethyl-N-nitrosourea-mutagenesis screen for T cell-lymphopenic mice prompted us to evaluate a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles. Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency.