Francisco Espinosa-Rosales

Primary Immunodeficiency Diseases in Latin America: The Second Report of the LAGID Registry

This is the second report on the continuing efforts of LAGID to increase the recognition and registration of patients with primary immunodeficiency diseases in 12 Latin American countries: Argentina, Brazil, Chile, Colombia, Costa Rica, Honduras, Mexico, Panama, Paraguay, Peru, Uruguay, and Venezuela. This report reveals that from a total of 3321 patients registered, the most common form of primary immunodeficiency disease was predominantly antibody deficiency (53.2%) with IgA deficiency reported as the most frequent phenotype. This category was followed by 22.6% other well-defined ID syndromes, 9.5% combined T- and B-cell inmunodeficiency, 8.6% phagocytic disorders, 3.3% diseases of immune dysregulation, and 2.8% complement deficiencies. All countries that participated in the first publication in 1998 reported an increase in registered primary immunodeficiency cases, ranging between 10 and 80%. A comparison of the estimated minimal incidence of X-linked agammaglobulinemia, chronic granulomatous disease, and severe combined immunodeficiency between the first report and the present one shows an increase in the reporting of these diseases in all countries. In this report, the estimated minimal incidence of chronic granulomatous disease was between 0.72 and 1.26 cases per 100,000 births in Argentina, Chile, Costa Rica, and Uruguay and the incidence of severe combined immunodeficiency was 1.28 and 3.79 per 100,000 births in Chile and Costa Rica, respectively. However, these diseases are underreported in other participating countries. In addition to a better diagnosis of primary immunodeficiency diseases, more work on improving the registration of patients by each participating country and by countries that have not yet joined LAGID is still needed.

IL-12Rβ1 deficiency: mutation update and description of the IL12RB1 variation database

IL‐12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL‐12Rβ1 is a receptor chain of both the IL‐12 and the IL‐23 receptor and deficiency of IL‐12Rβ1 thus abolishes both IL‐12 and IL‐23 signaling. IL‐12Rβ1 deficiency is caused by bi‐allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL‐12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL‐12Rβ1 protein. In addition to disease‐causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL‐12Rβ1 and molecular genetics of human IL12RB1.

First Report of the Hyper-IgM Syndrome Registry of the Latin American Society for Immunodeficiencies: Novel Mutations, Unique Infections, and Outcomes

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.

Attending to Warning Signs of Primary Immunodeficiency Diseases Across the Range of Clinical Practice

PurposePatients 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.MethodsConsidering 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.ResultsTables 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.ConclusionsThis 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.

Brutonˈs tyrosine kinase—an integral protein of B cell development that also has an essential role in the innate immune system

Btk is the protein affected in XLA, a disease identified as a B cell differentiation defect. Btk is crucial for B cell differentiation and activation, but its role in other cells is not fully understood. This review focuses on the function of Btk in monocytes, neutrophils, and platelets and the receptors and signaling cascades in such cells with which Btk is associated.

Advances in primary immunodeficiency diseases in Latin America: epidemiology, research, and perspectives.

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.

Corticosteroid therapy for refractory infections in chronic granulomatous disease: case reports and review of the literature

BACKGROUND Chronic granulomatous disease (CGD) is a primary phagocyte immunodeficiency. It is often accompanied by an exuberant and aberrant inflammatory response, with granulomata and obstruction of the gastrointestinal and genitourinary tracts and inflammatory bowel disease. Although corticosteroids are successful in managing the obstructive and inflammatory disorders of CGD, they are not ordinarily used for the management of infection because of the possibility of further compromising the patients immune system. OBJECTIVES To discuss the pros and cons of the use of corticosteroids for the treatment of infections in CGD. METHODS We describe 2 patients with CGD and refractory infections who were successfully treated with systemic corticosteroids in addition to antimicrobial agents. We also review the medical literature in which corticosteroids have been used for CGD infection. RESULTS Our cases add to 3 other reports in which antibiotics and corticosteroids were used successfully in patients with CGD. However, in the presence of a potential pathogen, notably, aspergilla, corticosteroids may mask or favor dissemination of the fungus, especially in adults. CONCLUSIONS Corticosteroids may play an important adjunctive role in CGD refractory infections.

Clinical and Genotypic Spectrum of Chronic Granulomatous Disease in 71 Latin American Patients: First Report from the LASID Registry

We analyzed data from 71 patients with chronic granulomatous disease (CGD) with a confirmed genetic diagnosis, registered in the online Latin American Society of Primary Immunodeficiencies (LASID) database.

Hyper-IgE syndrome and autoimmunity in Mexican children

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent skin abscesses, recurrent pneumonia with pneumatocele formation, eczema, eosinophilia, and elevated levels of serum IgE. Patients with the autosomal recessive (AR) form of HIES appear to be prone to developing autoimmune diseases. We present two cases of HIES with autoimmune complications; one case was a product of a consanguineous marriage, the other one was a sporadic case. The first patient presented with recurrent episodes of erythema nodosum, warts, bronchiolitis obliterans and thrombocytopenia. The second patient developed glomerulonephritis resulting in endstage renal failure. She later developed malar rash, oral ulcers, cerebral infarcts with vasculitis and positive ANA, anti-dsDNA, and antiphospholipid antibodies. We discuss the dilemma in treating patients who present with both primary immunodeficiency and autoimmunity.

Increased Pro-inflammatory Cytokine Production After Lipopolysaccharide Stimulation in Patients with X-linked Agammaglobulinemia

PurposeTo evaluate the lipopolysaccharide (LPS)-induced pro-inflammatory cytokine response by peripheral blood mononuclear cells (PBMCs) from XLA patients.MethodsThirteen patients with XLA were included in the study. LPS-induced TNF-α, IL-1β, IL-6, and IL-10 production was determined in PBMCs from patients and matched healthy controls by ELISA. Cytokine production was correlated with the severity of mutation, affected domain and clinical characteristics.ResultsIn response to LPS, PBMCs from XLA patients produced significantly higher amounts of pro-inflammatory cytokines and IL-10 compared to controls, and this production was influenced neither by the severity of the mutation nor the affected domain. PBMCs from patients with a history of more hospital admissions before their diagnosis produced higher levels of TNF-α. PBMCs from patients with lower serum IgA levels showed a higher production of TNF-α and IL-1β. Less severe (punctual) mutations in the Btk gene were associated with higher serum IgG levels at diagnosis.ConclusionsOur results demonstrate a predominantly inflammatory response in XLA patients after LPS stimulation and suggest a deregulation of TLR signaling in the absence of Btk. This response may be influenced by environmental factors.