Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1: Mexico experience.

BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. METHODS: Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. RESULTS: We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. CONCLUSIONS: Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country.

[Autoimmunity and Freiburg classification in common variable immunodeficiency]. / Autoinmunidad y clasificación de Freiburg en pacientes con inmunodeficiencia común variable.

Introduction: Up to 25% of patients with common variable immunodeficiency (CVID) debut with autoimmunity, which is related to the Freiburg classification, which is based on flow cytometry. Objective: to determine the frequency and type of autoimmune diseases and their association with the Freiburg classification in adults with CVID. Methods: A cross-sectional, analytical and observational study was carried out with 33 patients belonging to the Primary Immunodeficiency Clinic of a third level hospital, with a diagnosis of CVID. They were divided into 3 phenotypes according to the Freiburg classification. Results: Of the 33 patients studied, 66.6% presented autoimmune diseases, 19 of them (86.3%) had cytopenia; 42.1% belonged to Freiburg group Ia, 36.8% to Ib and 21% to phenotype II. In 36.6% of the patients, autoimmune cytopenia were the first manifestation of CVID; and up to 70% of them belong to the Freiburg phenotype Ia (p = 0.086). Patients with autoimmune cytopenia had a lower percentage of isotype-switched memory B cells (p = 0.018), no higher percentage of CD21low B cells (p = 0.226). Conclusions: Classification by CVID phenotypes allows the identification of the patient's profile according to the percentage of memory B cells with isotype change, which is useful to intentionally search for non-infectious complications of the disease.

Introducción: hasta el 25% de los pacientes con inmunodeficiencia común variable (IDCV) debutan con autoinmunidad, la cual guarda relación con la clasificación de Freiburg, que se basa en la citometría de flujo. Objetivo: determinar la frecuencia y tipo de enfermedades autoinmunes y su asociación con la clasificación de Freiburg en adultos con IDCV. Métodos: se realizó un estudio transversal, analítico y observacional con 33 pacientes pertenecientes a la Clínica de Inmunodeficiencias Primarias de un hospital de tercer nivel con diagnóstico de IDCV. Se dividieron en tres fenotipos según la clasificación de Freiburg. Resultados: de los 33 pacientes estudiados, el 66.6% presentó enfermedades autoinmunes, de ellos 19 (86.3%) tuvieron citopenias. El 42.1% se clasificó en el grupo Ia de Freiburg, el 36.8% en el grupo Ib y el 21% en el fenotipo II. En el 36.6% de los pacientes las citopenias autoinmunes fueron la primera manifestación de IDCV, y hasta el 70% de ellos pertenecen al fenotipo Ia de Freiburg (p = 0.086). Los pacientes con citopenias autoinmunes tuvieron un menor porcentaje de células B de memoria con cambio de isotipo (p = 0.018), sin mayor porcentaje de células B CD21low (p = 0.226). Conclusiones: la clasificación por fenotipos en IDCV permite identificar el perfil del paciente y el tipo de manifestaciones asociadas, lo que es útil para buscar de manera intencionada complicaciones no infecciosas propias de la enfermedad.

[Hyper-IgM syndrome with early liver involvement]. / Síndrome de hiper-IgM con afectación hepática temprana.

INTRODUCTION: Hyper-IgM syndrome is an innate error of immunity in which there is a defect in change of isotype of immunoglobulins, with decreased values of IgG, IgA, and IgE, but normal or increased level of IgM. This predisposes to infectious processes at the respiratory and gastrointestinal levels, as well as autoimmune diseases and neoplasm. CASE REPORT: A 5 year 7-month-old boy with a history of 2 pneumonias, one of them severe, and chronic diarrhea since he was 2 years old. Persistent moderate neutropenia decreased IgG and elevated IgM. Cytometry flow confirmed absence of CD40L. Clinical evolution with early hepatic involvement. DISCUSSION: Hyper-IgM syndrome predisposes to liver damage, so a complete evaluation is required as well as early diagnosis. Active anti-infective treatment and control of the inflammatory response are key to the treatment of liver damage.

INTRODUCCIÓN: El síndrome de hiper-IgM es un error innato de la inmunidad, caracterizado por un defecto en el cambio de isotipo de inmunoglobulina, con valores disminuidos de IgG, IgA e IgE, y concentraciones normales o elevadas de IgM. Predispone a procesos infecciosos en el sistema respiratorio y aparato gastrointestinal, además de enfermedades autoinmunes y neoplasias. REPORTE DE CASO: Paciente pediátrico de género masculino, de 5 años y 7 meses de edad, con antecedente de dos cuadros de neumonía (uno de estos grave) y diarrea crónica desde los 2 años. Neutropenia moderada persistente, disminución de la concentración de IgG y elevación de IgM. La citometría de flujo confirmó la ausencia de CD40L. Durante la evolución clínica tuvo afectación hepática temprana. CONCLUSIÓn: El síndrome de hiper-IgM predispone a daño hepático, por lo que se requiere la evaluación completa y el diagnóstico oportuno. El tratamiento antiinfeccioso activo y el control de la respuesta inflamatoria son factores decisivos para establecer el tratamiento del daño hepático.

Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1

Background: Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. Methods: Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. Results: We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. Conclusions: Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country (AU)

Activating de novo monoallelic variants causing inborn errors of immunity in two unrelated children born of HIV-seroconcordant couples.

INTRODUCTION: Around 20% of all inborn errors of immunity (IEI) are autosomal dominant or monoallelic, either by haploinsufficiency, negative dominance, or gain of function (GOF). GOF phenotypes usually include autoinflammation, autoimmunity, lymphoproliferation, allergies, and some infections. CASE SERIES: We describe the cases of two unrelated patients born of HIV-seroconcordant parents. Both patients are HIV-negative but carry de novo GOF missense variants that resulted in inflammatory lymphoproliferative IEI diseases: signal transducer and activator of transcription 3 (STAT3)-GOF and phosphatidylinositol 3-kinase, catalytic delta (PIK3CD)-GOF. Both variants were found through whole-exome sequencing and confirmed by Sanger.An 11-year-old male with recurrent sinopulmonary infections, dysmorphism, growth delay, bronchiectasis, and mild mental retardation, as well as lymphopenia, thrombocytopenia, and high immunoglobulin M. Both his parents were known to be HIV-positive under anti-retroviral treatment. HIV infection was repeatedly ruled out in the patient, whom through whole-exome sequencing was found to have a heterozygous missense variant in exon 24 of PIK3CD, a hotspot transition, and the most reported variant in PIK3CD-GOF patients.A 6-year-old male with autoimmune hemolytic anemia, lymphoproliferation, short stature, and intractable diarrhea. Both his parents were found to be HIV-positive. HIV was repeatedly ruled out in the patient by ELISA and viral load. He was found to have a heterozygous missense/splice variant in exon 22 of STAT3, a hotspot transition, and the most reported variant in STAT3-GOF patients. DISCUSSION: The AID/APOBEC3 A-H family of proteins are cytidine deaminases that induce G>A hypermutation in both the invading viral DNA and the host genome, which results in stop codons inside the endogenized retroviral sequence. Both variants found in our patients are G to A transitions. Retroviral infection might thus have resulted in host genome instability, and our patients' rare congenital diseases are the unfortunate consequence of somatic hypermutation in one of their parents' gametes.

Not enough by half: NFAT5 haploinsufficiency in two patients with Epstein-Barr virus susceptibility.

Introduction: The transcription factor Nuclear factor of activated T cells 5 (NFAT5), pivotal in immune regulation and function, can be induced by osmotic stress and tonicity-independent signals. Objective: We aimed to investigate and characterize two unrelated patients with Epstein-Barr virus susceptibility and no known genetic etiology. Methods: After informed consent, we reviewed the electronic charts, extracted genomic DNA, performed whole-exome sequencing, filtered, and prioritized their variants, and confirmed through Sanger sequencing, family segregation analysis, and some functional assays, including lymphoproliferation, cytotoxicity, and characterization of natural killer cells. Results: We describe two cases of pediatric Mexican patients with rare heterozygous missense variants in NFAT5 and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis. Discussion: NFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.

Improved HUMARA for the Detection of X-Linked Agammaglobulinemia Carriers.

Background: Fragment analysis of exon 1 of the human androgen receptor, known as HUMARA, is a polymerase chain reaction (PCR)-based method for detecting X-linked agammaglobulinemia (XLA) carriers. This method takes advantage of X-chromosome inactivation (XCI) in female cells. XLA is caused by mutations in the Bruton tyrosine kinase (BTK) gene, located in Xq22.1. In this study, XCI is nonrandom or skewed in B-cells. B-cells with an active X-chromosome carrying a BTK mutation do not mature. Peripheral B-cells in XLA carriers inactivate the mutated X-chromosome. Methods: HUMARA was performed using DNA from purified B-cells and total leukocytes. DNA was digested using methylation-sensitive HhaI. The PCR of the HUMARA polymorphic marker was performed with the HhaI digested samples. The lengths of the PCR products were determined. If a suspected carrier showed skewed XCI in their B-cells, the marker length that corresponded with the length determined in the index patient indicated their carrier status. Results: HUMARA was conducted on purified B-cells; this allowed easier identification of the mutated or inactive allele, as the active allele was enzymatically digested. Analysis of 30 possible carriers using modified HUMARA corroborated that the carrier status in all samples that were heterozygous for the marker using XCI calculation for leukocytes showed a Gaussian distribution, while the carrier B-cell DNA showed a skewed XCI. Conclusion: Carrier status was successfully determined for most of the analyzed samples. B-cell enrichment resulted in precise carrier determination data, reduced the sample size, and facilitated inactive and active allele identification.

Atypical patterns of STAT3 phosphorylation in subpopulations B cells in patients with common variable immunodeficiency.

BACKGROUND: Common Variable Immunodeficiency (CVID) is a heterogeneous disorder characterized by defective B cell differentiation and antibody production. Interleukin (IL)-21 activates STAT3, a potent regulator of B cell differentiation into plasma cells. We have studied the phosphorylation of STAT3 in CVID patients and its contribution to B cells subsets. METHODS: We studied 23 CVID patients and 14 healthy donors (HD), determining pSTAT3 in naïve and memory B cells, stimulated with IL-21 at 15 and 60 min. RESULTS: pSTAT3 was increased in total (p = 0.044), naïve (p = 0.023), and memory (p = 0.001) B cells at 60 min in CVID patients compared with HD. We classified patients by the percentage of isotype-switched memory B cells. We observed an increase in pSTAT3 at 60 min in memory B cells in both CVID groups of patients (p = 0.026, p = 0.007, respectively). Interestingly, the analysis of each group individually; demonstrated that patients with decreased memory B cells exhibited an increase in pSTAT3 at 60 min (p = 0.023), while HD had an expected decrease in pSTAT3 (p = 0.045). CONCLUSION: CVID patients showed an increased atypical of pSTAT3, which could affect the differentiation of B cells. Further studies in the IL-21 pathway are necessary to understand how this alteration could promote differentiation defects in patient B cells.

[Autoimmune diseases in patients with common variable immunodeficiency]. / Enfermedades autoinmunitarias en pacientes con inmunodeficiencia común variable.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency with an estimated prevalence of one in 10,000 to 50,000 inhabitants. This heterogeneous disease is characterized by decreased levels of serum immunoglobulins, a poor production of specific antibodies upon vaccination, and recurrent bacterial infections, particularly in the respiratory and gastrointestinal tract. A subgroup of patients is characterized by additional, and often predominant, manifestations of immune deregulation rather than pure immunodeficiency. Approximately, 30% of patients with CVID develop autoimmunity. Half of those complications can be attributed to autoimmune cytopenia, but also to other types of autoimmunity, such as organ-specific autoimmune diseases, often manifest as inflammatory disease, including inflammatory bowel disease, celiac disease, interstitial lung disease, some forms of arthritis, and vitiligo, among many others. New monogenic defects elucidate the immunopathological mechanism that causes the coincidence of immunodeficiency and autoimmunity. Autoimmune diseases have become the major clinical challenge in CVID, with new diagnostic tools, especially genetic ones, that improve the understanding of the different forms of immune deregulation.

La inmunodeficiencia común variable (IDCV) es la inmunodeficiencia primaria sintomática más prevalente: se estima un caso entre 10 000 a 50 000 habitantes. Esta enfermedad heterogénea se caracteriza por disminución de las inmunoglobulinas séricas, una producción deficiente de anticuerpos específicos tras la vacunación y por infecciones bacterianas recurrentes, en particular de los tractos respiratorio y gastrointestinal. Un subgrupo de pacientes se caracteriza por manifestaciones adicionales, a menudo predominantes, de desregulación inmunitaria en lugar de inmunodeficiencia pura. Aproximadamente, 30 % de los pacientes con IDCV desarrolla autoinmunidad. La mitad de las complicaciones se puede atribuir a citopenia autoinmunitaria, pero también a otros tipos de autoinmunidad tales como enfermedades autoinmunitarias específicas de órganos, que se manifiestan a menudo como enfermedad inflamatoria: enfermedad inflamatoria intestinal, enfermedad celiaca, enfermedad pulmonar intersticial, algunas formas de artritis, vitíligo y muchas otras. Nuevos defectos monogénicos aclaran el mecanismo inmunopatológico que provoca la coincidencia de inmunodeficiencia y autoinmunidad. Las enfermedades autoinmunitarias se han convertido en el principal desafío clínico en la IDCV, con nuevas herramientas de diagnóstico, especialmente genéticas, que mejoran la comprensión de las formas variantes de desregulación inmunitaria.

COVID-19 in the Context of Inborn Errors of Immunity: a Case Series of 31 Patients from Mexico.

INTRODUCTION: Patients with inborn errors of immunity (IEI) have a compromised or inappropriate immune response. Although they might be considered a high-risk group for severe SARS-CoV-2 infection, the reported impact of COVID-19 in these patients has been reassuring, while the differential susceptibility of distinct types of IEI remains unclear. OBJECTIVE: We aimed to describe the findings and outcomes of our known patients with IEI who were diagnosed with COVID-19. METHODS: In a retrospective study from March 2020 to February 2021, four centers in Mexico collected clinical, laboratory, and genetic data from pediatric and adult patients with known diagnoses of IEI who presented with COVID-19, based on compatible symptoms and positive SARS-CoV-2 testing or known household exposure. RESULTS: We report 31 patients with known IEI from Mexico who presented with SARS-CoV-2 infection. Seventy-four percent were male, 52% were pediatric, and 81% survived. Their ages ranged from 5 months to 56 years, with a median of 17 years. Sixty-five percent had predominant antibody deficiencies, 48% were hospitalized, and 26% required ICU. Pediatric patients had a higher hospital admission rate than adults. Inpatient mortality was 40%, and ICU mortality rate was 63%. Forty-eight percent developed pneumonia, while 36% had evidence of hyperinflammation (4 adults and 7 children). Predominant laboratory features were lymphopenia and thrombocytopenia, seen in 70 and 44% of patients, respectively. The serum D-dimer median value was 2.6 (0.5-20.6) µg/mL, and the median highest ferritin value was 1015 (32-10,303) ng/mL. Intravenous immunoglobulin was used in 80% of patients. Other treatments included macrolides (39%) and corticosteroids (29%). Six patients died from secondary infection or uncontrolled systemic inflammation. DISCUSSION: Although impaired immunity due to IEI may be a predisposing factor for severe COVID-19, most of our patients with IEI who acquired the SARS-CoV-2 infection developed a well-tolerated infection and survived, as have more than 80% of worldwide reported patients to date. An impaired immune or inflammatory response may be a predisposing factor for some and a protective factor for others. A systematic review of the literature could help identify those patients at risk of severe disease and complications. Healthcare-associated infections should be aggressively prevented.

Clinical Manifestations, Mutational Analysis, and Immunological Phenotype in Patients with RAG1/2 Mutations: First Cases Series from Mexico and Description of Two Novel Mutations.

Mutations in recombinase activating genes 1 and 2 (RAG1/2) result in human severe combined immunodeficiency (SCID). The products of these genes are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Mutations resulting in null-recombination activity in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with hypomorphic mutations may develop leaky SCID, including Omenn syndrome (OS). A group of previously unrecognized clinical phenotypes associated with granulomata and/or autoimmunity have been described as a consequence of hypomorphic mutations. Here, we present six patients from unrelated families with missense variants in RAG1 or RAG2. Phenotypes observed in these patients ranged from OS to severe mycobacterial infections and granulomatous disease. Moreover, we report the first evidence of two variants that had not been associated with immunodeficiency. This study represents the first case series of RAG1- or RAG2-deficient patients from Mexico and Latin America.

Erratum to "Partial and Transient Clinical Response to Omalizumab in IL-21-Induced Low STAT3-Phosphorylation on Hyper-IgE Syndrome".

[This corrects the article DOI: 10.1155/2019/6357256.].

Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance.

PURPOSE: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. METHODS: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. RESULTS: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. CONCLUSION: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.

B Cell Subsets as Severity-Associated Signatures in COVID-19 Patients.

Background: SARS-CoV-2 infection represents a global health problem that has affected millions of people. The fine host immune response and its association with the disease course have not yet been fully elucidated. Consequently, we analyze circulating B cell subsets and their possible relationship with COVID-19 features and severity. Methods: Using a multiparametric flow cytometric approach, we determined B cell subsets frequencies from 52 COVID-19 patients, grouped them by hierarchical cluster analysis, and correlated their values with clinical data. Results: The frequency of CD19+ B cells is increased in severe COVID-19 compared to mild cases. Specific subset frequencies such as transitional B cell subsets increase in mild/moderate cases but decrease with the severity of the disease. Memory B compartment decreased in severe and critical cases, and antibody-secreting cells are increased according to the severity of the disease. Other non-typical subsets such as double-negative B cells also showed significant changes according to disease severity. Globally, these differences allow us to identify severity-associated patient clusters with specific altered subsets. Finally, respiratory parameters, biomarkers of inflammation, and clinical scores exhibited correlations with some of these subpopulations. Conclusions: The severity of COVID-19 is accompanied by changes in the B cell subpopulations, either immature or terminally differentiated. Furthermore, the existing relationship of B cell subset frequencies with clinical and laboratory parameters suggest that these lymphocytes could serve as potential biomarkers and even active participants in the adaptive antiviral response mounted against SARS-CoV-2.

[General concepts of humoral immune deficiencies]. / Conceptos generales de las inmunodeficiencias humorales.

Humoral immune deficiencies (HID) comprise a group of diseases characterized by the impossibility to develop an effective immune response mediated by immunoglobulins (Ig). Patients with HID have infections caused by capped extracellular bacteria, mainly in the respiratory and/or gastrointestinal tract, and a higher predisposition to suffer from autoimmune diseases and cancer. Some of them are caused by well-defined genetic defects, while the cause of others is unknown. The clinical manifestations of some HID may be late and the diagnosis is supported by laboratory tests, such as serum level of the Ig, determination of lymphocyte populations, and functional studies. Gamma-globulin replacement therapy significantly decreases serious infections. In order to achieve an early diagnosis, it is necessary to maintain a high index of suspicion and evaluate the clinical and laboratory manifestations that suggest HID. Mass sequencing technologies have favored the description of mutations in various genes that lead to a clinical HID phenotype; which paves the way to a better understanding of immune pathologies in HID.

Las inmunodeficiencias humorales (IDH) comprenden un grupo de enfermedades caracterizadas por la imposibilidad de desarrollar una respuesta inmune efectiva mediada por inmunoglobulinas. Los pacientes con IDH presentan infecciones por bacterias extracelulares encapsuladas, principalmente en el tracto respiratorio o gastrointestinal y una mayor predisposición a padecer enfermedades autoinmunes y cáncer. Algunas se originan por defectos genéticos bien definidos y en otras se desconoce la causa. Las manifestaciones clínicas de algunas IDH pueden ser tardías y el diagnóstico se apoya en pruebas de laboratorio como la concentración en suero de las inmunoglobulinas, determinación de poblaciones linfocitarias y estudios funcionales. El tratamiento de reemplazo con gammaglobulinas disminuye significativamente las infecciones graves. Para lograr un diagnóstico temprano es necesario un alto índice de sospecha y evaluar las manifestaciones clínicas y de laboratorio sugestivas de IDH. Las tecnologías de secuenciación masiva han favorecido la descripción de mutaciones en varios genes que llevan a un fenotipo clínico de IDH, con lo que se abre el camino para comprender mejor las inmunopatologías en las IDH.

Lipopolysaccharide-responsive beige-like anchor acts as a cAMP-dependent protein kinase anchoring protein in B cells.

Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) protein was initially described as a monogenetic cause for common variable immune deficiency, a syndrome characterized by low levels of B cells, defects in memory B cell differentiation and hypogammaglobulinaemia. LRBA was identified as an LPS up-regulated gene in B cells, macrophages and T cells. LRBA weighs 320 kDa and has 2863 amino acids. Its sequence contains multiple domains, suggesting that LRBA can act as a scaffolding protein. It contains two putative binding sites for cAMP-dependent kinase (PKA) regulatory subunits, suggesting this protein can act as A-kinase anchor protein (AKAP); however, physical interactions involving LRBA and PKA have not been demonstrated to date, and functional roles for such interactions are unexplored. In this work, we investigated physical interactions involving LRBA with regulatory subunits of PKA in human B cell lines and primary human B cells. PKA is a holoenzyme composed of two regulatory subunits, which can be RIα, RIß, RIIα or RIIß, and two catalytic subunits, Cα or Cß. We co-immunoprecipitated LRBA using Ramos B cell lymphoma cells and observed that LRBA interacts with RIIß. Interestingly, St-Ht31, an inhibitory peptide that disrupts AKAP interactions with regulatory subunits, reduced the amount of interacting protein. Furthermore, in primary human B cells, LRBA was induced after CD40L and IL-4 stimulation, and under such activation, we found that LRBA interacts with RIIα and RIIß, suggesting that LRBA acts as an AKAP and binds RII subunits. Interestingly, we also identified that LRBA interacts with activation-induced cytidine deaminase in primary B cells, suggesting that it is involved in B cell function.

Flow-cytometry as an auxiliary in the diagnosis of primary humoral immunodeficiencies.

BACKGROUND: Antibody deficiencies encompass a wide spectrum of pathologies and constitute approximately 50 % of primary immunodeficiencies; with cytometry, it is possible to evaluate the immune status rapidly, effectively and at low cost. OBJECTIVE: To assess, by means of flow cytometry, the cells of patients with three types of primary humoral immunodeficiencies. METHOD: Using flow cytometry, blood samples from patients and healthy subjects were analyzed with different monoclonal antibodies. RESULTS: Using various stains, a severe decrease in B lymphocytes was shown in patients with X-linked agammaglobulinemia, as well as a lack of CD154 expression in patients with hyper-immunoglobulin M syndrome, and heterogeneity of B lymphocyte subpopulations in patients with common variable immunodeficiency. CONCLUSION: Flow cytometry enables early diagnosis of primary immunodeficiencies with a high level of confidence and, in many cases, identification of the genes involved.

ANTECEDENTES: Las deficiencias de anticuerpos abarcan un amplio espectro de patologías y constituyen aproximadamente 50 % de las inmunodeficiencias primarias; con la citometría es posible evaluar el estado inmunológico de forma rápida, efectiva y a bajo costo. OBJETIVO: Evaluar mediante citometría de flujo, las células de pacientes con tres tipos de inmunodeficiencias primarias humorales. MÉTODO: Mediante citometría de flujo se analizaron muestras de sangre de pacientes y sujetos sanos con distintos anticuerpos monoclonales. RESULTADOS: Mediante diversas tinciones se demostró disminución severa de linfocitos B en pacientes con agammaglobulinemia ligada al cromosoma X, la falta de expresión de CD154 en pacientes con síndrome de hiperinmunoglobulina M y heterogeneidad de subpoblaciones de linfocitos B en pacientes con inmunodeficiencia común variable. CONCLUSIÓN: Con la citometría de flujo es posible realizar el diagnóstico temprano de inmunodeficiencias primarias con un nivel de confianza elevado y, en muchos casos, identificar los genes implicados.

La citometría de flujo como auxiliar en el diagnóstico de las inmunodeficiencias primarias humorales / Flow-cytometry as an auxiliary in the diagnosis of primary humoral immunodeficiencies

Resumen Antecedentes: Las deficiencias de anticuerpos abarcan un amplio espectro de patologías y constituyen aproximadamente 50 % de las inmunodeficiencias primarias; con la citometría es posible evaluar el estado inmunológico de forma rápida, efectiva y a bajo costo. Objetivo: Evaluar mediante citometría de flujo, las células de pacientes con tres tipos de inmunodeficiencias primarias humorales. Método: Mediante citometría de flujo se analizaron muestras de sangre de pacientes y sujetos sanos con distintos anticuerpos monoclonales. Resultados: Mediante diversas tinciones se demostró disminución severa de linfocitos B en pacientes con agammaglobulinemia ligada al cromosoma X, la falta de expresión de CD154 en pacientes con síndrome de hiperinmunoglobulina M y heterogeneidad de subpoblaciones de linfocitos B en pacientes con inmunodeficiencia común variable. Conclusión: Con la citometría de flujo es posible realizar el diagnóstico temprano de inmunodeficiencias primarias con un nivel de confianza elevado y, en muchos casos, identificar los genes implicados.

Abstract Background: Antibody deficiencies encompass a wide spectrum of pathologies and constitute approximately 50 % of primary immunodeficiencies; with cytometry, it is possible to evaluate the immune status rapidly, effectively and at low cost. Objective: To assess, by means of flow cytometry, the cells of patients with three types of primary humoral immunodeficiencies. Method: Using flow cytometry, blood samples from patients and healthy subjects were analyzed with different monoclonal antibodies. Results: Using various stains, a severe decrease in B lymphocytes was shown in patients with X-linked agammaglobulinemia, as well as a lack of CD154 expression in patients with hyper-immunoglobulin M syndrome, and heterogeneity of B lymphocyte subpopulations in patients with common variable immunodeficiency. Conclusion: Flow cytometry enables early diagnosis of primary immunodeficiencies with a high level of confidence and, in many cases, identification of the genes involved.

[The neurology of COVID-19]. / La neurología de COVID-19.

The clinical manifestations of COVID-19 are reminiscent of those of acute respiratory distress syndrome induced by cytokine release syndrome and secondary hemophagocytic lymphohistiocytosis that is observed in patients with other coronaviruses such as SARS-CoV and MERS-CoV. Neurologists face the challenge of assessing patients with pre-existing neurological diseases who have contracted SARS-CoV-2, patients with COVID-19 who present neurological emergencies, and patients who are carriers of the virus and have developed secondary neurological complications, either during the course of the disease or after it. Some authors and recent literature reports suggest that the presence of neurological manifestations in patients who are carriers of SARS-CoV-2 may be associated with a greater severity of the disease.

Las manifestaciones clínicas de COVID-19 recuerdan las del síndrome de insuficiencia respiratoria aguda inducido por el síndrome de liberación de citocinas y la linfohistiocitosis hemofagocitica observada en pacientes con otros coronavirus como SARS-CoV y MERS-CoV. Los neurólogos tienen el reto de evaluar pacientes con enfermedades neurológicas preexistentes que contraen SARS-CoV-2, pacientes con COVID-19 que presentan emergencias neurológicas y pacientes portadores del virus que desarrollan complicaciones neurológicas secundarias, durante el curso de la enfermedad o posterior a la misma. Algunos autores y reportes en la literatura recientes sugieren que las manifestaciones neurológicas en pacientes portadores de SARS-CoV-2 pueden asociarse con mayor gravedad de la enfermedad.