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This paper aims to compare the cellular immune response to the SARS-CoV-2 BNT162b2 vaccine of pediatric patients with autoimmune inflammatory rheumatic disease (pAIIRD) and healthy controls. A prospective longitudinal study was conducted between April 2021 and December 2022 at the Tel Aviv Medical Center. Children <18 years, with pediatric-onset AIIRD and healthy controls, who have received at least two doses of the BNT162b2 vaccine, were included. Humoral response was evaluated by serum levels of anti-SARS-CoV-2 receptor-binding domain antibodies. Cellular response was evaluated by flow cytometry, measuring IFNγ and TNFα production by CD4+ T cells following stimulation with SARS-CoV-2 Spike peptide mix. The study included 20 pAIIRD patients and 11 controls. The mean age of participants was 12.6â ±â 2.94 years, with 58.1% females. The cellular response to the BNT162b2 vaccine was statistically similar in both groups. However, the humoral response was statistically lower in pAIIRD compared with the healthy control group. There was no statistically significant correlation between the humoral response and cellular response. During the study period, 43.75% of AIIRD children and 72.7% of controls had a breakthrough COVID-19 infection (Pâ =â 0.48). Bivariate models examining the effect of the cellular response and presence of an AIIRD on breakthrough infections found no effect. Compared with healthy controls, pAIIRD demonstrated similar cellular responses. Patients showed reduced humoral response compared with healthy adolescents, but similar breakthrough infection rates. These findings may support the importance of the cellular response in protecting against COVID-19 infections.
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Anticuerpos Antivirales , Vacuna BNT162 , COVID-19 , Inmunidad Celular , Enfermedades Reumáticas , SARS-CoV-2 , Humanos , Femenino , Vacuna BNT162/inmunología , Masculino , Niño , COVID-19/inmunología , COVID-19/prevención & control , Adolescente , SARS-CoV-2/inmunología , Enfermedades Reumáticas/inmunología , Estudios Prospectivos , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Enfermedades Autoinmunes/inmunología , Estudios Longitudinales , Vacunas contra la COVID-19/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Inmunidad Humoral/inmunología , Linfocitos T CD4-Positivos/inmunología , Interferón gamma/inmunologíaRESUMEN
Background: Recent studies have shown good serological and cellular immune responses in people living with human immunodeficiency virus (PLWH) after receipt of 2 doses of messenger RNAA (mRNA) severe acute respiratory syndrome coronavirus 2 vaccine. Data are missing regarding the response after 3 vaccine doses. Methods: We followed up a group of PLWH who received 3 doses of the mRNA BNT162b2 vaccine and for whom data of humoral immune response after 2 vaccine doses were available. Patients provided a blood sample 4-6 months after the booster dose. The aim of the study was to measure the serological and cellular response after the third dose and to evaluate factors associated with the vaccine response. Results: Fifty patients have provided a serum sample for serological evaluation after the booster. The anti-receptor-binding domain (RBD) immunoglobulin (Ig) G titers were higher after the booster with a median delta of 3240â arbitrary units/mL. The median CD4+ T-cell count was 660/µL (interquartile range, 515-958/µL) and had no influence on the antibody level. Factors associated with lower delta included higher CD8+ T-cell count (P = .02) and longer time between the third dose and the blood test (P = .01). Higher anti-RBD IgG titer after the second vaccine (P = .03), as well as a longer interval between second and third doses (P = .031) were associated with higher delta. There was no increase in the median number of activated interferon γ+ and tumor necrosis factor α+ CD4+ T cells after the booster (n = 8). Conclusions: The anti-RBD IgG level after 3 doses of mRNA BNT162b2 vaccine was higher than the level after 2 doses, suggesting additional value of the booster. Cellular response did not further increase after a booster.
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Dermatitis , Trasplante de Células Madre Hematopoyéticas , Síndrome de Wiskott-Aldrich , Humanos , Síndrome de Wiskott-Aldrich/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Proteína del Síndrome de Wiskott-AldrichRESUMEN
Pathogenic variants in LRBA, encoding the LPS Responsive Beige-Like Anchor (LRBA) protein, are responsible for recessive, early-onset hypogammaglobulinemia, severe multi-organ autoimmunity, and lymphoproliferation, with increased risk for malignancy. LRBA deficiency has a wide clinical spectrum with variable age of onset and disease severity. Three apparently unrelated patients with LRBA deficiency, of Georgian Jewish descent, were homozygous for LRBA c.6640C > T, p.R2214*, leading to a stop upstream of the LRBA BEACH domain. Despite carrying the same LRBA genotype, the three patients differed in clinical course: the first patient was asymptomatic until age 25 years; the second presented with failure to thrive at age 3 months; and the third presented at age 7 years with immune cytopenias and severe infections. Two of the patients developed malignancies: the first patient was diagnosed with recurrent Hodgkin's disease at age 36 years, and the second patient developed aggressive gastric cancer at age 15 years. Among Georgian Jews, the carrier frequency of the LRBA p.R2214* allele was 1.6% (4 of 236 Georgian Jewish controls). The allele was absent from other populations. Haplotype analysis showed a shared origin of the mutation. These three patients revealed a pathogenic LRBA founder allele in the Georgian Jewish population, support the diverse and complex clinical spectrum of LRBA deficiency, and support the possibility that LRBA deficiency predisposes to malignancy.
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Dermatitis , Judíos , Humanos , Lactante , Niño , Adulto , Adolescente , Judíos/genética , Alelos , Recurrencia Local de Neoplasia/genética , Genotipo , Mutación/genética , Dermatitis/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
The complement system regulator CD55 was initially found to carry the Cromer blood group system antigens, and its complete loss of function was subsequently revealed to cause a severe monogenic gastrointestinal syndrome characterized by protein-losing enteropathy and susceptibility to venous thrombosis. Here we present homozygosity to the CD55 c.596C>T; p.Ser199Leu variant, which was previously described as the Cromer Dr(a-) genotype, in two Bukharan Jewish CD55-deficiency patients with variable disease severity. We confirm that this missense variant causes aberrant splicing and deletion of 44 bp in exon 5, leading to premature termination and low expression of the CD55 protein. Furthermore, Patient 1 exhibited a mildly abnormal B cell immunophenotyping profile. By population screening we established that this variant is highly prevalent in the Bukharan Jewish population, with a carrier frequency of 1:17, suggesting that many similar patients are un- or mis-diagnosed. The phenotypic variability, ranging from abdominal pain when eating a high-fat diet to the full CD55-deficiency phenotype, is likely related to modifiers affecting the proportion of the variant that is able to escape aberrant splicing. Establishing the diagnosis of CD55-deficiency in a timely manner, even in patients with milder symptoms, may have a critical effect on their management and quality-of-life since treatment with the complement inhibitor eculizumab is highly effective in ameliorating disease manifestations. Awareness of founder mutations within certain populations can further guide genetic testing and prevent a diagnostic odyssey, by placing this CD55 variant high on the differential diagnosis.
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Antígenos de Grupos Sanguíneos , Judíos , Humanos , Antígenos CD55/genética , Antígenos de Grupos Sanguíneos/genética , Fenotipo , GenotipoRESUMEN
OBJECTIVES: To evaluate long-term kinetics of the BNT162b2 mRNA vaccine-induced immune response in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) and immunocompetent controls. METHODS: A prospective multicentre study investigated serum anti-SARS-CoV-2 S1/S2 IgG titre at 2-6 weeks (AIIRD n=720, controls n=122) and 6 months (AIIRD n=628, controls n=116) after the second vaccine, and 2-6 weeks after the third vaccine dose (AIIRD n=169, controls n=45). T-cell immune response to the third vaccine was evaluated in a small sample. RESULTS: The two-dose vaccine regimen induced a higher humoral response in controls compared with patients, postvaccination seropositivity rates of 100% versus 84.72%, p<0.0001, and 96.55% versus 74.26%, p<0.0001 at 2-6 weeks and at 6 months, respectively. The third vaccine dose restored the seropositive response in all controls and 80.47% of patients with AIIRD, p=0.0028. All patients treated with methotrexate monotherapy, anticytokine biologics, abatacept and janus kinase (JAK) inhibitors regained the humoral response after the third vaccine, compared with only a third of patients treated with rituximab, entailing a 16.1-fold risk for a negative humoral response, p≤0.0001. Cellular immune response in rituximab-treated patients was preserved before and after the third vaccine and was similar to controls. Breakthrough COVID-19 rate during the Delta surge was similar in patients and controls, 1.83% versus 1.43%, p=1. CONCLUSIONS: The two-dose BNTb262 regimen was associated with similar clinical efficacy and similar waning of the humoral response over 6 months among patients with AIIRD and controls. The third vaccine dose restored the humoral response in all of the controls and the majority of patients.
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Enfermedades Autoinmunes , Vacuna BNT162 , COVID-19 , Inmunogenicidad Vacunal , Enfermedades Reumáticas , Abatacept/uso terapéutico , Adulto , Anticuerpos Antivirales , Antirreumáticos/uso terapéutico , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/tratamiento farmacológico , Vacuna BNT162/inmunología , COVID-19/prevención & control , Humanos , Inmunoglobulina G/uso terapéutico , Quinasas Janus , Metotrexato/uso terapéutico , Estudios Prospectivos , Enfermedades Reumáticas/tratamiento farmacológico , Rituximab/uso terapéuticoRESUMEN
BACKGROUND: Most solid organ transplant recipients did not develop an appreciable serologic response after 2 doses of the mRNA SARS-CoV-2 vaccine. METHODS: We analyzed the humoral response after a third dose of the BNT162b2 vaccine in 130 kidney transplant recipients, compared to 48 health care workers, and associated factors, including prevaccine cellular immune response, by evaluating intracellular cytokine production after stimulation of donor's peripheral blood mononuclear cells. RESULTS: After 2 doses, most of the controls (47 out of 48, 98%) and only 40% of kidney recipients (52 of 130) kidney recipients were seropositive (P < .001). Most seronegative recipients developed a serologic response after the booster (47 out 78, 60%), thus bringing the total number of seropositive recipients to 99 out of 130 (76%). After the third dose, there was a significant increase in antibodies titers in both groups. Decreased humoral response was significantly associated with an older age, lower lymphocyte count, and a lower level of antibodies before booster administration. CD4+TNFα+ and CD4+INFγ+ were correlated with mean increase in antibody titers. CONCLUSIONS: A third dose of the BNT162b2 mRNA vaccine in kidney recipients is safe and effectively results in increased IgG anti-S levels, including in individuals who were seronegative after 2 doses. Long-term studies of the length of the immune response and protection are required.
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Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , Trasplante de Riñón , Receptores de Trasplantes , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Humanos , Inmunización Secundaria/efectos adversos , Inmunoglobulina G , Trasplante de Riñón/efectos adversos , Leucocitos Mononucleares , ARN Mensajero , SARS-CoV-2 , Factor de Necrosis Tumoral alfa , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
Background: Little is known about vaccine efficacy and sustainability among people with HIV (PWH). We estimated humoral and cellular immune responses postvaccination with BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccine among PWH in Tel-Aviv Medical Center. Methods: The vaccine humoral response was evaluated by measuring immunoglobulin G (IgG) titers of antispike receptor-binding domain antibodies (anti-RBD IgG). Cellular response was assessed by stimulating donor peripheral blood mononuclear cells with pooled complete S-peptide mix. Results: One hundred thirty-six PWH who completed 2 doses of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine were tested for anti-RBD IgG and compared with 61 vaccinated health care workers (HCWs). The antibody titers were similar between the groups (median, 118 BAU/mL for PWH and 101.4 BAU/mL for HCWs; Pâ =â .231), although the mean time from second vaccine was 4.5 months in PWH and 6.7 months in HCWs (Pâ <â .0001). Longer time from second vaccine dose was associated with decreased antibody level, as were CD4 counts <300 cells/µL compared with higher CD4 counts (25.1 BAU/mL vs 119.3 BAU/mL, respectively; Pâ =â .047). There was no difference in cellular immune response between vaccinated PWH, convalescent unvaccinated PWH, and vaccinated HCWs. Conclusions: The humoral immune response of PWH was comparable to that of HCWs after BNT162b2 mRNA vaccination. Cellular immune response did not differ between vaccinated PWH, convalescent PWH, and vaccinated HCWs. PWH with CD4 counts <300 cells/µL (nâ =â 9) had lower antibody titers compared with patients with counts >300 cells/µL (nâ =â 127).
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Patients with delayed B-cell reconstitution/B-cell aplasia after cellular therapy show decreased immunogenicity to the BNT162b2 mRNA COVID-19 vaccine. We prospectively evaluated both humoral and cellular immune response to a third vaccine dose in patients after allogeneic HCT (n = 10) or CD19-based chimeric antigen receptor T cells (CAR-T) therapy (n = 6) with low absolute B cell numbers and who failed to mount a humeral response after 2 vaccine doses. Humoral response was documented in 40% and 17% after allogeneic HCT and CAR-T therapy, respectively. None of the patients with complete B-cell aplasia developed anti-vaccine antibodies. Cellular response was documented in all patients after allogeneic HCT and in 83% of the patients after CAR-T. T-cell subclasses levels were not predictive for response, while a longer duration from infusion of cells was associated with a better cellular response. We conclude that cellular response develops with repeated vaccine doses even in patients with B-cell aplasia or delayed B-cell reconstitution, and these patients should therefore be vaccinated. These results should be considered in future studies analyzing immunogenicity in this population. Larger and longer follow-up studies are required to confirm whether cellular immunogenicity translates into vaccine efficacy.
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COVID-19 , Receptores Quiméricos de Antígenos , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , Inmunidad Celular , Inmunidad Humoral , Estudios Prospectivos , ARN Mensajero , SARS-CoV-2RESUMEN
Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) caused by dominant negative (DN) variants in the signal transducer and activator of transcription 3 gene (STAT3) is characterized by recurrent Staphylococcal abscesses, severe eczema, chronic mucocutaneous candidiasis (CMC), and non-immunological facial and skeletal features. Objectives: To describe our experience with the diagnosis and treatment of adult patients with AD-HIES induced by DN-STAT3 variants. Methods: The medical records of adult patients (>18 years) treated at the Allergy and Clinical Immunology Clinic of Hadassah Medical Center, Jerusalem, Israel, were retrospectively analyzed. Immune and genetic workups were used to confirm diagnosis. Results: Three adult patients (2 males; age 29-41 years) were diagnosed with DN-STAT3 variants. All patients had non-immunological features, including coarse faces and osteopenia. Serious bacterial infections were noted in all patients, including recurrent abscesses, recurrent pneumonia, and bronchiectasis. CMC and diffuse dermatophytosis were noted in two patients. Two patients had severe atopic dermatitis refractory to topical steroids and phototherapy. Immune workup revealed elevated IgE in three patients and eosinophilia in two patients. Whole exome sequencing revealed DN-STAT3 variants (c.1166C>T; p.Thr389Ile in two patients and c.1268G>A; p. Arg423Gln in one patient). Variants were located in DNA-binding domain (DBD) and did not hamper STAT3 phosphorylation Treatment included antimicrobial prophylaxis with trimethoprim/sulfamethoxazole (n=2) and amoxycillin-clavulanic acid (n=1), and anti-fungal treatment with fluconazole (n=2) and voriconazole (n=1). Two patients who had severe atopic dermatitis, were treated with dupilumab with complete resolution of their rash. No adverse responses were noted in the dupilumab-treated patients. Discussion: Dupilumab can be used safely as a biotherapy for atopic dermatitis in these patients as it can effectively alleviate eczema-related symptoms. Immunologists and dermatologists treating AD-HIES adult patients should be aware of demodicosis as a possible manifestation. DN-STAT3 variants in DBD do not hamper STAT3 phosphorylation.
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Dermatitis Atópica , Eccema , Síndrome de Job , Factor de Transcripción STAT3 , Adulto , Humanos , Masculino , Absceso , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/genética , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Síndrome de Job/terapia , Estudios Retrospectivos , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , FemeninoRESUMEN
Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19+ cells were associated with a positive humoral response, whereas a higher CD4+/CD8+ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Vacuna BNT162 , Vacunas contra la COVID-19 , Femenino , Humanos , Estudios Prospectivos , ARN Mensajero/genética , SARS-CoV-2RESUMEN
BACKGROUND: In mid-December 2020, Israel started a nationwide mass vaccination campaign against coronavirus disease 2019 (COVID-19). In the first few weeks, medical personnel, elderly citizens, and patients with chronic diseases were prioritized. As such, patients with primary and secondary immunodeficiencies were encouraged to receive the vaccine. Although the efficacy of RNA-based COVID-19 vaccines has been demonstrated in the general population, little is known about their efficacy and safety in patients with inborn errors of immunity (IEI). OBJECTIVE: Our aim was to evaluate the humoral and cellular immune response to COVID-19 vaccine in a cohort of patients with IEI. METHODS: A total of 26 adult patients were enrolled, and plasma and peripheral blood mononuclear cells were collected from them 2 weeks following the second dose of Pfizer-BioNTech COVID-19 vaccine. Humoral response was evaluated by testing anti-SARS-CoV-2 spike (S) receptor-binding domain and antinucleocapsid antibody titers and evaluating neutralizing ability by inhibition of receptor-binding domain-angiotensin-converting enzyme 2 binding. Cellular immune response was evaluated by using ELISpot, estimating IL-2 and IFN-γ secretion in response to pooled SARS-CoV-2 S- or M-peptides. RESULTS: Our cohort included 18 patients with a predominantly antibody deficiency, 2 with combined immunodeficiency, 3 with immune dysregulation, and 3 with other genetically defined diagnoses. Twenty-two of them were receiving immunoglobulin replacement therapy. Of the 26 patients, 18 developed specific antibody response, and 19 showed S-peptide-specific T-cell response. None of the patients reported significant adverse events. CONCLUSION: Vaccinating patients with IEI is safe, and most patients were able to develop vaccine-specific antibody response, S-protein-specific cellular response, or both.
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Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Inmunogenicidad Vacunal , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Adulto , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/etiología , COVID-19/virología , Susceptibilidad a Enfermedades , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunidad Celular , Masculino , Persona de Mediana Edad , Enfermedades de Inmunodeficiencia Primaria/genética , SARS-CoV-2/inmunología , Adulto JovenRESUMEN
Posttransplantation lymphoproliferative disease (PTLD) is a potentially fatal disorder arising after solid organ or hematopoietic cell transplantation. Survival rates of PTLD with diffuse large B-cell lymphoma (DLBCL) phenotype have improved due to the introduction of rituximab, however, reports on curative management of refractory PTLD are scarce. Here, we describe successful management of three patients with refractory EBV-negative PTLD with chimeric antigen receptor T-cell (CAR-T) therapy. All patients continued calcineurin inhibitors throughout the whole course of treatment. T-cell immunophenotyping was performed on both the apheresed cells and CAR-T product to investigate the T-cell compartment subpopulations. All three patients responded to a single infusion of tisagenlecleucel and two of them achieved CR. Toxicity profile was similar to other patients with non-PTLD DLBCL treated with CAR-T. No transplanted graft dysfunction was observed during the course of therapy. To our knowledge, this is the first report demonstrating that patients with EBV-negative refractory PTLD may benefit from CAR-T therapy, similarly to other patients with relapse/refractory DLBCL. A larger cohort of patients is needed to further establish proof-of-concept.
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Inmunoterapia Adoptiva , Trastornos Linfoproliferativos , Receptores Quiméricos de Antígenos , Antígenos CD19 , Herpesvirus Humano 4 , Humanos , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/etiología , Recurrencia Local de NeoplasiaAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD55/deficiencia , Antígenos CD55/genética , Células Germinativas/efectos de los fármacos , Enteropatías Perdedoras de Proteínas/tratamiento farmacológico , Enteropatías Perdedoras de Proteínas/genética , Adulto , Femenino , HumanosRESUMEN
Background: More than 50 different monogenic disorders have been identified as directly causing inflammatory bowel diseases, typically manifesting in the first years of life. We present the clinical course and immunological work-up of an adult patient who presented in adolescent years with an atypical gastrointestinal phenotype and was diagnosed more than two decades later with a monogenic disorder with important therapeutic implications. Methods: Whole exome sequencing was performed in a 37-years-old patient with a history of diarrhea since adolescence. Sanger sequencing was used to validate the suspected variant. Mass cytometry (CyTOF) and flow cytometry were conducted on peripheral blood mononuclear cells for deep immunophenotyping. Next-generation sequencing of the TCRB and IgH was performed for global immune repertoire analysis of circulating lymphocytes. Results: We identified a novel deleterious c.1455C>A (p.Y485X) mutation in LRBA. CyTOF studies demonstrated significant changes in immune landscape in the LRBA-deficient patient, including an increase in myeloid derived suppressor cells and double-negative T cells, decreased B cells, low ratio of naïve:memory T cells, and reduced capacity of T cells to secrete various cytokines following stimulation, including tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). In addition, this patient exhibited low frequency of regulatory T cells, with a reduction in their CTLA4 expression and interleukin (IL)-10 secretion. Finally, we show marked oligoclonal expansion of specific B- and T-cell clones in the peripheral blood of the LRBA-deficient patient. Conclusions: LRBA deficiency is characterized by marked immunological changes in innate and adaptive immune cells. This case highlights the importance of advanced genetic studies in patients with a unique phenotype, regardless of their age at presentation.
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Proteínas Adaptadoras Transductoras de Señales/genética , Inmunodeficiencia Variable Común/genética , Análisis Mutacional de ADN , Secuenciación del Exoma , Enfermedades Inflamatorias del Intestino/genética , Mutación , Adulto , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/terapia , Diagnóstico Tardío , Predisposición Genética a la Enfermedad , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/terapia , Masculino , Fenotipo , Valor Predictivo de las Pruebas , Factores de TiempoRESUMEN
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by defects in the NADPH oxidase complex. Mutations in NCF2 encoding the cytosolic factor p67phox result in autosomal recessive CGD. We describe three patients with a novel c.855G>C NCF2 mutation presenting with diverse clinical phenotype. Two siblings were heterozygous for the novel mutation and for a previously described exon 8-9 duplication, while a third unrelated patient was homozygous for the novel mutation. Mutation pathogenicity was confirmed by abnormal DHR123 assay and absent p67phox production and by sequencing of cDNA which showed abnormal RNA splicing. Clinically, the homozygous patient presented with suspected early onset interstitial lung disease and NCF2 mutation was found on genetic testing performed in search for surfactant-related defects. The two siblings also had variable presentation with one having history of severe pneumonia, lymphadenitis, and recurrent skin abscesses and the other presenting in his 30s with discoid lupus erythematosus and without significant infectious history. We therefore identified a novel pathogenic NCF2 mutation causing diverse and unusual clinical phenotype.