RESUMEN
BACKGROUND: Although previous studies described the production of IgG antibodies in a subgroup of patients with common variable immunodeficiency (CVID) following messenger RNA vaccinations with BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (CVID responders), the functionality of these antibodies in terms of avidity as measured by the dissociation rate constant (kdis) and the antibody response to booster immunization has not been studied. OBJECTIVE: We sought to analyze in CVID responders and healthy individuals, the avidity of anti-SARS-CoV-2 serum antibodies and their neutralization capacity as measured by surrogate virus-neutralizing antibodies in addition to IgG-, IgM-, and IgA-antibody levels and the response of circulating (peripheral blood) follicular T-helper cells after a third vaccination with BNT162b2 SARS-CoV-2 messenger RNA vaccine. METHODS: Binding IgG, IgA, and IgM serum levels were analyzed by ELISA in patients with CVID responding to the primary vaccination (CVID responders, n = 10) and healthy controls (n = 41). The binding avidity of anti-spike antibodies was investigated using biolayer interferometry in combination with biotin-labeled receptor-binding-domain of SARS-CoV-2 spike protein and streptavidin-labeled sensors. Antigen-specific recall T-cell responses were assessed by measuring activation-induced markers by flow cytometry. RESULTS: After the third vaccination with BNT162b2, IgG-, IgM-, and IgA-antibody levels, surrogate virus-neutralizing antibody levels, and antibody avidity were lower in CVID responders than in healthy controls. In contrast, anti-SARS-CoV-2 spike protein avidity was comparable in CVID responders and healthy individuals following primary vaccination. Follicular T-helper cell response to booster vaccination in CVID responders was significantly reduced when compared with that in healthy individuals. CONCLUSIONS: Impaired affinity maturation during booster response provides new insight into CVID pathophysiology.
Asunto(s)
COVID-19 , Inmunodeficiencia Variable Común , Humanos , Vacuna BNT162 , Formación de Anticuerpos , COVID-19/prevención & control , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Vacunas contra la COVID-19 , Anticuerpos Bloqueadores , Anticuerpos Antivirales , Inmunoglobulina A , Inmunoglobulina MRESUMEN
Recent studies identified an emerging role of group 2 and 3 innate lymphoid cells (ILCs) as key players in the generation of T-dependent and T-independent antibody production. In this retrospective case-control study, CD117+ ILCs (including the majority of ILC2 and ILC3) were reduced in patients with common variable immunodeficiency (CVID). The reduction in CD117+ ILCs was distinctive to CVID and could not be observed in patients with X-linked agammaglobulinemia. Patients with a more pronounced reduction in CD117+ ILC numbers showed significantly lower numbers of peripheral MZ-like B cells and an increased prevalence of chronic, non-infectious enteropathy. Subsequent phenotyping of ILC subsets in CVID revealed that the reduction in CD117+ ILC numbers is due to a reduction in ILC2 numbers. In vitro expansion of CVID ILC2 in response to IL-2, IL-7, IL-25 and IL-33 was impaired. Furthermore, upregulation of MHCII and IL-2RA in response to IL-2, IL-7, IL-25 and IL-33 was impaired in CVID ILC2. Thus, our results indicate a dysregulation of ILC subsets with a reduction in ILC2 numbers in CVID, however, further studies are needed to explore whether ILC abnormalities are a primary finding or secondary to disease complications encountered in CVID.
Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Subgrupos Linfocitarios/inmunología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-kit/inmunología , Estudios RetrospectivosRESUMEN
Over the past decades, a pleiotropic spectrum of B-cell intrinsic defects leading to early onset agammaglobulinemia and absent B cells has been described. Herein we report terminal 14q32.33 deletion as a novel cause of agammaglobulinemia. We describe a 20-year old man with a 1MB terminal 14q32.33 deletion resulting in a loss of the entire Immunoglobulin heavy chain gene region of chromosome 14. The patient presented with absent serum immunoglobulin levels and absent circulating B cells since age 2. The clinical picture was dominated by severe episodes of recurrent upper respiratory tract infections. In the literature, the most prevalent features of terminal 14q32.33 deletions include mental disability, facial malformation, hypotonia, seizures, and visual problems with retinal abnormalities. Neither increased susceptibility to infections nor agammaglobulinemia have been described as a manifestation of terminal 14q32.33 deletion. Thus, our findings expand the known clinical spectrum of terminal 14q32.33 deletion to include susceptibility to infections.
Asunto(s)
Agammaglobulinemia/genética , Deleción Cromosómica , Cromosomas Humanos Par 14/genética , Agammaglobulinemia/inmunología , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Masculino , Adulto JovenRESUMEN
BACKGROUND: Nosocomial infections caused by the bacterial pathogen Staphylococcus aureus can lead to serious complications due to the varying presence of secreted toxins. Comparative studies of genomic information and production rates are needed to assess the pathogenic potential of isolated strains. Genotypic and phenotypic profiling of clinical and colonising isolates of S. aureus was used to characterise the release of exotoxins. Blood isolates were compared with colonisation strains to determine similarities and differences of single strains and clusters. RESULTS: Fifty-one fresh isolates obtained from colonised individuals (n = 29) and S. aureus bacteremia (SAB) patients (n = 22) were investigated. The prevalence of genes encoding for three cytolysins (alpha/beta/gamma toxin) and twenty-four superantigens (SEA-SElX) was determined. Isolates exhibited eighteen distinct combinations of superantigens. Sequence analysis identified mutated open reading frames in hla in 13.7% of all strains, in selw (92.2%) and in selx (15.7%). All corrupted genes were associated with specific clonal complexes. Functional assessment of alpha toxin activity by a rabbit erythrocyte lysis assay revealed that supernatants lacking alpha toxin still displayed hemolysis. This was due to the presence of gamma toxin, as proven by inhibition experiments using antisera raised against the respective recombinant proteins. Alpha toxin, SEC, and TSST1 production was quantified by enzyme-linked immunosorbent assays on supernatants of all hla, sec, and tst positive isolates. Blood isolates and colonising strains showed comparable amounts of secreted proteins within a wide range. Agr types I to IV were identified, but did not allow a prediction of high or low production rates. In contrast, alpha toxin production rates between distinct clonal complexes clearly differed. Spa typing was performed and revealed thirty-two unique spa gene patterns and eight small clusters comprising nineteen isolates. Recognised spa-typing clusters displayed highly similar production rates. CONCLUSION: Production rates of the three most prevalent exotoxins varied within both groups of blood isolates and colonising strains. By comparing genotypes and secretion, we found that identical complex gene patterns did not allow predictions of toxin production and function. However, identification of spa typing clusters was suitable to predict similar quantities of released exotoxins.
Asunto(s)
Proteínas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Hemolíticos/metabolismo , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Animales , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/toxicidad , Eritrocitos/citología , Eritrocitos/efectos de los fármacos , Genotipo , Hemolíticos/toxicidad , Humanos , Fenotipo , Conejos , Staphylococcus aureus/clasificación , Staphylococcus aureus/aislamiento & purificación , Staphylococcus aureus/metabolismoRESUMEN
PURPOSE: Idiopathic CD4 lymphopenia constitutes a heterogeneous group of immunodeficiencies with characteristically low CD4+ T-cell counts with largely unknown genetic etiology. We here sought to determine the underlying molecular cause in an index family with two patients suffering from combined immunodeficiency that evolved into predominant CD4+ lymphopenia. The more severely affected index patient also presented with selective antibody deficiency against bacterial polysaccharide antigens. METHODS: For the genetic analysis, we used combined homozygosity mapping and exome sequencing. Functional assays included immunoblot analysis, flow cytometry and TCR Vß spectratyping. RESULTS: A novel homozygous missense mutation was revealed in the kinase domain of JAK3 (c.T3196C, p.Cys1066Arg). Further analysis showed revertant chimerism in CD8+ T-cells in both patients. The additional presence of revertant CD4+ T-cells was associated with a milder clinical and immunological phenotype in the second patient, although the role somatic chimerism plays in amelioration of disease phenotype is uncertain, as presence of revertant cells had no effect on residual CD4 cell JAK3 signaling function. Residual activity of JAK3-dependent STAT3 and STAT5 signaling was also found in immortalized B-cell lines indicating a hypomorphic nature of the described mutation which likely contributes to the milder clinical phenotype. CONCLUSIONS: We here present the first case of revertant mosaicism in JAK3 deficiency, manifesting as combined immunodeficiency evolving into predominant CD4+ lymphopenia. Revertant chimerism or hypomorphic mutations in genes typically associated with more severe T-cell deficiency should be considered when assessing patients with milder forms of combined immunodeficiencies.
Asunto(s)
Linfocitos T CD4-Positivos , Janus Quinasa 3/genética , Linfopenia , Inmunodeficiencia Combinada Grave , Adolescente , Adulto , Secuencia de Aminoácidos , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Niño , Preescolar , Quimerismo , Femenino , Humanos , Inmunoglobulinas/sangre , Lactante , Janus Quinasa 3/metabolismo , Linfopenia/genética , Masculino , Datos de Secuencia Molecular , Mutación , Factor de Transcripción STAT5/metabolismo , Alineación de Secuencia , Transducción de Señal/genéticaAsunto(s)
Proteínas de Unión al ADN/deficiencia , Proteínas de Homeodominio/genética , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Proteínas Nucleares/deficiencia , Adulto , Proteínas de Unión al ADN/genética , Humanos , Síndromes de Inmunodeficiencia/fisiopatología , Proteínas Nucleares/genética , PrevalenciaRESUMEN
Background: Toxic shock syndrome toxin-1 (TSST-1) is a superantigen produced by Staphylococcus aureus that causes the life-threatening toxic shock syndrome. The development of a safe and immunogenic vaccine against TSST-1 remains an unmet medical need. We investigated the safety, tolerability and immunogenicity of a recombinant TSST-1 variant vaccine (rTSST-1v) after 1-3 injections in healthy volunteers. Methods: In this randomised, double-blind, adjuvant-controlled, parallel-group, phase 2 trial, healthy adults aged 18-64 were randomly allocated to undergo 1-3 injections of either 10 or 100 µg rTSST-1v or Al(OH)3. The primary endpoint was safety and tolerability of rTSST-1v in the intention-to-treat population. The per-protocol population was used for the immunogenicity analysis. The trial is registered with EudraCT#: 2015-003714-24; ClinicalTrials.gov#: NCT02814708. Findings: Between April and November 2017,140 subjects were enrolled and 126 completed the trial. rTSST-1v showed a good safety and tolerability profile. A total of 855 systemic adverse events occurred, 280 of which were suspected related adverse events, without dose dependency. Two participants were discontinued early because of allergic reactions. Seroconversion occurred in >81% of subjects within 3 months of the first immunisation which was sustained until 18 months after the third immunisation in over 70% of subjects in the pooled low-dose group and in over 85% in the pooled high-dose group. Interpretation: rTSST-1v in cumulative doses of up to 300 µg was safe, well-tolerated and highly immunogenic. Two immunisations with 100 µg rTSST-1v provided the most persistent immune response and may be evaluated in future trials. Funding: Biomedizinische Forschung & Bio-Produkte AG funded this study.
RESUMEN
Herpes simplex virus (HSV) immediate-early protein ICP0 is a transcriptional activator with E3 ubiquitin ligase activity that induces the degradation of ND10 proteins, including the promyelocytic leukemia protein (PML) and Sp100. Moreover, ICP0 has a role in the derepression of viral genomes and in the modulation of the host interferon response to virus infection. Here, we report that ICP0 interacts with SIAH-1, a cellular E3 ubiquitin ligase that is involved in multiple cellular pathways and is itself capable of mediating PML degradation. This novel virus-host interaction profoundly stabilized SIAH-1 and recruited this cellular E3 ligase into ICP0-containing nuclear bodies. Moreover, SIAH-1 mediated the polyubiquitination of HSV ICP0 in vitro and in vivo. After infection of SIAH-1 knockdown cells with HSV, higher levels of ICP0 were produced, ICP0 was less ubiquitinated, and the half-life of this multifunctional viral regulatory protein was increased. These results indicate an inhibitory role of SIAH-1 during lytic infection by targeting ICP0 for proteasomal degradation.
Asunto(s)
Proteínas Inmediatas-Precoces/metabolismo , Proteínas Nucleares/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Secuencia de Bases , Línea Celular , Cartilla de ADN , Interacciones Huésped-Patógeno , Humanos , Hidrólisis , Reacción en Cadena de la Polimerasa , Unión Proteica , UbiquitinaciónRESUMEN
Staphylococcus aureus is a human and animal pathogen as well as a commensal bacterium. It can be a causative agent of severe, life-threatening infections with high mortality, e.g., toxic shock syndrome, septic shock, and multi-organ failure. S. aureus strains secrete a number of toxins. Exotoxins/enterotoxins are considered important in the pathogenesis of the above-mentioned conditions. Exotoxins, e.g., superantigen toxins, cause uncontrolled and polyclonal T cell activation and unregulated activation of inflammatory cytokines. Here we show the importance of genomic analysis of infectious strains in order to identify disease-causing exotoxins. Further, we show through functional analysis of superantigenic properties of staphylococcal exotoxins that even very small amounts of a putative superantigenic contaminant can have a significant mitogenic effect. The results show expression and production of two distinct staphylococcal exotoxins, SEC and SEL, in several strains from clinical isolates. Antibodies against both toxins are required to neutralise the superantigenic activity of staphylococcal supernatants and purified staphylococcal toxins.
Asunto(s)
Choque Séptico , Infecciones Estafilocócicas , Animales , Citocinas/metabolismo , Enterotoxinas/genética , Enterotoxinas/toxicidad , Exotoxinas/genética , Humanos , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/metabolismo , Superantígenos/genética , Superantígenos/toxicidadRESUMEN
Previous studies on immune responses following COVID-19 vaccination in patients with common variable immunodeficiency (CVID) were inconclusive with respect to the ability of the patients to produce vaccine-specific IgG antibodies, while patients with milder forms of primary antibody deficiency such as immunoglobulin isotype deficiency or selective antibody deficiency have not been studied at all. In this study we examined antigen-specific activation of CXCR5-positive and CXCR5-negative CD4+ memory cells and also isotype-specific and functional antibody responses in patients with CVID as compared to other milder forms of primary antibody deficiency and healthy controls six weeks after the second dose of BNT162b2 vaccine against SARS-CoV-2. Expression of the activation markers CD25 and CD134 was examined by multi-color flow cytometry on CD4+ T cell subsets stimulated with SARS-CoV-2 spike peptides, while in parallel IgG and IgA antibodies and surrogate virus neutralization antibodies against SARS-CoV-2 spike protein were measured by ELISA. The results show that in CVID and patients with other milder forms of antibody deficiency normal IgG responses (titers of spike protein-specific IgG three times the detection limit or more) were associated with intact vaccine-specific activation of CXCR5-negative CD4+ memory T cells, despite defective activation of circulating T follicular helper cells. In contrast, CVID IgG nonresponders showed defective vaccine-specific and superantigen-induced activation of both CD4+T cell subsets. In conclusion, impaired TCR-mediated activation of CXCR5-negative CD4+ memory T cells following stimulation with vaccine antigen or superantigen identifies patients with primary antibody deficiency and impaired IgG responses after BNT162b2 vaccination.
Asunto(s)
Vacuna BNT162/inmunología , Linfocitos T CD4-Positivos/inmunología , COVID-19/inmunología , Enfermedades de Inmunodeficiencia Primaria/inmunología , SARS-CoV-2/inmunología , Adulto , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/prevención & control , Inmunodeficiencia Variable Común/inmunología , Enterotoxinas/inmunología , Femenino , Humanos , Inmunoglobulina G/inmunología , Activación de Linfocitos , Masculino , Células T de Memoria/inmunología , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T/inmunología , Receptores CXCR5/inmunología , Células T Auxiliares Foliculares/inmunología , VacunaciónRESUMEN
Mutations of the interleukin 2 receptor γ chain (IL2RG) result in the most common form of severe combined immunodeficiency (SCID), which is characterized by severe and persistent infections starting in early life with an absence of T cells and natural killer cells, normal or elevated B cell counts and hypogammaglobulinemia. SCID is commonly fatal within the first year of life, unless the immune system is reconstituted by hematopoietic stem cell transplantation (HSCT) or gene therapy. We herein describe a male infant with X-linked severe combined immunodeficiency (X-SCID) diagnosed at 5 months of age. Genetic testing revealed a novel C to G missense mutation in exon 1 resulting in a 3' splice site disruption with premature stop codon and aberrant IL2 receptor signaling. Following the diagnosis of X-SCID, the patient subsequently underwent a TCRαß/CD19-depleted haploidentical HSCT. Post transplantation the patient presented with early CD8+ T cell recovery with the majority of T cells (>99%) being non-donor T cells. Genetic analysis of CD4+ and CD8+ T cells revealed a spontaneous 14 nucleotide insertion at the mutation site resulting in a novel splice site and restoring the reading frame although defective IL2RG function was still demonstrated. In conclusion, our findings describe a spontaneous second-site mutation in IL2RG as a novel cause of somatic mosaicism and early T cell recovery following haploidentical HSCT.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Trasplante de Células Madre Hematopoyéticas , Mutación , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X , Aloinjertos , Humanos , Lactante , Subunidad gamma Común de Receptores de Interleucina/genética , Subunidad gamma Común de Receptores de Interleucina/inmunología , Masculino , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/inmunología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/terapiaRESUMEN
X-linked lymphoproliferative disease (XLP1) is a combined immunodeficiency characterized by severe immune dysregulation caused by mutations in the SH2D1A/SAP gene. Loss or dysfunction of SH2D1A is associated with the inability in clearing Epstein-Barr-Virus (EBV) infections. Clinical manifestation is diverse and ranges from life-threatening hemophagocytic lymphohistiocytosis (HLH) and fulminant infectious mononucleosis (FIM) to lymphoma and antibody deficiency. Rare manifestations include aplastic anemia, chronic gastritis and vasculitis. Herein, we describe the case of a previously healthy eight-year old boy diagnosed with XLP1 presenting with acute non-EBV acute meningoencephalitis with thrombotic occlusive vasculopathy. The patient developed multiple cerebral aneurysms leading to repeated intracerebral hemorrhage and severe cerebral damage. Immunological examination was initiated after development of a susceptibility to infections with recurrent bronchitis and one episode of severe pneumonia and showed antibody deficiency with pronounced IgG1-3-4 subclass deficiency. We could identify a novel hemizygous SH2D1A point mutation affecting the start codon. Basal levels of SAP protein seemed to be detectable in CD8+ and CD4+ T- and CD56+ NK-cells of the patient what indicated an incomplete absence of SAP. In conclusion, we could demonstrate a novel SH2D1A mutation leading to deficient SAP protein expression and a rare clinical phenotype of non-EBV associated acute meningoencephalitis with thrombotic occlusive vasculopathy.
Asunto(s)
Infecciones por Virus de Epstein-Barr/inmunología , Trastornos Linfoproliferativos/inmunología , Meningoencefalitis/inmunología , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/inmunología , Trombosis/inmunología , Niño , Infecciones por Virus de Epstein-Barr/diagnóstico , Humanos , Trastornos Linfoproliferativos/diagnóstico , Masculino , Meningoencefalitis/diagnóstico , Mutación , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/genética , Trombosis/diagnósticoRESUMEN
Staphylococcal toxic shock syndrome toxin 1 (TSST-1) is the major cause of toxic shock syndrome and is important in the pathophysiology of staphylococcal septic shock. Our study about the biological effects of TSST-1 in the rabbit 3 and 6 h and 7 days postinjection provides evidence that TSST-1 induces leukopenia, lymphopenia, and monocytopenia as a result of extravasation of cells in a Vss-unrestricted manner. Cells in the circulation, reduced significantly in numbers, show the same phenotypic distribution as before TSST-1 injection. Three hours post-in vivo TSST-1 injection, we demonstrated compartmentalization of the response. By quantitative RT-PCR, the induction of mRNA expression of TH1 and inflammatory cytokines in the spleen and lung and a complete lack of induction in PBMC could be shown. Proliferation assays revealed that 3 h after TSST-1, PBMC were neither activated nor responsive to in vitro restimulation, even when IL-2 was added. In contrast, 7 days later, PBMC and spleen cells were anergic: showing no response to TSST-1 but a vigorous response upon addition of IL-2. The results presented extend our understanding of the pathophysiology of toxic and septic shock as a result of superantigen toxin-producing Staphylococcus aureus. Demonstration of compartmentalization of the response proves that erroneous conclusions could be drawn by the exclusive analysis of PBMCs. The results reveal further that in nonresponsiveness to the antigen, different immunological mechanisms may be operational. Measurements of the induction of cytokine gene activation provide important complementary information to that of serum cytokine levels.
Asunto(s)
Toxinas Bacterianas/farmacología , Anergia Clonal , Enterotoxinas/farmacología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Staphylococcus aureus/inmunología , Superantígenos/farmacología , Animales , Células Cultivadas , Quimiotaxis , Citocinas/biosíntesis , Citocinas/genética , Enterotoxinas/fisiología , Femenino , Leucocitos/inmunología , Leucocitos/patología , Leucopenia/sangre , Leucopenia/inmunología , Pulmón/inmunología , Activación de Linfocitos , Linfopenia/sangre , Linfopenia/inmunología , ARN Mensajero/biosíntesis , Conejos , Proteínas Recombinantes/farmacología , Bazo/inmunología , Superantígenos/fisiología , Factores de TiempoRESUMEN
Staphylococcal superantigen toxins lead to a devastating cytokine storm resulting in shock and multi-organ failure. We have previously assessed the safety and immunogenicity of a recombinant toxic shock syndrome toxin 1 variant vaccine (rTSST-1v) in clinical trials (NCT02971670 and NCT02340338). The current study assessed neutralizing antibody titers after repeated vaccination with escalating doses of rTSST-1v. At study entry, 23 out of 34 subjects (67.6%) had neutralizing antibody titers inhibiting T cell activation as determined by 3H-thymidine incorporation at a serum dilution of ≤1:100 with similar figures for inhibition of IL-2 activation (19 of 34 subjects, 55.9%) as assessed by quantitative PCR. After the first vaccination, numbers of subjects with neutralization titers inhibiting T cell activation (61.7% ≥ 1:1000) and inhibiting IL-2 gene induction (88.2% ≥ 1:1000) increased. The immune response was augmented after the second vaccination (inhibiting T cell activation: 78.8% ≥ 1:1000; inhibiting IL-2 induction: 93.9% ≥ 1:1000) corroborated with a third immunization months later in a small subgroup of subjects. Assessment of IFNγ, TNFα and IL-6 inhibition revealed similar results, whereas neutralization titers did not change in placebo participants. Antibody titer studies show that vaccination with rTSST-1v in subjects with no/low neutralizing antibodies can rapidly induce high titer neutralizing antibodies persisting over months.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Anticuerpos Neutralizantes/sangre , Toxinas Bacterianas/administración & dosificación , Síndrome de Liberación de Citoquinas/prevención & control , Enterotoxinas/administración & dosificación , Inmunogenicidad Vacunal , Choque Séptico/prevención & control , Infecciones Estafilocócicas/prevención & control , Vacunas Estafilocócicas/administración & dosificación , Staphylococcus aureus/efectos de los fármacos , Superantígenos/administración & dosificación , Toxinas Bacterianas/genética , Toxinas Bacterianas/inmunología , Células Cultivadas , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/microbiología , Citocinas/genética , Citocinas/metabolismo , Método Doble Ciego , Enterotoxinas/genética , Enterotoxinas/inmunología , Humanos , Activación de Linfocitos/efectos de los fármacos , Estudios Prospectivos , Choque Séptico/inmunología , Choque Séptico/microbiología , Método Simple Ciego , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Vacunas Estafilocócicas/genética , Vacunas Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Staphylococcus aureus/patogenicidad , Superantígenos/genética , Superantígenos/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Vacunación , Vacunas Sintéticas/administración & dosificaciónRESUMEN
Vasculitis can be a life-threatening complication associated with high mortality and morbidity among patients with primary immunodeficiencies (PIDs), including variants of severe and combined immunodeficiencies ((S)CID). Our understanding of vasculitis in partial defects in recombination activating gene (RAG) deficiency, a prototype of (S)CIDs, is limited with no published systematic evaluation of diagnostic and therapeutic modalities. In this report, we sought to establish the clinical, laboratory features, and treatment outcome of patients with vasculitis due to partial RAG deficiency. Vasculitis was a major complication in eight (13%) of 62 patients in our cohort with partial RAG deficiency with features of infections and immune dysregulation. Vasculitis occurred early in life, often as first sign of disease (50%) and was complicated by significant end organ damage. Viral infections often preceded the onset of predominately non-granulomatous-small vessel vasculitis. Autoantibodies against cytokines (IFN-α, -ω, and IL-12) were detected in a large fraction of the cases tested (80%), whereas the majority of patients were anti-neutrophil cytoplasmic antibodies (ANCA) negative (>80%). Genetic diagnosis of RAG deficiency was delayed up to 2 years from the onset of vasculitis. Clinical cases with sole skin manifestation responded well to first-line steroid treatment, whereas systemic vasculitis with severe end-organ complications required second-line immunosuppression and/or hematopoietic stem cell transplantation (HSCT) for definitive management. In conclusion, our data suggest that vasculitis in partial RAG deficiency is prevalent among patients with partial RAG deficiency and is associated with high morbidity. Therefore, partial RAG deficiency should be included in the differential diagnosis of patients with early-onset systemic vasculitis. Diagnostic serology may be misleading with ANCA negative findings, and search for conventional autoantibodies should be extended to include those targeting cytokines.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Homeodominio/genética , Proteínas Nucleares/genética , Inmunodeficiencia Combinada Grave/inmunología , Vasculitis/inmunología , Adolescente , Adulto , Autoanticuerpos/sangre , Biomarcadores/sangre , Niño , Preescolar , Proteínas de Unión al ADN/deficiencia , Bases de Datos Factuales , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Interferón Tipo I/inmunología , Interferón-alfa/inmunología , Interleucina-12/inmunología , Masculino , Persona de Mediana Edad , Proteínas Nucleares/deficiencia , Fenotipo , Prevalencia , Pronóstico , Inmunodeficiencia Combinada Grave/epidemiología , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/terapia , Vasculitis/epidemiología , Vasculitis/terapia , Adulto JovenRESUMEN
BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.
Asunto(s)
Proteínas de Homeodominio , Síndromes de Inmunodeficiencia , Adolescente , Adulto , Autoinmunidad , Niño , Preescolar , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/terapia , Inmunosupresores/uso terapéutico , Lactante , Inflamación , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
The provision of antibodies to prevent and treat infection began with the application of "curative serum" in the first years of the last century. After the process of large-scale plasma fractionation was developed in the 1940s, the general use of immunoglobulin expanded. Intravenous immunoglobulin products became available in the 1970s, and their only use for the provision of antibodies governed the opinion of experts over the next decade. Modulation of inflammation and immunosuppression were introduced in treatment of inflammatory and autoimmune diseases and became accepted indications. The history of adverse events of treatment and their management are outlined in this article. Consensus indications and evidence-based off-label uses are discussed.
Asunto(s)
Inmunización Pasiva/historia , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/efectos adversos , Síndromes de Inmunodeficiencia/terapia , Animales , Anticuerpos Monoclonales/uso terapéutico , Consensus Development Conferences, NIH as Topic , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Inmunoglobulinas Intravenosas/química , Inmunoglobulinas Intravenosas/inmunología , Síndromes de Inmunodeficiencia/historia , National Institutes of Health (U.S.)/historia , Estados UnidosRESUMEN
BACKGROUND: Patients with common variable immunodeficiency have defective T-cell activation after stimulation via T-cell receptor (TCR)/CD28 or by recall antigens. OBJECTIVE: In the current study, we investigated whether TNF-receptor 2 (RII) costimulation, which is important for sufficient TCR/CD28 stimulation, was significantly impaired in common variable immunodeficiency (CVID). METHODS: We studied T-cell activation events such as CD69 induction, calcium flux through store operated calcium channels, protein kinase C-theta translocation, and costimulation via TNF-RII compared with costimulation via CD28. RESULTS: By measuring TNF receptor-associated factor 1 expression, which is induced by TCR alone and can be upregulated by either CD28 or TNF-RII costimulation, we show that costimulation via CD28 is intact, whereas costimulation via TNF-RII in these patients is impaired. The ras-activation pathway as tested by CD69 induction, calcium flux through store operated calcium channels, and protein kinase C-theta translocation were comparable in CVID and control T cells. CONCLUSION: Taken together, these data indicate that the primary TCR signal as well as the signal derived from CD28 are normal but that TNF-RII-supported TCR costimulation is defective, most likely leading to impairment of an important amplification loop, such as TNF-RII augmented nuclear factor-kappaB activation. CLINICAL IMPLICATIONS: The finding of defective TNF-RII cosignaling in patients with CVID may help to define the activation pathway affected, thus potentially leading to a characterization of the molecular defect and molecular diagnosis in at least some of these patients.
Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Receptores Tipo II del Factor de Necrosis Tumoral/fisiología , Linfocitos T/inmunología , Adulto , Anciano , Antígenos CD28/fisiología , Señalización del Calcio , Femenino , Humanos , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Proteína Quinasa C/metabolismo , Transporte de Proteínas , Receptores Tipo II del Factor de Necrosis Tumoral/agonistas , Proteínas ras/metabolismoRESUMEN
Herpes Simplex Virus type 2 (HSV-2) is a neurotropic human pathogen. Upon de novo infection, the viral infected cell protein 0 (ICP0) is immediately expressed and interacts with various cellular components during the viral replication cycle. ICP0 is a multifunctional regulatory protein that has been shown to be important for both efficient viral replication and virus reactivation from latency. In particular, as previously demonstrated in transfected tissue culture models, ICP0 interacts with the cellular E3 ubiquitin ligase SIAH-1, which targets ICP0 for proteasomal degradation. However, the consequence of this virus-host interaction during the establishment of HSV-2 infection in vivo has not yet been elucidated. Here we confirmed that ICP0 of HSV-2 interacts with SIAH-1 via two conserved PxAxVxP amino acid binding motifs. We also demonstrate in vitro that a SIAH-1 binding-deficient HSV-2 strain, constructed by homologous recombination technology, exhibits an attenuated growth curve and impaired DNA and protein synthesis. This attenuated phenotype was also confirmed in an in vivo ocular infection mouse model. Specifically, viral load of the SIAH-1 binding-deficient HSV-2 mutant was significantly reduced in the trigeminal ganglia and brain stem at day 5 and 7 post infection. Our findings indicate that the interplay between ICP0 and SIAH-1 is important for efficient HSV-2 replication in vivo, thereby affecting viral dissemination kinetics in newly infected organisms, and possibly revealing novel targets for antiviral therapy.
Asunto(s)
Herpesvirus Humano 2/fisiología , Interacciones Huésped-Patógeno/fisiología , Proteínas Inmediatas-Precoces/metabolismo , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Virales/metabolismo , Replicación Viral/fisiología , Animales , Sitios de Unión/genética , Tronco Encefálico/metabolismo , Tronco Encefálico/virología , Línea Celular , Chlorocebus aethiops , Cricetinae , Modelos Animales de Enfermedad , Ojo/metabolismo , Ojo/virología , Infecciones Virales del Ojo/genética , Infecciones Virales del Ojo/metabolismo , Femenino , Herpes Simple/genética , Herpes Simple/metabolismo , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/crecimiento & desarrollo , Interacciones Huésped-Patógeno/genética , Humanos , Proteínas Inmediatas-Precoces/genética , Ratones Endogámicos C57BL , Proteínas Nucleares/genética , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/virología , Ubiquitina-Proteína Ligasas/genética , Proteínas Virales/genética , Replicación Viral/genéticaRESUMEN
B cell activation via the B cell receptor (BCR) signalosome involves participation of signaling molecules such as BTK and BLNK. Genetic defects in these molecules are known to impair B cell differentiation and subsequently lead to agammaglobulinemia. Here we identified novel mutations in BTK and BLNK in two unrelated patients that perturb the intrinsic B-cell receptor signaling pathway and lead to selective IgM deficiency, whereas production of other immunoglobulin isotypes and IgG antibody response remain intact. Currently it is unknown how BCR signaling strength affects mature B cell development in humans. Both patients show reduced levels of BCR signalosome phosphorylation as well as impaired BCR-dependent Ca2+ influx, which was accompanied by a marked decrease in IgD+IgM+CD27+ MZ-like B-cells. We further describe reduced expression of essential B cell differentiation factors such as BAFF-R and T-Bet in the patients' B-cells, which might contribute to the observed deficiency of MZ-like B cells. MZ-like B cells are known to produce natural IgM antibodies that play an essential role in immune homeostasis. By using surface plasmon resonance (SPR) technology and a synthetic blood group A trisaccharide as antigen we were able to show that both patients lack the presence of anti-blood group A IgM considered to be prototypical natural antibodies whereas IgG levels were normal. Antibody binding dynamics and binding affinity of anti-blood group A IgG were comparable between patients and healthy controls. These results indicate that human IgM deficiency can be associated with signaling defects in the BCR signalosome, defective production of natural IgM antibodies in the blood group A/B/0 system and abnormalities in B cell development.