RESUMEN
Most viral infections can be self-limited, with no requirement for medical intervention. However, the same viruses can cause severe diseases in patients with compromised immunity due to single-gene diseases, acquired immune deficiency syndrome, or hematologic malignancies or those receiving immunosuppressive drugs. Occasionally, these immunocompromised patients harbor >1 infectious agent, requiring several concomitant diagnostic tests. We have developed, to our knowledge, a previously unreported whole-transcriptome sequencing-based pipeline that allows virome profiling, quantitation, and expression pattern analysis of 926 distinct viruses by sequencing of RNA isolated from a single lesional skin biopsy. This pipeline can also explore host genetics if there is a Mendelian predisposition to infection. We applied this pipeline to 6 Iranian patients with viral-induced skin lesions associated with immune deficiency secondary to HIV, human T-lymphotropic virus 1, chronic lymphocytic leukemia, and post transplant immunosuppression. In 5 cases, definitive human papillomavirus infections were identified, some caused by multiple viral types. In addition to human papillomavirus, coinfection with other viruses (Merkle cell polyomavirus, cytomegalovirus, and human herpesvirus 4) was detected in some lesions. In 1 case, whole-transcriptome sequencing validated the clinical diagnosis of adult T-cell leukemia/lymphoma in a patient with an initial diagnosis of mycosis fungoides/Sézary syndrome. These findings attest to the power of whole-transcriptome sequencing in profiling the cutaneous virome in the context of compromised immunity.
RESUMEN
SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses.
Asunto(s)
Linfocitos B , Linfocitos T CD4-Positivos , Proteínas Qa-SNARE , Animales , Proteínas Qa-SNARE/metabolismo , Proteínas Qa-SNARE/genética , Linfocitos B/inmunología , Linfocitos B/metabolismo , Ratones , Humanos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL , Femenino , Masculino , Centro Germinal/inmunología , Centro Germinal/metabolismo , Inmunidad Humoral , ExocitosisRESUMEN
UNC93B1 is a transmembrane domain protein mediating the signaling of endosomal Toll-like receptors (TLRs). We report five families harboring rare missense substitutions (I317M, G325C, L330R, R466S, and R525P) in UNC93B1 causing systemic lupus erythematosus (SLE) or chilblain lupus (CBL) as either autosomal dominant or autosomal recessive traits. As for a D34A mutation causing murine lupus, we recorded a gain of TLR7 and, to a lesser extent, TLR8 activity with the I317M (in vitro) and G325C (in vitro and ex vivo) variants in the context of SLE. Contrastingly, in three families segregating CBL, the L330R, R466S, and R525P variants were isomorphic with respect to TLR7 activity in vitro and, for R525P, ex vivo. Rather, these variants demonstrated a gain of TLR8 activity. We observed enhanced interaction of the G325C, L330R, and R466S variants with TLR8, but not the R525P substitution, indicating different disease mechanisms. Overall, these observations suggest that UNC93B1 mutations cause monogenic SLE or CBL due to differentially enhanced TLR7 and TLR8 signaling.
Asunto(s)
Eritema Pernio , Lupus Eritematoso Sistémico , Receptor Toll-Like 7 , Femenino , Humanos , Masculino , Eritema Pernio/genética , Mutación con Ganancia de Función , Células HEK293 , Lupus Eritematoso Cutáneo/genética , Lupus Eritematoso Cutáneo/patología , Lupus Eritematoso Sistémico/genética , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Mutación Missense , Linaje , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/genética , Receptor Toll-Like 8/metabolismo , Preescolar , Niño , Adulto Joven , AdultoRESUMEN
CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαß+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αß T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.
Asunto(s)
Linfocitos T CD4-Positivos , Linfocitos T Colaboradores-Inductores , Humanos , Linfocitos T CD8-positivos , Activación de Linfocitos , Antígenos HLA , Isoformas de Proteínas/metabolismoRESUMEN
The detection of a high serum immunoglobulin E (IgE) level is first suggestive of allergy, atopy or parasitosis. However, some very high values can be a sign of more severe diseases. We propose a diagnostic strategy based on clinical and biological data to identify the various hereditary immune diseases that also present with abnormally high serum IgE levels.
Asunto(s)
Hipersensibilidad , Síndromes de Inmunodeficiencia , Humanos , Inmunoglobulina E , HipergammaglobulinemiaRESUMEN
A vacina viva atenuada do vírus da febre amarela (YFV) pode, em casos raros, causar doença com risco de vida, geralmente em pacientes sem história prévia de doença viral grave. A deficiência completa de IFNAR1 autossômica recessiva (AR) foi relatada em um paciente de 12 anos de idade. Aqui, nós estudamos sete outros pacientes previamente saudáveis ââcom idades entre 13 e 80 anos com doença inexplicável associada à vacina YFV com risco de vida. Um paciente de 13 anos tinha deficiência completa de IFNAR2 de AR. Três outros pacientes vacinados com idades de 47, 57 e 64 anos apresentaram altos títulos de auto-Abs circulantes contra pelo menos 14 dos 17 IFNs do tipo I individuais. Esses anticorpos foram recentemente demonstrados como subjacentes a pelo menos 10% dos casos de pneumonia COVID-19 com risco de vida. Os auto-Abs foram neutralizantes in vitro, bloqueando o efeito protetor do IFN-α2 contra cepas vacinais de YFV. A deficiência de AR IFNAR1 ou IFNAR2 e auto-Abs neutralizantes contra IFNs do tipo I foram responsáveis ââpor mais da metade dos casos de doença associada à vacina YFV com risco de vida estudados aqui. Indivíduos previamente saudáveis ââpodem ser testados para ambas as predisposições antes da vacinação anti-YFV.