RESUMEN
BACKGROUND: The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22; R620W) exhibits one of the strongest and most consistent associations with sporadic autoimmune disease. Although autoimmunity is common in patients with primary antibody deficiency (PAD), it remains unknown whether its pathogenesis is similar when it arises in this context compared with in immunocompetent patients. OBJECTIVE: We set out to determine whether the 1858T allele of PTPN22 was associated with PAD or with autoimmunity in the context of PAD. METHODS: We genotyped rs2476601 (g.1858C>T), a single nucleotide polymorphism encoding substitution of arginine for tryptophan in PTPN22 (R620W), in 193 patients with PAD and 148 control subjects from an Australian cohort. We also performed a subgroup analysis according to the presence of autoimmunity and B-cell phenotypes. RESULTS: C/T and T/T PTPN22 genotypes were more common in patients with PAD than in the matched control subjects (C/T, 18.1% vs 9.5%; T/T, 1.04% vs 0.6%). The T allele was associated with an increased risk of PAD relative to control subjects (odds ratio, 2.10; 95% CI, 1.11-4.00). The distribution of genotypes in control subjects was similar to those reported previously and did not deviate significantly from Hardy-Weinberg equilibrium. We found a strong association between the 1858T allele and PAD with coexistent autoimmune diseases. In patients with PAD and autoimmunity, 16 (43.2%) of 37 had at least one T allele of PTPN22 compared with 27 (17.3%) of 156 with the C/C genotype (P=.0014; odds ratio, 3.64; 95% CI, 1.68-7.88). We found no evidence that this effect was mediated by enrichment of CD21low B cells. CONCLUSION: The 1858T PTPN22 allele is strongly associated with autoimmunity in patients with PAD.
Asunto(s)
Sustitución de Aminoácidos , Autoinmunidad/genética , Síndromes de Inmunodeficiencia/genética , Polimorfismo de Nucleótido Simple , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Adulto , Alelos , Australia , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/patología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Técnicas de Genotipaje , Humanos , Síndromes de Inmunodeficiencia/inmunología , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Proteína Tirosina Fosfatasa no Receptora Tipo 22/inmunología , Factores de RiesgoRESUMEN
We present a patient with previously diagnosed hypocomplementemic urticarial vasculitis syndrome, with skin, lung, and renal involvement, who presented with congestive cardiac failure. During the course of her hospitalization, she was also found to have profound proximal muscle weakness in both upper and lower limbs associated with raised creatinine kinase levels. A muscle biopsy was performed, which demonstrated evidence of an inflammatory myositis with vasculitis, which had returned despite on-going immunosuppression. This occurrence of a new autoimmune disease may well be an example of the "waste disposal" hypothesis.
Asunto(s)
Complemento C1q/deficiencia , Enfermedades del Sistema Inmune/complicaciones , Miositis/complicaciones , Urticaria/complicaciones , Vasculitis/complicaciones , Antirreumáticos/uso terapéutico , Complemento C1q/efectos de los fármacos , Femenino , Humanos , Metotrexato/uso terapéutico , Persona de Mediana Edad , Miositis/tratamiento farmacológico , Miositis/inmunología , Síndrome , Urticaria/tratamiento farmacológico , Urticaria/inmunología , Vasculitis/tratamiento farmacológico , Vasculitis/inmunologíaRESUMEN
Engagement of cytokine receptors by specific ligands activate Janus kinase-signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
Asunto(s)
Diferenciación Celular/fisiología , Memoria Inmunológica/fisiología , Interleucinas/inmunología , Células Plasmáticas/inmunología , Factor de Transcripción STAT3/inmunología , Transducción de Señal/fisiología , Formación de Anticuerpos/fisiología , Antígenos/genética , Antígenos/inmunología , Humanos , Inmunoglobulinas/genética , Inmunoglobulinas/inmunología , Interleucinas/genética , Células Plasmáticas/citología , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT3/genética , Factores de TiempoRESUMEN
Hyper-immunoglobulin E syndrome (HIES) is a primary immune deficiency characterized by abnormal and devastating susceptibility to a narrow spectrum of infections, most commonly Staphylococcus aureus and Candida albicans. Recent investigations have identified mutations in STAT3 in the majority of HIES patients studied. Despite the identification of the genetic cause of HIES, the mechanisms underlying the pathological features of this disease remain to be elucidated. Here, we demonstrate a failure of CD4+ T cells harboring heterozygous STAT3 mutations to generate interleukin 17-secreting (i.e., T helper [Th]17) cells in vivo and in vitro due to a failure to express sufficient levels of the Th17-specific transcriptional regulator retinoid-related orphan receptor t. Because Th17 cells are enriched for cells with specificities against fungal antigens, our results may explain the pattern of infection susceptibility characteristic of patients with HIES. Furthermore, they underscore the importance of Th17 responses in normal host defense against the common pathogens S. aureus and C. albicans.