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The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.
Assuntos
Linfócitos B , Proteínas de Ligação a DNA , Proteínas de Homeodomínio , Proteínas Nucleares , Diferenciação Celular , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Humanos , Tolerância Imunológica , Contagem de Linfócitos , Proteínas Nucleares/deficiênciaRESUMO
BACKGROUND: Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation. OBJECTIVES: Objectives of this study were to characterize the natural history, immune phenotype, and biomarkers in pDGS with AIC. METHODS: Data on clinical presentation, disease severity, immunological phenotype, treatment selection, and response for patients with pDGS with AIC were collected via retrospective chart review. Flow cytometric analysis was done to assess T and B cell subsets, including biomarkers of immune dysregulation. RESULTS: Twenty-nine patients with the diagnosis of pDGS and AIC were identified from 5 international institutions. Nineteen (62%) patients developed Evan's syndrome (ES) during their clinical course and twenty (69%) had antibody deficiency syndrome. These patients demonstrated expansion in T follicular helper cells, CD19hiCD21lo B cells, and double negative cells and reduction in CD4 naïve T cells and regulatory T cells. First-line treatment for 17/29 (59%) included corticosteroids and/or high-dose immunoglobulin replacement therapy. Other overlapping therapies included eltrombopag, rituximab, and T cell immunomodulators. CONCLUSIONS: AIC in pDGS is often refractory to conventional AIC treatment paradigms. Biomarkers may have utility for correlation with disease state and potentially even response to therapy. Immunomodulating therapies could be initiated early based on early immune phenotyping and biomarkers before the disease develops or significantly worsens.
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Citopenia , Síndrome de DiGeorge , Humanos , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/terapia , Estudos Retrospectivos , Antígenos CD19 , Progressão da DoençaRESUMO
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.
Assuntos
Agamaglobulinemia , Síndromes de Imunodeficiência , Linfopenia , Neutropenia , Verrugas , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/genética , Verrugas/diagnóstico , Verrugas/epidemiologia , Verrugas/genética , Agamaglobulinemia/genética , Receptores CXCR4/genética , Neutropenia/genética , Linfopenia/complicações , Progressão da DoençaRESUMO
[This corrects the article DOI: 10.3389/fonc.2022.843741.].
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Background: Patients with inborn errors of immunity (IEI) have increased risk of developing cancers secondary to impaired anti-tumor immunity. Treatment of patients with IEI and cancer is challenging as chemotherapy can exacerbate infectious susceptibility. However, the literature on optimal cancer treatment in the setting of IEI is sparse. Objectives: We present a patient with specific antibody deficiency with normal immunoglobins (SADNI), immune dysregulation (ID), and stage III ovarian carcinoma as an example of the need to modify conventional treatment in the context of malignancy, IEI, and ongoing infections. Methods: This is a retrospective chart review of the patient's clinical manifestations, laboratory evaluation and treatment course. Results: Our patient is a female with SADNI and ID diagnosed with stage III ovarian carcinoma at 60 years of age. Her ID accounted for antinuclear antibody positive (ANA+) mixed connective tissue diseases, polyarthralgia, autoimmune neutropenia, asthma, autoimmune thyroiditis, and Celiac disease. Due to the lack of precedent in the literature, her treatment was modified with continuous input from infectious disease, allergy/immunology and oncology specialist using a multidisciplinary approach.The patient completed debulking surgery and 6 cycles of chemotherapy. The dosing for immunoglobulin replacement therapy was increased for prophylaxis. Chemotherapy doses were lowered for all cycles preemptively for IEI. The therapy included carboplatin, paclitaxel, bevacizumab, and pegfilgrastim. The patient completed six-months of maintenance medication involving bevacizumab.Her treatment course was complicated by Mycobacterium avium-complex (MAC) infection, elevated bilirubin and liver enzymes attributed to excessive immunoglobulin replacement therapy, and urinary tract infection (UTI) and incontinence.Cancer genetic analysis revealed no targetable markers and primary immunodeficiency gene panel of 407 genes by Invitae was unrevealing. Lab tests revealed no evidence of Epstein-Barr Virus (EBV) infection. Post-chemotherapy imaging revealed no evidence of cancer for 1 year and 4 months, but the disease relapsed subsequently. The patient's lung scarring requires vigilance. Conclusions: Our patient with ovarian cancer and IEI required modified treatment and prevention of complications. In cases of IEI, optimal chemotherapy should be titrated to minimize immunosuppression yet treat cancer aggressively while decreasing the risk of infection with prophylactic antibiotics and prolonged post-treatment surveillance, including pulmonary evaluation.
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Background: Activated phosphoinositide 3 kinase (PI3K) -delta syndrome (APDS) is an inborn error of immunity with variable clinical phenotype of immunodeficiency and immune dysregulation and caused by gain-of-function mutations in PIK3CD. The hallmark of immune phenotype is increased proportions of transitional B cells and plasmablasts (PB), progressive B cell loss, and elevated levels of serum IgM. Objective: To explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS. Methods: Clinical and immunological data was collected from 24 patients with APDS. In five cases, we performed an in-depth analysis of B cell phenotypes and cultured purified naïve B cells to evaluate their survival, activation, Ig gene class switch recombination (CSR), PB differentiation and antibody secretion. We also analyzed PB differentiation capacity of sorted CD27-IgD- double-negative B (DNB) cells. Results: The patients had increased B cell sizes and higher proportions of IgM+ DNB cells than healthy controls (HC). Their naïve B cells exhibited increased death, impaired CSR but relatively normal PB differentiation. Upon stimulation, patient's DNB cells secreted a similar level of IgG but a higher level of IgM than DNB cells from HC. Targeted therapy of PI3K inhibition partially restored B cell phenotypes. Conclusions: The present study suggests additional mechanistic insight into B cell pathology of APDS: (1) decreased peripheral B cell numbers may be due to the increased death of naïve B cells; (2) larger B cell sizes and expanded DNB population suggest enhanced activation and differentiation of naïve B cells into DNB cells; (3) the impaired CSR yet normal PB differentiation can predominantly generate IgM-secreting cells, resulting in elevated IgM levels.