Common Variable Immunodeficiency Non-Infectious Disease Endotypes Redefined Using Unbiased Network Clustering in Large Electronic Datasets

Common variable immunodeficiency (CVID) is increasingly recognized for its association with autoimmune and inflammatory complications. Despite recent advances in immunophenotypic and genetic discovery, clinical care of CVID remains limited by our inability to accurately model risk for non-infectious disease development. Herein, we demonstrate the utility of unbiased network clustering as a novel method to analyze inter-relationships between non-infectious disease outcomes in CVID using databases at the United States Immunodeficiency Network (USIDNET), the centralized immunodeficiency registry of the United States, and Partners, a tertiary care network in Boston, MA, USA, with a shared electronic medical record amenable to natural language processing. Immunophenotypes were comparable in terms of native antibody deficiencies, low titer response to pneumococcus, and B cell maturation arrest. However, recorded non-infectious disease outcomes were more substantial in the Partners cohort across the spectrum of lymphoproliferation, cytopenias, autoimmunity, atopy, and malignancy. Using unbiased network clustering to analyze 34 non-infectious disease outcomes in the Partners cohort, we further identified unique patterns of lymphoproliferative (two clusters), autoimmune (two clusters), and atopic (one cluster) disease that were defined as CVID non-infectious endotypes according to discrete and non-overlapping immunophenotypes. Markers were both previously described {high serum IgE in the atopic cluster [odds ratio (OR) 6.5] and low class-switched memory B cells in the total lymphoproliferative cluster (OR 9.2)} and novel [low serum C3 in the total lymphoproliferative cluster (OR 5.1)]. Mortality risk in the Partners cohort was significantly associated with individual non-infectious disease outcomes as well as lymphoproliferative cluster 2, specifically (OR 5.9). In contrast, unbiased network clustering failed to associate known comorbidities in the adult USIDNET cohort. Together, these data suggest that unbiased network clustering can be used in CVID to redefine non-infectious disease inter-relationships; however, applicability may be limited to datasets well annotated through mechanisms such as natural language processing. The lymphoproliferative, autoimmune, and atopic Partners CVID endotypes herein described can be used moving forward to streamline genetic and biomarker discovery and to facilitate early screening and intervention in CVID patients at highest risk for autoimmune and inflammatory progression

Association of Immunoglobulin Levels, Infectious Risk, and Mortality With Rituximab and Hypogammaglobulinemia

Importance: Rituximab is an anti-CD20 chimeric antibody used in a wide variety of clinical indications. There has not been widespread adoption of consistent immune monitoring before and after rituximab therapy. However, there is a subset of patients who develop prolonged, symptomatic hypogammaglobulinemia following rituximab, and monitoring before and after rituximab therapy could help to identify these patients and initiate measures to prevent excess morbidity and mortality. Objective: To determine the current levels of screening for hypogammaglobulinemia (specifically, low immunoglobulin G), infectious risks associated with hypogammaglobulinemia, and variables associated with an increased risk of mortality. Design, Setting, and Participants: A cohort study was conducted of 8633 patients receiving rituximab from January 1, 1997, to December 31, 2017, at a large, tertiary referral center (Partners HealthCare System). Exposures: Rituximab administration. Main Outcomes and Measures: The primary outcome measures were immunoglobulin measurements, infectious complications, and mortality. Cox regression analysis was used to examine the results of infectious complications on survival, adjusted for age, sex, and indication for rituximab use. Results: Of the 8633 patients who received rituximab in the large, academic, health care system, 4479 satisfied inclusion criteria, with a mean (SD) age of 59.8 (16.2) years; 2280 patients (50.9%) were women. Most patients (3824 [85.4%]) did not have immunoglobulin levels checked before rituximab therapy. Of those who had levels determined, hypogammaglobulinemia was noted in 313 (47.8%) patients before initiation of rituximab. Following rituximab administration, worsening hypogammaglobulinemia was noted. There was an increase in severe infections after rituximab use in the study cohort (from 17.2% to 21.7%; P \u3c .001). In the survival analysis, increased mortality was associated with increasing age (hazard ratio [HR], 1.02; 95% CI, 1.01-1.02; P \u3c .001), male sex (HR, 1.14; 95% CI, 1.02-1.28; P = .02), and severe infectious complications in the 6 months before (HR, 3.14; 95% CI, 2.77-3.55; P \u3c .001) and after (HR, 4.97; 95% CI, 4.41-5.60; P \u3c .001) the first rituximab infusion. A total of 201 patients (4.5%) received immunoglobulin replacement following rituximab, and among these patients, higher cumulative immunoglobulin replacement dose was associated with a reduced risk of serious infectious complications (HR, 0.98; 95% CI, 0.96-0.99; P = .002). Conlusion: and Relevance Many patients are not being screened or properly identified as having hypogammaglobulinemia both before and after rituximab administration. Monitoring of immunoglobulin levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from immunoglobulin replacement, which may in turn help to avoid excess morbidity and mortality

Induction of Metabolic Quiescence Defines the Transitional to Follicular B Cell Switch

Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this transition was also associated with increased extracellular adenosine salvage. Follicular B cells increased the abundance of the cell surface ectonucleotidase CD73, which coincided with adenosine 5′-monophosphate–activated protein kinase (AMPK) activation. Differentiation to the follicular B cell stage in vitro correlated with surface acquisition of CD73 on human transitional B cells and was augmented with the AMPK agonist, AICAR. Last, individuals with gain-of-function PIK3CD (PI3Kδ) mutations and increased pS6 activation exhibited a near absence of circulating follicular B cells. Together, our data suggest that mTORC1 attenuation may be necessary for human follicular B cell development. These data identify a distinct metabolic switch during human B cell development at the transitional to follicular stages, which is characterized by an induction of extracellular adenosine salvage, AMPK activation, and the acquisition of metabolic quiescence

Induction of Metabolic Quiescence Defines the Transitional to Follicular B Cell Switch

Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this transition was also associated with increased extracellular adenosine salvage. Follicular B cells increased the abundance of the cell surface ectonucleotidase CD73, which coincided with adenosine 5′-monophosphate–activated protein kinase (AMPK) activation. Differentiation to the follicular B cell stage in vitro correlated with surface acquisition of CD73 on human transitional B cells and was augmented with the AMPK agonist, AICAR. Last, individuals with gain-of-function PIK3CD (PI3Kδ) mutations and increased pS6 activation exhibited a near absence of circulating follicular B cells. Together, our data suggest that mTORC1 attenuation may be necessary for human follicular B cell development. These data identify a distinct metabolic switch during human B cell development at the transitional to follicular stages, which is characterized by an induction of extracellular adenosine salvage, AMPK activation, and the acquisition of metabolic quiescence

Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis

Background Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis.Methods A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls.Results sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9–3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5–0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7–1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls.Conclusion Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis

Practical Guidance for the Evaluation and Management of Drug Hypersensitivity: Specific Drugs

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