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Here, we report a case of atopic dermatitis (AD) in a patient who received biweekly doses of dupilumab, an antibody against the IL-4 receptor α chain (IL-4Rα). Single cell RNA-sequencing showed that naïve B cells expressed the highest levels of IL4R compared to other B cell subpopulations. Compared to controls, the dupilumab-treated patient exhibited diminished percentages of IL4R+IGHD+ naïve B cells and down-regulation of IL4R, FCER2 (CD23), and IGHD. Dupilumab treatment resulted in upregulation of genes associated with apoptosis and inhibition of B cell receptor signaling and down-regulation of class-switch and memory B cell development genes. The dupilumab-treated patient exhibited a rapid decline in COVID-19 anti-spike and anti-receptor binding domain antibodies between 4 and 8 and 11 months post COVID-19 vaccination. Our data suggest that intact and persistent IL-4 signaling is necessary for maintaining robust survival and development of naïve B cells, and maintaining a long term vaccine response.

Objective: To determine if circulating autoantibodies (autoAbs) and T-helper cell cytokines correlate with a different class of lupus nephritis (LN), including class III/IV, compared to class V and other manifestations of systemic lupus erythematosus (SLE). Methods: All patients (N=62) met the SLE classification criteria of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) or Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. Demographic, clinical data, and serologic manifestations included anti-DNA, anti-Smith (Anti-Sm), C3, and C4 were included. Plasma levels of interferon gamma (IFNɣ), interleukin 17 (IL-17), interleukin 10 (IL-10) isotype-specific (IgG) anti-DNA, anti-Ro/SSA (SSA), and anti-Sm were measured using enzyme-linked immunosorbent assay (ELISA).Results: The most common manifestations by history were arthritis in 61% (N=38), photosensitivity rash in 53% (N=33), LN in 44% (N=27), and oral/nasal ulcer in 31% (N=19) SLE patients. AutoAbs (anti-DNA, anti-SSA, and anti-Sm), IFNɣ, and IL-17, but not IL-10, were significantly elevated in SLE patients compared to healthy controls. There were elevated plasma levels of anti-DNA (p = 0.0101) and anti-Sm (p = 0.0499) in patients with a history of LN compared to patients without LN. In contrast, plasma levels of anti-Sm were decreased in patients who had a history of acute mucocutaneous manifestations, including photosensitivity rash and/or malar rash (p = 0.0152). Among the three cytokines that were analyzed, IL-10 was significantly elevated in patients with a history of LN compared to patients without LN (p = 0.0216). IL-17 was positively correlated with anti-SSA (p = 0.0130) and was significantly higher in patients with discoid rash (p = 0.0238) and history of class V LN (p = 0.0055). IFNɣ was positively correlated with anti-DNA (p = 0.0355) and anti-SSA (p = 0.0402). Conclusion: This cross-sectional study supports the role of different T-helper cell cytokines that may be associated with the development of different autoAbs in influencing the diversity of SLE clinical manifestations. The results suggests that elevated IFNɣ and IL-17 are more generalized features in SLE patients. In contrast, higher levels of IL-10 were observed in patients with a history of LN. This provide insights into the pathogenic mechanisms of LN that can help guide future diagnosis and therapies.

To determine the extent to which the gut microbiome influences systemic autoimmunity in a mouse model of lupus.We generated germ-free (GF) lupus-prone BXD2 mice, which under normal conditions develop spontaneous germinal centers (GCs) and high titers of serum autoantibodies. GF status was confirmed by gut bacterial culture. The autoimmune phenotypes of 6- and 12-month-old gnotobiotic GF BXD2 mice and specific pathogen-free (SPF) BXD2 mice were compared. Serum levels of autoantibodies were measured by enzyme-linked immunosorbent assay. Histologic sections of the mouse kidney and joints were evaluated. Flow cytometry was used to analyze GCs and age-associated B cells. CD4+ T cells were analyzed for PD-1+ICOS+ activated T cells, T follicular regulatory (Tfr) cells (Foxp3+CD25+ PD-1+CXCR5+), and PD-1+ICOS+ T cells expressing interleukin-17A (IL-17A) or interferon-γ (IFNγ) after stimulation with phorbol myristate acetate (PMA)/ionomycin.In 6-month-old mice, GF status did not affect splenomegaly, GC B cells, age-associated B cells, or serum autoantibody levels, except for IgG antihistone. GF BXD2 mice exhibited a significantly higher percentage of Tfr cells compared to their SPF counterparts (P0.05). At 12 months of age, however, GF BXD2 mice had significantly diminished IgG autoantibody levels and a lower percentage of GC B cells and age-associated B cells (P0.05). Following stimulation with PMA/ionomycin, PD-1+ICOS+ CD4+ T cells expressed significantly lower IL-17A, but not IFNγ, levels in GF BXD2 mice compared to SPF BXD2 mice (P0.01). SPF BXD2 mice and GF BXD2 mice developed equivalent renal and joint disease with no significant differences in severity.Our results suggest a model in which genetics plays a dominant role in determining the initial development of autoimmunity. In contrast, gut microbiomes may regulate the persistence of certain aspects of systemic autoimmunity.

Background In systemic lupus erythematosus (SLE), detection of interferon-β (IFNβ) in B cells was found to be most prominent in patients with high anti-Smith (Sm) and renal disease, but a mechanistic connection was not clear. The objective of the present study is to determine the association of IFNβ in peripheral blood naïve B cells with the histopathological features of lupus nephritis (LN). Methods The percentage of IFNβ+ cells in IgD+CD27− naïve CD19+ B cells (B cell IFNβ) among peripheral blood mononuclear cells (PBMCs) from 80 SLE patients were analyzed using flow cytometry. Serological and clinical data were collected. The correlations of B cell IFNβ with LN classification and with histopathological findings (light, electron, and immunofluorescence [IF] microscopic analyses for deposition of IgM, IgG, IgA, C1q, and C3) were determined in 23 available biopsy specimens. Results B cell IFNβ is positively associated with anti-Sm (p = 0.001), anti-DNA (p = 0.013), and LN (p < 0.001) but was negatively associated with oral/nasal ulcer (p = 0.003) and photosensitivity (p = 0.045). B cell IFNβ positively correlated with immune complex (IC) deposit in the glomerular basement membrane (GBM) (p = 0.002) but not in the mesangial (p = 0.107) or tubular region (p = 0.313). Patients with high B cell IFNβ had statistically increased development of the proliferative LN (Classes III, IV and/or V), compared to patients with low B cell IFNβ (p p = 0.023), chronic glomerular lesions indicated by segmental sclerosis (p = 0.033), and a membranous pattern of renal damage indicated by spike/holes (p = 0.015). Conclusion B cell IFNβ correlates with history of severe LN, glomerular basement membrane (GBM) IC deposition, and anatomical features of both active and chronic glomerular lesions.

Background The risk of tuberculosis is increased in solid organ transplantation. Rates remain high in developed and developing countries. We developed protocols to better identify transplant recipients at risk of tuberculosis and initiate interventions to prevent tuberculosis. Objectives Report tuberculosis incidence in solid-organ transplant recipients and the results of expanded isoniazid prophylaxis in deceased-donor renal transplantation. Design Retrospective cohort study, comparing two time periods. Setting Large transplantation center in a WHO-medium endemicity country for tuberculosis. Methods In a cohort of all solid-organ transplant recipients performed between 2003 and 2012, tuberculosis-free transplantation follow-up is used for incidence calculation. Rates of tuberculosis in renal transplant recipients are compared before and after implementation of expanded isoniazid prophylaxis. Main outcome measure(s) Active tuberculosis post-transplantation. Results Of 1966 solid-organ transplant recipients (kidney: 1391, liver: 426, heart: 114, lung: 35), 20 recipients (1.02%) developed tuberculosis. Twelve cases (60%) developed tuberculosis within one year of transplantation. The incidence was 248 cases per 100 000 transplant-years. The proportion of transplant recipients (incidence of tuberculosis per 100 000 transplant-years) for specific organs were kidney 0.58% (127), liver 1.88% (594), heart: 1.75% (570), and lung 5.71% (4750). In the survival analysis, lung transplant recipients had significantly higher rates of tuberculosis compared to recipients of kidneys from living donors (P=.0001) with a rate ratio of 45.3 (95% CI: 7-313). Mortality was 5% among tuberculosis patients. After implementing expanded isoniazid prophylaxis among deceased-donor kidney recipients, no tuberculosis occurred in 177 recipients, compared to 3 out of 155 (2%) recipients before implementation. Conclusions Rates of tuberculosis among our solid transplant recipients are decreasing. Universal iso-niazid prophylaxis in transplant recipients could reduce transplant-associated tuberculosis in endemic areas. Limitations Donor data on tuberculosis exposure and prevention and tuberculosis prevention efforts before referral to our center are not available for all patients.