Objective
IgG4‐related disease (IgG4‐RD) is an immune‐mediated fibroinflammatory condition that can affect nearly any organ. Prior studies have focused on individual cases of IgG4‐RD or small case ...series. This study was undertaken to report detailed clinical and laboratory findings in a larger group of patients with IgG4‐RD whose diagnosis was established by strict clinicopathologic correlation.
Methods
The baseline features of 125 patients with biopsy‐proven IgG4‐RD were reviewed. The diagnosis was confirmed by pathologists’ review, based on consensus diagnostic criteria and correlation with clinicopathologic features. Disease activity and damage were assessed using the IgG4‐RD Responder Index (RI). Flow cytometry was used to assess levels of circulating plasmablasts.
Results
Of the 125 patients, 107 had active disease and 86 were not receiving treatment for IgG4‐RD. Only 51% of the patients with active disease had elevated serum IgG4 concentrations. However, patients with active disease and elevated serum IgG4 concentrations were older, had a higher IgG4‐RD RI score, a greater number of organs involved, lower complement levels, higher absolute eosinophil counts, and higher IgE levels compared to those with active disease but normal serum IgG4 concentrations (P < 0.01 for all comparisons). The correlation between IgG4+ plasmablast levels and the IgG4‐RD RI of disease activity (Spearman's ρ = 0.45, P = 0.003) was stronger than the correlation between total plasmablast levels and the IgG4‐RD RI. Seventy‐six (61%) of the patients were male, but no significant differences according to sex were observed with regard to disease severity, organ involvement, or serum IgG4 concentrations. Treatment with glucocorticoids failed to produce sustained remission in 77% of patients.
Conclusion
Nearly 50% of this patient cohort with biopsy‐proven, clinically active IgG4‐RD had normal serum IgG4 concentrations. Elevations in the serum IgG4 concentration appeared to identify a subset of patients with a more severe disease phenotype. In addition, the levels of IgG4+ plasmablasts correlated well with the extent of disease activity.
Sialic acids and autoimmune disease Mahajan, Vinay S.; Pillai, Shiv
Immunological reviews,
January 2016, Volume:
269, Issue:
1
Journal Article
Peer reviewed
Open access
Summary
An important underlying mechanism that contributes to autoimmunity is the loss of inhibitory signaling in the immune system. Sialic acid‐recognizing Ig superfamily lectins or Siglecs are a ...family of cell surface proteins largely expressed in hematopoietic cells. The majority of Siglecs are inhibitory receptors expressed in immune cells that bind to sialic acid‐containing ligands and recruit SH2‐domain‐containing tyrosine phosphatases to their cytoplasmic tails. They deliver inhibitory signals that can contribute to the constraining of immune cells, and thus protect the host from autoimmunity. The inhibitory functions of CD22/Siglec‐2 and Siglec‐G and their contributions to tolerance and autoimmunity, primarily in the B lymphocyte context, are considered in some detail in this review. The relevance to autoimmunity and unregulated inflammation of modified sialic acids, enzymes that modify sialic acid, and other sialic acid‐binding proteins are also reviewed.
Background IgG4 -related disease (IgG4 -RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and ...accumulation of IgG4 -expressing plasma cells at disease sites. Objective The role of B cells and IgG4 antibodies in IgG4 -RD pathogenesis is not well defined. We evaluated patients with IgG4 -RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disease pathogenesis. Methods B-cell populations from the peripheral blood of 84 patients with active IgG4 -RD were analyzed by using flow cytometry. The repertoire of B-cell populations was analyzed in a subset of patients by using next-generation sequencing. Fourteen of these patients were longitudinally followed for 9 to 15 months after rituximab therapy. Results Numbers of CD19+ CD27+ CD20− CD38hi plasmablasts, which are largely IgG4+ , are increased in patients with active IgG4 -RD. These expanded plasmablasts are oligoclonal and exhibit extensive somatic hypermutation, and their numbers decrease after rituximab-mediated B-cell depletion therapy; this loss correlates with disease remission. A subset of patients relapse after rituximab therapy, and circulating plasmablasts that re-emerge in these subjects are clonally distinct and exhibit enhanced somatic hypermutation. Cloning and expression of immunoglobulin heavy and light chain genes from expanded plasmablasts at the peak of disease reveals that disease-associated IgG4 antibodies are self-reactive. Conclusions Clonally expanded CD19+ CD27+ CD20− CD38hi plasmablasts are a hallmark of active IgG4 -RD. Enhanced somatic mutation in activated B cells and plasmablasts and emergence of distinct plasmablast clones on relapse indicate that the disease pathogenesis is linked to de novo recruitment of naive B cells into T cell–dependent responses by CD4+ T cells, likely driving a self-reactive disease process.
We examined the utility of circulating total and IgG4+ plasmablasts as biomarkers of diagnosis and disease activity in IgG4-related disease (IgG4-RD).
We evaluated patients with active, untreated, ...biopsy-proven IgG4-RD affecting various organs. Flow cytometry was used to measure total plasmablast and IgG4+ plasmablast counts by gating peripheral blood for CD19lowCD38+CD20-CD27+ cells and CD19lowCD38+CD20-CD27+IgG4+ cells. Serum IgG4 concentrations were measured by nephelometry. We compared 37 IgG4-RD patients to 35 controls, including healthy individuals (n=14) and patients with other inflammatory diseases before treatment (n=21).
The IgG4-RD patients' mean age was 59, and 68% were male. Fourteen patients (38%) had three or more organs involved. The IgG4-RD patients had substantially elevated total plasmablast counts (median 4698/mL, range 610-79524/mL) compared to both untreated disease controls (median 592/mL, range 19-4294/mL; p < 0.001) and healthy controls (median 94/mL, range 1-653/mL; p < 0.001). Thirteen IgG4-RD patients (36%) had normal serum IgG4 concentrations (mean 60 mg/dL, range 5-123 mg/dL, normal <135 mg/dL). However, the median plasmablast count was not significantly lower in that subset with normal serum IgG4 concentrations (3784/mL) compared to those with elevated serum IgG4 (5155/mL) (p = 0.242). Among the 12 rituximab (RTX)-treated patients, the median plasmablast level during disease flare was 6356/mL (range 1123-41589/mL), declining to 1419/mL (range 386/mL-4150/mL) during remission (p < 0.01).
Circulating plasmablasts are elevated in active IgG4-RD, even in patients with normal serum IgG4 concentrations. Plasmablast counts are a potentially useful biomarker for diagnosis, assessing response to treatment, and determining the appropriate time for re-treatment.
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ and is now being recognized with increasing frequency. IgG4-RD is characterized by ...a lymphoplasmacytic infiltrate composed of IgG4(+) plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate eosinophilia. The diagnosis of IgG4-RD unifies many eponymous fibroinflammatory conditions that had previously been thought to be confined to single organs. IgG4-RD lesions are infiltrated by T helper cells, which likely cause progressive fibrosis and organ damage. IgG4 antibodies are generally regarded as noninflammatory. Although autoreactive IgG4 antibodies are observed in IgG4-RD, there is no evidence that they are directly pathogenic. Rituximab-induced B cell depletion in IgG4-RD leads to rapid clinical and histological improvement accompanied by swift declines in serum IgG4 concentrations. Although IgG autoantibodies against various exocrine gland antigens have been described in IgG4-RD, whether they are members of the IgG4 subclass is unknown. The contribution of autoantibodies to IgG4-RD remains unclear.
IgG4-related disease (IgG4-RD) is a relapsing-remitting condition responsible for fibroinflammatory lesions that can lead to organ damage and life-threatening complications at nearly any anatomical ...site. The duration of remission following treatment varies and predictors of relapse are unclear. The objectives of this study were to review our experience with rituximab as remission induction in IgG4-RD, to clarify the duration of efficacy and to identify predictors of flare following treatment.
In this retrospective cohort study, all patients were treated with two doses of rituximab (1 g) separated by 15 days. Clinical, radiographic and laboratory data pertaining to rituximab response and disease relapse were collected from the electronic medical record. Kaplan-Meier curves were constructed to estimate the time to disease relapse. Log-rank analyses were performed to compare times to relapse among subgroups. Potential relapse predictors were evaluated with Cox regression analysis.
Fifty-seven of 60 patients (95%) had clinical responses to rituximab. Forty-one patients (68%) were treated without glucocorticoids. Twenty-one patients (37%) experienced relapses following treatment at a median time from the first infusion of 244 days. Baseline concentrations of serum IgG4, IgE and circulating eosinophils predicted subsequent relapses, with hazard ratios of 6.2 (95% CI: 1.2, 32.0), 8.2 (95% CI: 1.4, 50.0) and 7.9 (95% CI: 1.8, 34.7), respectively. The higher the baseline values, the greater the risk of relapse and the shorter the time to relapse. Only 10% of the patients had elevations of all three major risk factors, underscoring the importance of measuring all three at baseline.
Baseline elevations in serum IgG4, IgE and blood eosinophil concentrations all predict IgG4-RD relapses independently.
Background IgG4 -related disease (IgG4 -RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4+ T cells constitute the ...major inflammatory cell population in IgG4 -RD lesions. Objective We used an unbiased approach to characterize CD4+ T-cell subsets in patients with IgG4 -RD based on their clonal expansion and ability to infiltrate affected tissue sites. Methods We used flow cytometry to identify CD4+ effector/memory T cells in a cohort of 101 patients with IgG4 -RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor β chain gene was performed on CD4+ SLAMF7+ cytotoxic T lymphocytes (CTLs) and CD4+ GATA3+ TH 2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined by using quantitative multicolor imaging. Results CD4+ effector/memory T cells with a cytolytic phenotype were expanded in patients with IgG4 -RD. Next-generation sequencing revealed prominent clonal expansions of these CD4+ CTLs but not CD4+ GATA3+ memory TH 2 cells in patients with IgG4 -RD. The dominant T cells infiltrating a range of inflamed IgG4 -RD tissue sites were clonally expanded CD4+ CTLs that expressed SLAMF7, granzyme A, IL-1β, and TGF-β1. Clinical remission induced by rituximab-mediated B-cell depletion was associated with a reduction in numbers of disease-associated CD4+ CTLs. Conclusions IgG4 -RD is prominently linked to clonally expanded IL-1β– and TGF-β1–secreting CD4+ CTLs in both peripheral blood and inflammatory tissue lesions. These active, terminally differentiated, cytokine-secreting effector CD4+ T cells are now linked to a human disease characterized by chronic inflammation and fibrosis.
Microbial adhesion and contamination on shared surfaces can lead to life-threatening infections with serious impacts on public health, economy, and clinical practices. The traditional use of chemical ...disinfectants for sanitization of surfaces, however, comes with its share of health risks, such as hazardous effects on the eyes, skin, and respiratory tract, carcinogenicity, as well as environmental toxicity. To address this, we have developed a nonleaching quaternary small molecule (QSM)-based sprayable coating which can be fabricated on a wide range of surfaces such as nylon, polyethylene, surgical mask, paper, acrylate, and rubber in a one-step, photocuring technique. This contact-active coating killed pathogenic bacteria and fungi including drug-resistant strains of Staphylococcus aureus and Candida albicans within 15–30 min of contact. QSM coatings withstood multiple washes, highlighting their durability. Interestingly, the coated surfaces exhibited rapid killing of pathogens, leading to the prevention of their transmission upon contact. The coating showed membrane disruption of bacterial cells in fluorescence and electron microscopic investigations. Along with bacteria and fungi, QSM-coated surfaces also showed the complete killing of high loads of influenza (H1N1) and SARS-CoV-2 viruses within 30 min of exposure. To our knowledge, this is the first report of a coating for multipurpose materials applied in high-touch public places, hospital equipment, and clinical consumables, rapidly killing drug-resistant bacteria, fungi, influenza virus, and SARS-CoV-2.
Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem ...thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific “disease-related” B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.
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•Germinal centers are lost in lymph nodes and spleens in acute COVID-19•Bcl-6+ GC B cells and Bcl-6+ T follicular helper cells are markedly diminished•Abundant TH1 cells and aberrant TNF-α production are seen in COVID-19 lymph nodes•SARS-CoV-2-specific activated B cells accumulate in the blood of patients
Shiv Pillai and colleagues show that in acute COVID-19, there is a striking loss of germinal centers in lymph nodes and spleens and depletion of Bcl-6+ B cells but preservation of AID+ B cells. A specific block in germinal center type Bcl-6+ T follicular helper cell differentiation may explain the loss of germinal centers and the accumulation of non-germinal-center-derived activated B cells. These data suggest an underlying basis for the lower quality and lack of durability of humoral immune responses observed during natural infection with SARS-CoV-2 and have significant implications for expectations of herd immunity.
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