The formation of deformation, annealing and growth twins in face-centered cubic materials is discussed. Slip precedes deformation twinning, and twins form from the interaction between primary and ...secondary slip dislocations having co-planar, but different, Burgers vectors. The influence of several metallurgical variables on twinning can only be rationalized in terms of the model. Annealing twins form due to growth accidents on differently inclined {111} facets present on a migrating grain boundary. Growth twins also form by growth accidents on the {111} planes.
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.
IgG4‐related disease (IgG4‐RD) is a fibroinflammatory disorder that can affect virtually every organ system. T‐helper type 2 responses have been presumed to be pathogenic in this disease, and a high ...proportion of patients with IgG4‐RD are reported to have longstanding allergies, peripheral blood eosinophilia, and serum IgE elevation. It has therefore been proposed that allergic mechanisms drive IgG4‐RD. However, no epidemiological assessment of atopy, peripheral blood eosinophilia, and serum IgE concentrations has ever been undertaken in patients with IgG4‐RD. In this study, we evaluated these parameters in a large cohort of patients with IgG4‐RD in whom a wide range of organs were affected by disease. Our results demonstrate that the majority of patients with IgG4‐RD are nonatopic. Nevertheless, a subset of nonatopic subjects exhibit peripheral blood eosinophilia and elevated IgE, suggesting that processes inherent to IgG4‐RD itself rather than atopy per se contribute to the eosinophilia and IgE elevation observed in the absence of atopy.
Sialic acids and autoimmune disease Mahajan, Vinay S.; Pillai, Shiv
Immunological reviews,
January 2016, Letnik:
269, Številka:
1
Journal Article
Recenzirano
Odprti dostop
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.
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.
Abstract
The central nervous system (CNS) is an immunological privileged sanctuary site-providing reservoir for HIV-1 virus. Current anti-HIV drugs, although effective in reducing plasma viral ...levels, cannot eradicate the virus completely from the body. The low permeability of anti-HIV drugs across the blood-brain barrier (BBB) leads to insufficient delivery. Therefore, developing a novel approaches enhancing the CNS delivery of anti-HIV drugs are required for the treatment of neuro-AIDS. The aim of this study was to develop intranasal nanoemulsion (NE) for enhanced bioavailability and CNS targeting of saquinavir mesylate (SQVM). SQVM is a protease inhibitor which is a poorly soluble drug widely used as antiretroviral drug, with oral bioavailability is about 4%. The spontaneous emulsification method was used to prepare drug-loaded o/w nanoemulsion, which was characterized by droplet size, zeta potential, pH, drug content. Moreover, ex-vivo permeation studies were performed using sheep nasal mucosa. The optimized NE showed a significant increase in drug permeation rate compared to the plain drug suspension (PDS). Cilia toxicity study on sheep nasal mucosa showed no significant adverse effect of SQVM-loaded NE. Results of in vivo biodistribution studies show higher drug concentration in brain after intranasal administration of NE than intravenous delivered PDS. The higher percentage of drug targeting efficiency (% DTE) and nose-to-brain drug direct transport percentage (% DTP) for optimized NE indicated effective CNS targeting of SQVM via intranasal route. Gamma scintigraphy imaging of the rat brain conclusively demonstrated transport of drug in the CNS at larger extent after intranasal administration as NE.
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.
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.
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