β2-microglobulin (β2-m), a 11.8 kDa protein, pairs non-covalently with the α3 domain of the major histocompatibility class (MHC) I α-chain and is essential for the conformation of the MHC class I ...protein complex. Shed β2-m is measurable in circulation, and various disorders are accompanied by increases in β2-m levels, including several viral infections. Therefore, we explored whether β2-m levels could also be elevated in Coronavirus disease 2019 (Covid-19) and whether they predict disease severity. Serum β2-m levels were measured in a cohort of 34 patients infected with SARS-CoV-2 on admission to a tertiary care hospital in Riyadh, Saudi Arabia, as well as in an approximately age-sex matched group of 34 uninfected controls. Mean β2-m level was 3.25±1.68 mg/l (reference range 0.8-2.2 mg/l) in patients (mean age 48.2±21.6) and 1.98±0.61 mg/l in controls (mean age 48.2±21.6). 17 patients (mean age 36.9± 18.0) with mean β2-m levels of 2.27±0.64 mg/l had mild disease by WHO severity categorization, 12 patients (mean age 53.3±18.1) with mean β2-m levels of 3.57±1.39 mg/l had moderate disease, and five patients (of whom 2 died; mean age 74.4±13.8) with mean β2-m levels of 5.85±1.85 mg/l had severe disease (P < = 0.001, by ANOVA test for linear trend). In multivariate ordinal regression β2-m levels were the only significant predictor of disease severity. Our findings suggest that higher β2-m levels could be an early indicator of severity of disease and predict outcome of Covid-19. As the main limitations of the study are a single-center study, sample size and ethnicity, these results need confirmation in larger cohorts outside the Arabian Peninsula in order to delineate the value of β2-m measurements. The role of β2-m in the etiology and pathogenesis of severe Covid-19 remains to be elucidated.
Pathophysiology of ANCA-associated Vasculitis Al-Hussain, Turki; Hussein, Maged H; Conca, Walter ...
Advances in anatomic pathology,
2017-July, Volume:
24, Issue:
4
Journal Article
Peer reviewed
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized as inflammation of small-sized to medium-sized blood vessels and encompasses several clinicopathologic entities ...including granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited ANCA-associated vasculitis. Over the past several decades, significant progress has been made in understanding the pathophysiology of ANCA-associated vasculitis. Although neutrophils contain a multitude of granular proteins, clinically significant autoantibodies are only recognized against myeloperoxidase and proteinase 3, both of which are present in the azurophilic granules. The propensity to develop these antibodies depends on a variety of predisposing factors such as microbial infection, genetic factors, environmental agents, and therapeutic drugs among others. These factors are usually associated with production of proinflammatory cytokines with capacity to prime the neutrophils. As a result a high proportion of neutrophils in circulation may be primed resulting in exposure of cytoplasmic proteins including myeloperoxidase and proteinase 3 on the surface of the neutrophils. Primed neutrophils are activated by interaction with ANCA in circulation. Activated neutrophils attach to and transmigrate through endothelium and accumulate within the vessel wall. These neutrophils degranulate and produce reactive oxygen radicals and ultimately die, causing tissue injury. Endothelial injury results in leakage of serum proteins and coagulation factors causing fibrinoid necrosis. B cells produce ANCAs, as well as neutrophil abnormalities and imbalances in different T-cell subtypes with excess of Th17, which perpetuate the inflammatory process.
The evolution of adaptive immunity in
resulted in the concurrent expression of classic heterotetrameric and unconventional homodimeric heavy chain-only IgG antibodies. Heavy chain-only IgG bears a ...single variable domain and lacks the constant heavy (C
) γ1 domain required for pairing with the light chain. It has not been reported whether this distinctive feature of IgG is also observed in the IgA isotype.
Gene-specific primers were used to generate an IgA heavy chain cDNA library derived from RNA extracted from the dromedary's third eyelid where isolated lymphoid follicles and plasma cells abound at inductive and effector sites, respectively.
Majority of the cDNA clones revealed hallmarks of heavy chain-only antibodies,
camelid-specific amino acid substitutions in framework region 1 and 2, broad length distribution of complementarity determining region 3, and the absence of the C
α1 domain. In a few clones, however, the cDNA of the canonical IgA heavy chain was amplified which included the C
α1 domain, analogous to C
γ1 domain in IgG1 subclass. Moreover, we noticed a short, proline-rich hinge, and, at the N-terminal end of the C
α3 domain, a unique, camelid-specific pentapeptide of undetermined function, designated as the inter-α region. Immunoblots using rabbit anti-camel IgA antibodies raised against C
α2 and C
α3 domains as well as the inter-α region revealed the expression of a ~52 kDa and a ~60 kDa IgA species, corresponding to unconventional and canonical IgA heavy chain, respectively, in the third eyelid,
, small and large intestine. In contrast, the leporine anti-C
α1 antibody detected canonical, but not unconventional IgA heavy chain, in all the examined tissues, milk, and serum, in addition to another hitherto unexplored species of ~45 kDa in milk and serum. Immunohistology using anti-C
α domain antibodies confirmed the expression of both variants of IgA heavy chains in plasma cells in the third eyelid's lacrimal gland,
, tracheal and intestinal
.
We found that in the dromedary, the IgA isotype has expanded the immunoglobulin repertoire by co-expressing unconventional and canonical IgA heavy chains, comparable to the IgG class, thus underscoring the crucial role of heavy chain-only antibodies not only in circulation but also at the mucosal frontiers.
A wide spectrum of interstitial lung disease (ID) is common and is a well-established manifestation of idiopathic inflammatory myopathies. Yet, till now, the pathogenetic mechanisms are still poorly ...understood, classification is evolving and prognosis is variable. A refractory and rapidly aggressive form of interstitial lung disease (RPILD) associated with dermatomyositis (DM) with minimal muscle weakness and normal creatine kinase (termed clinically amyopathic DM) is increasingly being recognized, with more incidence in Asians. However, we are not aware of reports of the Arab region. Herein, we present a 38-year-old male with this condition that ended with a fatal outcome despite aggressive therapy, with a review of recent literature.
Growing evidence indicates a link between persistent infections and the development of autoimmune diseases. For instance, the inability to control
infection due to defective toll-like receptor ...(TLR)/myeloid differentiation primary response 88 (MyD88) signaling has linked the development of persistent infections to a breakdown in B cell tolerance. However, the extent of immune dysregulation in the absence of TLR-MyD88 signaling remains poorly characterized. Here, we show that MyD88
mice are unable to eliminate attenuated
serovar Typhimurium, even when challenged with a low-dose inoculum (200 CFUs/mouse), developing a persistent and progressive infection when compared to wild-type (MyD88
) animals. The splenic niche of MyD88
mice revealed increased counts of activated, Sca-1-positive, myeloid subpopulations highly expressing BAFF during persistent
infection. Likewise, the T cell compartment of
-infected MyD88
mice showed increased levels of CD4
and CD8
T cells expressing Sca-1 and CD25 and producing elevated amounts of IL-4, IL-10, and IL-21 in response to CD3/CD28 stimulation. This was associated with increased Tfh cell differentiation and the presence of CD4
T cells co-expressing IFN-γ/IL-4 and IFN-γ/IL-10. Noteworthy, infected MyD88
mice had enhanced serum titers of both anti-
antibodies as well as autoantibodies directed against double-stranded DNA, thyroglobulin, and IgG rheumatoid factor, positive nuclear staining with HEp-2 cells, and immune complex deposition in the kidneys of MyD88
mice infected with live but not heat-killed
. Infection with other microorganisms (
, or
) was unable to trigger the autoimmune phenomenon. Our findings suggest that dysregulation of the immune response in the absence of MyD88 is pathogen-dependent and highlight potentially important genotype-environmental factor correlations.
We report a 57-year-old man with acute thrombocytopenia, leucopenia, and multiorgan dysfunction. Patient was from North Korea and was temporarily working in Dubai, United Arab Emirates, when he fell ...ill in March 2009. At the same time and unknown to us, many patients with similar clinical manifestations were admitted to hospitals in China. The Chinese cases—identified between March and July 2009—were recently reported to have been infected with a tick-born strain of bunyavirus, a new disease. The virus infection was documented in patients from central China and the region that shares the border with North Korea. The clinical manifestations, the time of disease onset, and geographical link of the patient with the region in which the disease is endemic suggest that the patient had SFTS bunyavirus infection.
Significant immunological obstacles are to be negotiated before xenotransplantation becomes a clinical reality. An initial rejection of transplanted vascularized xenograft is attributed to ...Galα1,3Galβ1,4GlcNAc-R (Galα1,3-Gal)-dependent and -independent mechanisms. Hitherto, no receptor molecule has been identified that could account for Galα1,3-Gal-independent rejection. In this study, we identify the tetraspanin CD82 as a receptor molecule for the Galα1,3-Gal-independent mechanism. We demonstrate that, in contrast to human undifferentiated myeloid cell lines, differentiated cell lines are capable of recognizing xenogeneic porcine aortic endothelial cells in a calcium-dependent manner. Transcriptome-wide analysis to identify the differentially expressed transcripts in these cells revealed that the most likely candidate of the Galα1,3-Gal-independent recognition moiety is the tetraspanin CD82. Abs to CD82 inhibited the calcium response and the subsequent activation invoked by xenogeneic encounter. Our data identify CD82 on innate immune cells as a major "xenogenicity sensor" and open new avenues of intervention to making xenotransplantation a clinical reality.
The data set presented here is associated with the article “Intracellular calcium and NF-kB regulate hypoxia-induced leptin, VEGF, IL-6 and adiponectin secretion in human adipocytes” (Al-Anazi et ...al., 2018). Data illustrate hypoxia-induced VEGF and leptin expression in human adipocytes treated with the calcium chelator BAPTA-AM (1 µM). It also shows NF-κB p65 induced expression by hypoxia. Preadipocytes were differentiated for 14 days and then subjected to 0.5–1.5% oxygen in the presence and absence of BAPTA-AM or the NF-κB inhibitor SN50 for 48 h prior to RNA isolation and PCR analysis.
To clarify mechanisms responsible for the self-limiting and nonerosive features of autoinflammatory joint disease in familial Mediterranean fever (FMF), we performed a study on synovial tissue ...obtained surgically from an acutely inflamed hip joint from a boy feared to have septic arthritis but later found to be homozygous for mutation M694I in pyrin/marenostrin. We defined by immunohistology the infiltrating cells and examined the in situ expression of plausible protagonists in synovitis of FMF: myeloperoxidase, lysozyme, galectin 1, galectin 3, p65 (RelA)/nuclear factor κB, inducible nitric-oxide synthase, cyclooxygenase 2, and cleaved caspase 3. Neutrophils deficient in myeloperoxidase and lysozyme, macrophages, and mast cells outnumbered T and B lymphocytes as well as plasma cells. Among cells of adaptive immunity, B lymphocytes were predominant. Galectin 1 was detected in numerous cells of the innate immune system throughout the synovial tissue, whereas expression of galectin 3 was less abundant and scattered. p65 (RelA)/nuclear factor κB and inducible nitric-oxide synthase were both upregulated in most of the infiltrating cells. Cyclooxygenase 2 expression was low, and cleaved caspase 3 was undetectable. We conclude that the exquisitely inflammatory yet nondestructive character of FMF arthritis could correlate with the presence of nonpathogenic neutrophils lacking effector molecules and the widespread expression of anti-inflammatory galectin 1 in regulatory cells of the innate immune system. Intrinsic apoptosis seemed irrelevant for confining synovial autoinflammation, but regulation through pyroptosis or the adaptive immune system remains possible.
beta.sub.2 -microglobulin (beta.sub.2 -m), a 11.8 kDa protein, pairs non-covalently with the alpha3 domain of the major histocompatibility class (MHC) I alpha-chain and is essential for the ...conformation of the MHC class I protein complex. Shed beta.sub.2 -m is measurable in circulation, and various disorders are accompanied by increases in beta.sub.2 -m levels, including several viral infections. Therefore, we explored whether beta.sub.2 -m levels could also be elevated in Coronavirus disease 2019 (Covid-19) and whether they predict disease severity. Serum beta.sub.2 -m levels were measured in a cohort of 34 patients infected with SARS-CoV-2 on admission to a tertiary care hospital in Riyadh, Saudi Arabia, as well as in an approximately age-sex matched group of 34 uninfected controls. Mean beta.sub.2 -m level was 3.25±1.68 mg/l (reference range 0.8-2.2 mg/l) in patients (mean age 48.2±21.6) and 1.98±0.61 mg/l in controls (mean age 48.2±21.6). 17 patients (mean age 36.9± 18.0) with mean beta.sub.2 -m levels of 2.27±0.64 mg/l had mild disease by WHO severity categorization, 12 patients (mean age 53.3±18.1) with mean beta.sub.2 -m levels of 3.57±1.39 mg/l had moderate disease, and five patients (of whom 2 died; mean age 74.4±13.8) with mean beta.sub.2 -m levels of 5.85±1.85 mg/l had severe disease (P < = 0.001, by ANOVA test for linear trend). In multivariate ordinal regression beta.sub.2 -m levels were the only significant predictor of disease severity. Our findings suggest that higher beta.sub.2 -m levels could be an early indicator of severity of disease and predict outcome of Covid-19. As the main limitations of the study are a single-center study, sample size and ethnicity, these results need confirmation in larger cohorts outside the Arabian Peninsula in order to delineate the value of beta.sub.2 -m measurements. The role of beta.sub.2 -m in the etiology and pathogenesis of severe Covid-19 remains to be elucidated.
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