Apolipoprotein CII Amyloidosis Associated With p.Lys41Thr Mutation.

Introduction: Apolipoprotein CII amyloidosis (AApoCII) is a rare form of amyloidosis. Here, we report a novel mutation associated with AApoCII amyloidosis in 5 patients and describe their clinical, renal biopsy, and mass spectrometry findings.

Methods: Five patients with renal AApoCII p.

C4 Glomerulopathy: A Disease Entity Associated With C4d Deposition.

Complement-mediated glomerulonephritis, which includes C3 glomerulopathy, is characterized by dominant staining of C3 with minimal or no immunoglobulin deposits on immunofluorescence studies. We describe a new entity of complement-mediated glomerulonephritis that is characterized by bright C4d staining but with no or minimal C3 or immunoglobulin deposits on immunofluorescence studies. We label this entity as C4 glomerulopathy.

Disappearance of immunoglobulins from persistent renal amyloid deposits following stem cell transplantation for heavy-and light-chain amyloidosis.

Background: Immunoglobulin (Ig)-related amyloidosis is the most common type of systemic amyloidosis in the developed countries and involves the kidney in most cases. Clinical remission can be achieved with chemotherapy and/or autologous stem cell transplantation (ASCT). Previous case reports have showed persistence of renal amyloid mass in light-chain amyloidosis (AL) even in the setting of hematologic and renal response.

Proteomic detection of immunoglobulin light chain variable region peptides from amyloidosis patient biopsies.

Immunoglobulin light chain (LC) amyloidosis (AL) is caused by deposition of clonal LCs produced by an underlying plasma cell neoplasm. The clonotypic LC sequences are unique to each patient, and they cannot be reliably detected by either immunoassays or standard proteomic workflows that target the constant regions of LCs. We addressed this issue by developing a novel sequence template-based workflow to detect LC variable (LCV) region peptides directly from AL amyloid deposits.

IgD heavy-chain deposition disease: detection by laser microdissection and mass spectrometry.

Monoclonal Ig deposition disease (MIDD) is a rare complication of monoclonal gammopathy characterized by deposition of monoclonal Ig light chains and/or heavy chains along the glomerular and tubular basement membranes. Here, we describe a unique case of IgD deposition disease. IgD deposition is difficult to diagnose, because routine immunofluorescence does not detect IgD.

Transforming growth factor beta 1 induces CXCL16 and leukemia inhibitory factor expression in osteoclasts to modulate migration of osteoblast progenitors.

The processes of bone resorption and bone formation are tightly coupled in young adults, which is crucial to maintenance of bone integrity. We have documented that osteoclasts secrete chemotactic agents to recruit osteoblast lineage cells, contributing to coupling. Bone formation subsequent to bone resorption becomes uncoupled with aging, resulting in significant bone loss.

TGF-β induces Wnt10b in osteoclasts from female mice to enhance coupling to osteoblasts.

In young adults, bone lost through osteoclast-mediated resorption is precisely replaced in both location and amount. Understanding how these two processes are coupled is crucial to advancing treatments for osteoporosis, a disease that progresses when the processes become uncoupled. We documented that osteoclasts secrete the mammalian integration 1 gene that is the homolog of Drosophila Wngless (Wnt) 10b, bone morphogenetic protein 6 (BMP6), and the chemokine sphingosin 1 phosphate (S1P) to promote mesenchymal cell mineralization in vitro.

Clonally related follicular lymphomas and Langerhans cell neoplasms: expanding the spectrum of transdifferentiation.

The traditional model of hematopoiesis is based on unidirectional maturation of hematopoietic precursors into lineage-committed cells. However, recent studies indicate that mature B lymphocytes may demonstrate significant lineage plasticity. We and others have reported transdifferentiation of follicular lymphomas (FLs) into clonally related histiocytic/dendritic cell neoplasms.

Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases.

Background And Objectives: The kidney is the organ most commonly involved in systemic amyloidosis. This study reports the largest clinicopathologic series of renal amyloidosis.

Design, Setting, Participants, & Measurements: This study provides characteristics of 474 renal amyloidosis cases evaluated at the Mayo Clinic Renal Pathology Laboratory from 2007 to 2011, including age, sex, serum creatinine, proteinuria, type of amyloid, and tissue distribution according to type.

Exploring the amyloid proteome in immunoglobulin-derived lymph node amyloidosis using laser microdissection/tandem mass spectrometry.

Amyloidosis affecting lymph nodes (LN) may occur in the setting of systemic amyloidosis or as an entity localized to the site of production (peritumoral). Why some LN amyloid remains peritumoral is unknown. We speculated that the composition of amyloid in these two presentations differs.

Sclerostin is expressed in osteoclasts from aged mice and reduces osteoclast-mediated stimulation of mineralization.

Osteoclast-mediated bone resorption precedes osteoblast-mediated bone formation through early adulthood, but formation fails to keep pace with resorption during aging. We previously identified several factors produced by osteoclasts that promote bone formation. In this study, we determined if osteoclast-produced factors contribute to the impaired bone formation with aging.

Sphingosine 1-phosphate (S1P) receptors 1 and 2 coordinately induce mesenchymal cell migration through S1P activation of complementary kinase pathways.

Normal bone turnover requires tight coupling of bone resorption and bone formation to preserve bone quantity and structure. With aging and during several pathological conditions, this coupling breaks down, leading to either net bone loss or excess bone formation. To preserve or restore normal bone metabolism, it is crucial to determine the mechanisms by which osteoclasts and osteoblast precursors interact and contribute to coupling.

Renal amyloidosis associated with a novel sequence variant of gelsolin.

We present a case of a 75-year-old woman who presented with progressive kidney failure. Kidney biopsy performed to determine the cause of kidney failure showed amyloidosis of undetermined type. Laser microdissection of the Congo Red-positive glomeruli followed by mass spectrometry studies showed a large number of spectra matching apolipoprotein E, serum amyloid P component, and gelsolin, consistent with a diagnosis of gelsolin-associated renal amyloidosis.

Role of a glutamate bridge spanning the dimeric interface of human manganese superoxide dismutase.

The function in the structure, stability, and catalysis of the interfaces between subunits in manganese superoxide dismutase (MnSOD) is currently under scrutiny. Glu162 in homotetrameric human MnSOD spans a dimeric interface and forms a hydrogen bond with His163 of an adjacent subunit which is a direct ligand of the manganese. We have examined the properties of two site-specific mutants of human MnSOD in which Glu162 is replaced with Asp (E162D) and Ala (E162A).

Structural mobility in human manganese superoxide dismutase.

Human manganese superoxide dismutase (MnSOD) is a homotetramer of 22 kDa subunits, a dimer of dimers containing dimeric and tetrameric interfaces. We have investigated conformational mobility at these interfaces by measuring amide hydrogen/deuterium (H/D) exchange kinetics and 19F NMR spectra, both being excellent methods for analyzing local environments. Human MnSOD was prepared in which all nine tyrosine residues in each subunit are replaced with 3-fluorotyrosine.

Crystal structure of nitrated human manganese superoxide dismutase: mechanism of inactivation.

A cellular consequence of the reaction of superoxide and nitric oxide is enhanced peroxynitrite levels. Reaction of peroxynitrite with manganese superoxide dismutase (MnSOD) causes nitration of the active-site residue Tyr34 and nearly complete inhibition of catalysis. We report the crystal structures at 2.

Exchange of (18)O in the reaction of peroxynitrite with CO(2).

We have observed an exchange of (18)O in the reactions of CO(2) with peroxynitrite using membrane-inlet mass spectrometry and HPLC negative electrospray ionization mass spectrometry. The exchange appeared on addition of peroxynitrite to a solution containing (18)O-labeled CO(2) in equilibrium with bicarbonate. It was observed as a temporarily enhanced rate of depletion of (18)O from CO(2), a rate that was greater than the rate of (18)O depletion caused by the hydration/dehydration cycle of CO(2).