Circulating clonally related earlier cells are present in multiple myeloma (MM) and may be involved in the dissemination of this disease, its recurrence, and chemoresistance. The nature, stage of ...differentiation, and size of this cell population remain uncertain. Unlike other B-cell markers, CD22 membrane expression is limited to the late differentiation stages comprised between mature B cells (CD22+) and plasma cells (PC; CD22-) and may thus be useful in delimiting the maturational state of circulating early myeloma cells. Peripheral blood clone-related cells were detected by anti-idiotypic (Id) monoclonal antibodies and found to express CD22 (92% to 95%), monotypic light and heavy chain (100%), and CD38 (45%), whereas bone marrow PC were CD22-negative. CD22 expression was also documented on functional myeloma PC precursors, defined as peripheral blood cells capable of in vitro cytokine-driven monotypic PC differentiation, because up to approximately 70% inhibition of this process was obtained in 10 myeloma patients through the use of biospecific antibodies (BsAb) that deliver the plant toxin saporin to CD22+ cells. As further evidence of CD22 on circulating abnormal cells, it was found that in the only patient analyzed for DNA content, a portion of the peripheral blood CD22+ cells killed were hyperdiploid. Collectively, these findings indicate that most peripheral blood myeloma PC precursors are mature or later B cells presenting membrane CD22. The pattern of CD22 expression suggests the existence in MM of a differentiation process analogous to the normal antigenic response, in which CD22+ B cells migrate to the bone marrow and lose CD22 with PC differentiation. In addition, the sensitivity of myeloma PC precursors to the cytotoxic effects of the anti-CD22 BsAb and the possibility of interfering with their differentiation have potential therapeutic relevance.
We identified a novel missense mutation in the apolipoprotein A-I gene, T2069C Leu
174 → Ser, in a patient affected by familial systemic nonneuropathic amyloidosis. The amyloid deposits mostly ...affected the heart of the proband, who underwent transplantation for end-stage congestive heart failure. Amyloid fibrils of myocardial and periumbilical fat samples immunoreacted exclusively with anti-ApoA-I antibodies. Amyloid fibrils extracted from the heart were constituted, according to amino acid sequencing and mass spectrometry analysis, by an amino-terminal polypeptide ending at Val
93 of apolipoprotein A-I (apoA-I); no other significant fragments were detected. The mutation segregates with the disease; it was demonstrated in the proband and in an affected uncle and excluded in three healthy siblings. The plasma levels of high-density lipoprotein and apoA-I were significantly lower in the patient than in unaffected individuals. This represents the first case of familial apoA-I amyloidosis in which the mutation is outside the polypeptide fragment deposited as fibrils. Visualization of the mutation in the three-dimensional structure of lipid-free apoA-I, composed of four identical polypeptide chains, indicates that position 174 of one chain is located near position 93 of an adjacent chain and suggests that the amino acid replacement in position 174 is permissive for a proteolytic split at the C-terminal of Val
93.
Systemic reactive (AA) amyloidosis, leading to renal failure, is a severe complication of most hereditary periodic fever syndromes. The risk of developing this life‐threatening condition varies ...widely among these disorders, being higher for patients affected by familial Mediterranean fever and tumor necrosis factor receptor–associated periodic syndrome. In spite of an acute‐phase response during attacks, amyloidosis has never, to date, been described in patients affected with the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). This is the first report to describe the occurrence of renal AA amyloidosis causing severe nephrotic syndrome in a young Italian man affected with HIDS. The diagnosis of HIDS was established according to clinical, laboratory, and genetic criteria as required by the international Nijmegen HIDS registry. In this patient, 2 mutations in the mevalonate kinase gene were identified, one of which, the leucine‐to‐arginine substitution at codon 265, is novel.
The diagnosis of amyloidosis requires that amyloid deposits are demonstrated in patient’s tissues. Congo red staining is still the most commonly used method to detect amyloid deposits. Nevertheless, ...the results of Congo red stain may be ambiguous, especially if it is performed in centers with limited expertise in its execution and/or interpretation. Furthermore, Congo red stain does not provide any information concerning the nature of amyloidogenic protein. The characterization of amyloid proteins by light microscopic immunohistochemistry in paraffin-embedded samples frequently yields nonspecific results. Based on our experience at the Amyloid Center and Pathology Unit of IRCCS Policlinico San Matteo/University of Pavia, the ultrastructural examination of abdominal fat aspirate and other tissue biopsies is capable of confirming or ruling out a diagnosis of amyloidosis and can detect even very small deposits of amyloid fibrils. Moreover, immunoelectron microscopy can correctly characterize the amyloidogenic protein in all the commonest forms of amyloidosis, i.e., AL, AA, ATTR, Aβ2M, and AApoAI.
Amyloidotic cardiomyopathy is still a widely underdiagnosed condition that usually requires endomyocardial biopsy (EMB) for a definite diagnosis.
99m
Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (
...99m
Tc-DPD) has proven highly sensitive for detecting amyloidotic cardiomyopathy due to transthyretin-related amyloid deposition. Herein we report the first description of the
99m
Tc-DPD scintigraphy profile in a patient with suspected amyloidotic cardiomyopathy and a final EMB- and genetically-proven diagnosis of familial apolipoprotein AI amyloidosis due to Leu174Ser variant.
Abbreviations: AL: light-chain associated amyloidosis; ApoAI: apolipoprotein AI; ATTR: hereditary transthyretin-related amyloidosis; EMB: endomyocardial biopsy; HCM: hypertrophic cardiomyopathy; HR: heart retention; H/WB: heart/whole-body retention ratio; LV: left ventricular; SPECT: single-photon emission computed tomography; SSA: senile systemic amyloidosis;
99m
Tc-DPD:
99m
Tc-3,3-diphosphono-1,2-propanodicarboxylic acid; TDI: tissue Doppler imaging; TTR: transthyretin.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Obesity is a major health problem associated with systemic diseases whose pathogenesis has been linked to inflammation, but the underlying mechanisms are poorly understood. Leptin, an ...adipokine secreted by adipose tissue, is known to augment the antigen-dependent release of pro-inflammatory cytokines by T lymphocytes. Cytokine production is tightly regulated by cytoplasmic Ca2+ (Cac ) which is under the control of ion channels (Kv1.3, KCa3.1, calcium release activated Ca2+channel CRAC, formed by Orai1 and Stim1). We tested the hypothesis that ion channels contribute to the pro-inflammatory effects of leptin. CD3+ T cells isolated from healthy human donors were treated with 100-250 ng/ml leptin and ion channels’ gene expression was measured by RT-qPCR. Leptin induced a dose- and time-dependent increase in Orai1 expression up to 1.53 ± 0.21 (100 ng/ml) and 2.04 ± 0.40 folds (250 ng/ml, n=3) at 12 h. There was no significant difference in Stim1, Kv1.3 and KCa3.1 expression. CRAC channels are important for activation-mediated Ca2+ influx in T cells. Thus, we investigated whether Orai1 regulation by leptin affects Cac using a protocol that bypasses the T cell receptor and allows assessment of ion channel-dependent changes in Cac. Incubation with leptin-depleted serum reduced Ca2+ fluxes, while addition of 250 ng/ml of leptin to the leptin-free serum augmented Ca2+ fluxes. These findings suggest that leptin may promote hyperactivity of T cells via upregulation of ion channels.
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