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Abstract Introduction Russell body inflammation of the digestive tract (RBIDT) is a rare chronic inflammation of the digestive tract mucosa that commonly presents as Russell body gastritis (RBG). This disease is usually associated with Helicobacter pylori (HP) infection. However, it can also occur in individuals without HP infection and with specific immune profiles, as seen in HIV and hepatitis C infections. The aetiology and pathogenesis of this disease remain controversial. Given the rarity of the disease and the diversity of the immunophenotypes, there is a high probability of misdiagnosis. Case presentation A male patient with RBG and HP infection was included in this study. The case of RBG with an unusual morphology of Mott cells that mimics stamped ring cells.Endoscopy performed during the follow-up revealed regression of the lesion 1 week after anti-HP treatment. Conclusions A case of RBG with a high likelihood of misdiagnosis of signet ring cell carcinoma (SRC) has been reported in this study along with a review of the relevant literature and an overview of RBIDT.

In pediatric patients who undergo heart transplantation, severe immune‐mediated bowel disease has been reported. Management is complex, and there are little data discussing the use of basiliximab for immune‐mediated bowel disease. This case report discusses a pediatric patient who developed immune‐mediated bowel disease following heart transplantation and was successfully managed with basiliximab. [ABSTRACT FROM AUTHOR]

Blockade of the secretion of immunoglobulins leads to their accumulation in plasma cells, resulting in condensed immunoglobulins in the rough endoplasmic reticulum of plasma cells, termed Russell bodies. They are sometimes found in lymphoplasmacellular inflammation of the intestinal mucosa and in lymphoid cell malignancies, but only very rarely in skin diseases. Here, we report an 86-year-old female who presented with a lesion with the prominent accumulation of Russell bodies underlying pseudocarcinomatous hyperplasia with fungal infection in the face. Immunohistochemical staining showed the cells containing Russell bodies to be positive for CD138 and the Russell bodies to be positive for immunoglobulin κ and λ light chains. The present case suggests that when inflammatory cell infitration with abundant round intracellular eosinophilic materials is observed in the dermis, the dermal accumulation of Russell bodies should be considered in cases with reactive pseudocarcinomatous hyperplasia with fungal infection. [ABSTRACT FROM AUTHOR]

Introduction: Russell body inflammation of the digestive tract (RBIDT) is a rare chronic inflammation of the digestive tract mucosa that commonly presents as Russell body gastritis (RBG). This disease is usually associated with Helicobacter pylori (HP) infection. However, it can also occur in individuals without HP infection and with specific immune profiles, as seen in HIV and hepatitis C infections. The aetiology and pathogenesis of this disease remain controversial. Given the rarity of the disease and the diversity of the immunophenotypes, there is a high probability of misdiagnosis. Case presentation: A male patient with RBG and HP infection was included in this study. The case of RBG with an unusual morphology of Mott cells that mimics stamped ring cells.Endoscopy performed during the follow-up revealed regression of the lesion 1 week after anti-HP treatment. Conclusions: A case of RBG with a high likelihood of misdiagnosis of signet ring cell carcinoma (SRC) has been reported in this study along with a review of the relevant literature and an overview of RBIDT. [ABSTRACT FROM AUTHOR]

Warthin tumor with ulceration of the surrounding skin is extremely rare, making it difficult to differentiate from parotid cancer in the clinical setting. We report a 65-year-old man with a Warthin tumor in the right parotid gland that had ulceration of the overlying skin. The patient presented with right upper neck mass 2 years ago. Ultrasound and fine needle aspiration were done, and Warthin tumor was suspected. One year later, the mass was enlarged with ulceration of the skin. Superficial parotidectomy with fusiform excision of the skin was performed, and histopathological diagnosis revealed a Warthin tumor with inflammatory change. We proposed that this unique manifestation may have been induced by fine needle aspiration, enlargement of the tumor, and ischemic changes secondary to pulmonary arteriovenous malformations. [ABSTRACT FROM AUTHOR]

Hematoxylin and eosin staining is widely used for routine histopathological analysis under light microscopic examination to determine alterations of tissue architecture and cellular components in animal studies. Aside from hematoxylin/eosin staining, periodic acid Schiff (PAS) staining is used to detect polysaccharides and carbohydrate-rich macromolecules, and is essential in immunological fields for evaluation of glomerular lesions of kidneys in autoimmune animals. Since erythrocytes are not stained by PAS, this stain is also helpful for identifying changes in immune cells in the red pulp of the spleen, which is filled with erythrocytes. This article describes a protocol to detect Mott cells, bizarre plasma cells containing immunoglobulin inclusion bodies (Russell bodies) in the cytoplasm. The protocol can be used for formalin-fixed, paraffin-embedded tissue sections, frozen tissue sections, tissue-touch preparations, blood films, and cytocentrifuged cell smears. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Detection of Mott cells by PAS staining in formalin-fixed, paraffin-embedded tissue sections Basic Protocol 2: Detection of Mott cells by PAS staining in frozen tissue sections, touch preparations, blood films, and cytocentrifuged cell smears., (© 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC.)

Russell bodies are accumulation of immunoglobulin in plasma cells forming intracytoplasmic inclusions. Russell body colitis is rare with only 3 cases described in the English literature up to date. We report a 78-year-old male with cirrhosis showing prominent cecal infiltration of Russell body containing plasma cells. Plasma cells showed no nuclear atypia or mitoses, and no evidence of light chain restriction. In this article, we report a fourth case of Russell body colitis, that is unique in being localized to the cecum in contrast to the other 3, 1 of which was in an inflammatory polyp in the sigmoid colon, 1 in a rectal tubulovillous adenoma and 1 as part of diffuse gastrointestinal disease. This is therefore the first report of localized Russell body typhlitis, occurring in a cirrhotic patient in whom an adjacent erosion was likely nonsteroidal anti-inflammatory drug-associated, a combination that may have facilitated the formation of Russell bodies. [ABSTRACT FROM AUTHOR]

Abstract An abnormal clonal plasma cell proliferation with Russell bodies is rare in chronic inflammatory reactions in adult patients. We describe the first case of light chain restricted Russell body accumulation within germinal centers of lymphoid follicles of the tonsil in a child. This should not be confused with a neoplastic process.

A rare gastric mucosal lesion characterized by Russell body-containing plasma cell infiltration is termed as Russell body gastritis. This lesion is highly suggested to be correlated with Helicobacter pylori-induced chronic gastritis, and often misdiagnosed as mucosa-associated lymphoid tissue lymphoma, signet ring cell carcinoma, plasmacytoma, or xanthoma. However, Russell body gastritis is easily discriminated by its polyclonal immunoreaction to immunoglobulin light chains contrary to monoclonal immunoreaction of neoplastic disease. We report here a case of Russell body gastritis associated with H. pylori infection, which disappeared after H. pylori eradication.

Russell body gastritis is considered as a rare, benign, incidental finding characterized by dense accumulation of plasma cells containing Russell bodies in the lamina propria. In this study, clinical and histopathological features of 12 cases of Russell body gastritis/duodenitis were presented. Clinical data, histopathological findings including Helicobacter pylori infection, Sydney system classification, Russell body density and immunohistochemical findings were evaluated in 11 gastric and 1 duodenal mucosal biopsy from 11 patients. Six cases were male, 5 were female and the mean age was 72 (44–87). The most common site was antrum (10/12), one case was located in cardia and one in heterotopic gastric mucosa of duodenal bulb. H. pylori was detected in half of the cases. One of the cases was accompanied by gastric tubular adenoma, one by gastric well-differentiated adenocarcinoma and one by plasma cell neoplasm. In all cases, globules were positive with PAS stain. Russell body gastritis must be kept in mind while reporting endoscopic biopsies because this entity may be misdiagnosed as signet ring carcinoma and may be associated with neoplasms. Absence of nuclear atypia, mucin stains, cytokeratins, plasma cell and hematolymphoid antigen markers are useful in differential diagnosis. Associated H. pylori infection, as well as rarely carcinomas, adenomas and plasma cell neoplasms, may be observed. • Russell body gastritis is an inflammatory process characterized by a dense accumulation of Mott cells in the lamina propria. • This is the largest case series reported about Russell body gastritis/duodenitis in English literature. • It is mostly appearing in the antrum, has a male predominance and often associated with Helicobacter pylori. • Its differential diagnosis includes carcinomas, plasma cell neoplasms, lymphomas and accompanying neoplasms was also reported. [ABSTRACT FROM AUTHOR]

A 64-year-old man was found to have a nodule in his right lung. He also complained of nausea and abdominal pain during the clinical course. Esophagogastroduodenoscopy revealed a duodenal ulcer associated with severe stenosis and a suspicion of malignancy. However, three subsequent biopsies revealed no evidence of malignancy. The fourth biopsy showed scattered large eosinophilic cells with an eccentric nucleus, leading to a diagnosis of Russell body duodenitis (RBD). RBD is an extremely rare disease, and little is known about its etiology and clinical course. The pathogenesis of RBD is discussed based on our experience with this case.

An abnormal clonal plasma cell proliferation with Russell bodies is rare in chronic inflammatory reactions in adult patients. We describe the first case of light chain restricted Russell body accumulation within germinal centers of lymphoid follicles of the tonsil in a child. This should not be confused with a neoplastic process. [ABSTRACT FROM AUTHOR]

Russell body gastritis (RBG), which can be associated with Helicobacter pylori (HP) infection, is a recently acknowledged lesion characterized by the presence of eosinophilic intracytoplasmic inclusions in plasmacytes. Herein the authors discuss the morphological aspects of a case of RBG in a male patient with clinical complaint of epigastric pain. Upper endoscopy revealed areas of erythema/edema in the antrum. As far as microscopy is concerned, a mononuclear inflammatory infiltrate was identified on the lamina propria, with plasma cells containing Schiff acid periodic (PAS) positive eosinophilic intracytoplasmic globules, which showed positive immunostaining for CD79a, CD138, and kappa/lambda light chains. HP was identified by Giemsa stains.A gastrite com corpúsculos de Russell (RBG), que pode estar associada à infecção por Helicobacter pylori (HP), é uma lesão recentemente reconhecida que se caracteriza pela presença de inclusões eosinofílicas intracitoplasmáticas em plasmócitos. Neste relato, os autores discutem os aspectos morfológicos de um caso de RBG em um paciente masculino com queixa clínica de dor epigástrica. A endoscopia revelou áreas de eritema/edema no antro. À microscopia, um infiltrado inflamatório mononuclear foi identificado na lâmina própria, com plasmócitos exibindo glóbulos eosinofílicos intracitoplasmáticos ácido periódico de Schiff (PAS) positivos, que apresentaram imunoexpressão positiva para CD79a,CD138 e cadeias leves kappa/lambda. HP foi identificado na coloração de Giemsa.

Russell body gastritis is a rare form of chronic gastritis. It is characterized by the invasion of lamina propria by plasma cells that included eosinophilic cytoplasmic inclusion. In the literature, most of the cases are associated with Helicobacter pylori. Russell body gastritis and Helicobacter pylori infection are generally seen together incidentally. We report here two cases of Russell body gastritis with Helicobacter pylori infection in a 51-yr-old woman and a 39-yr-old man from Eskisehir, Turkey. [ABSTRACT FROM AUTHOR]

Objective To examine the expression of unfolded protein response (UPR) genes, a set of genes that are activated to assist in protein trafficking and cellular homeostasis when endoplasmic reticulum (ER) stress occurs, in inflamed and uninflamed periodontal tissues, with or without Russell bodies (RB). RB are a histologically apparent extension of the ER that represents an accumulation of abnormal proteins that cannot be secreted or degraded and may serve as a marker of ER stress. Design Periodontal tissue specimens were collected and categorised histologically based on the presence of inflammation and the quantity of RB. The differential regulation of 84 UPR-related genes was examined by qRT 2 -PCR. Results UPR genes related to the inositol-requiring ER-to-nucleus signal kinase (IRE)-1 pathway, molecular chaperones and ER quality control were up-regulated in RB + tissues compared with RB − tissues, irrespective of inflammation. Inflamed periodontal tissues showed a marked down-regulation of heat shock protein (HSP)-70 family members. Conclusion The presence of RB in inflamed periodontal tissues correlated with the expression of a unique set of ER stress-related genes and therefore may serve as a marker of UPR response in periodontal inflammation. Inflamed periodontal tissues showed a marked down-regulation of UPR genes, in particular HSP70. This may be contributory to disease progression in periodontal disease. [ABSTRACT FROM AUTHOR]

A 12-year-old, male castrated Domestic Shorthair cat was presented to Animal Medical Center of Gifu Univeristy with anorexia and vomiting. Physical examination revealed an enlarged left tonsil and right mandibular lymph node (approximately 2-3× the normal size), and a submucosal mass on the right side of the epiglottis (1.5 × 2.0 cm). On computed tomography images, an enlarged left tonsil, and enlarged right mandibular, right pharyngeal, and left and right cervical lymph nodes were observed. Cytologic examination of smears of tonsil and lymph nodes revealed numerous medium- to large-sized neoplastic lymphoid cells, approximately half of which contained one or several light-blue homogenous globoid cytoplasmic inclusions (5-10 μm), which stained magenta with periodic acid-Schiff ( PAS) stain. Histopathologic examination of the left tonsil revealed diffuse proliferation of medium- to large-sized neoplastic lymphoid cells effacing the original lymphoid architecture. Half of the cells contained one or several eosinophilic globoid cytoplasmic inclusions, which stained magenta with PAS and showed positive immunohistochemical reactions for immunoglobulin M (IgM) and λ light chain. Neoplastic lymphoid cells were also CD20+, Pax5+, and MUM1+, and CD3−. Thus, the neoplastic lymphoid cells expressed a B-cell immunophenotype, and the globoid cytoplasmic inclusions represented an aberrant IgM λ light chain accumulation, similar to Russell bodies. B-cell lymphoma with Mott cell differentiation was diagnosed based on cytologic, histopathologic, and immunohistochemical features. This is the first report of B-cell lymphoma with Mott cell differentiation in a cat. [ABSTRACT FROM AUTHOR]

Russell bodies represent a cellular response to overstimulation of plasma cells, leading to the accumulation of abundant, nondegradable, condensed immunoglobulin in dilated rough endoplasmic reticulum cisternae. Russell body gastritis was first described 1998 by Tazawa and Tsutsumi. Since then only 39 cases involving the gastrointestinal tract have been reported in English literature, which include Russell body gastritis, duodenitis, and esophagitis. We report a case of a 44-year-old female with a history of diabetes mellitus, status post kidney and pancreas transplant who presented with multiple episodes of watery diarrhea associated with abdominal pain, nausea, and vomiting. Upper gastroendoscopic examination showed diffuse mild erythema in the gastric body and a clean-based duodenal ulcer. Lower gastroendoscopic examination was normal. Examination of multiple biopsies from duodenal, gastric, terminal ileum, and colonic mucosae revealed numerous plasma cells with abundant eosinophilic granular cytoplasm (Russell bodies) and eccentric nuclei, highlighted by PAS stain and CD 138 plasma cell marker. Helicobacter pylori stains were performed on gastric biopsies and were negative for organisms. To date, there are no cases described in English literature with multifocal Russell body infiltrates in gastrointestinal tract in a single patient including ileum and/or colon. This makes our case the first to be reported with these unique findings; thus, the spectrum of Russell body–associated chronic inflammation of the gastrointestinal tract would be more suitably referred to as “Russell body gastroenterocolitis.” [ABSTRACT FROM AUTHOR]

Russell body gastroenteritis has been reported as a reactive inflammatory process in most cases and many of the reports were from the upper gastrointestinal tract, especially the stomach, which may be associated with Helicobacter pylori infection and rarely associated with gastric carcinoma. Russell body containing Mott cells have been rarely seen in Barrett's esophagus and duodenum, and only 2 cases have been reported in colon, including a transplant patient with diarrhea and a rectal tubulovillous adenoma. In this article, we report another localized form of Russell body containing Mott cells in colon as an inflammatory polyp without adenomatous change. [ABSTRACT FROM AUTHOR]

Abstract: Crystalline bodies (CBs) can develop in the endoplasmic reticulum (ER) of antibody-producing cells. Although this phenotype is often reported in association with plasma cell dyscrasias and other hematological disorders, the details of CB biogenesis and CB's roles in pathophysiology remain poorly understood. Using an imaging-based screening method, we identified a secretion-competent human IgG2/λ clone that develops spindle-shaped intracellular crystals in transiently-transfected HEK293 cells upon Brefeldin A treatment. When stably overexpressed from CHO cells, the IgG2/λ clone spontaneously produced spindle-shaped CBs in the ER. Some CBs were released to the extracellular space while remaining enclosed by the membranes of secretory pathway origin. Structural modeling on the variable-region did not uncover prominent surface characteristics such as charge clusters. In contrast, alterations to the constant domain-encoded properties revealed their modulatory roles in CB-inducing propensities and CB morphology. For example, deletion of the entire Fc domain changed the morphology of CBs into thin filaments. Elimination of an N-linked glycan by a N297A mutation promoted Russell body biogenesis accompanied by marked reduction in IgG secretion. Isotype class switching from the original IgG2 to IgG1 and IgG4 changed the crystal morphology from spindle-shaped to long needle and acicular shaped, respectively. The IgG3 version, in contrast, suppressed the CB formation. Either the HC or LC alone or the Fc-domain alone did not trigger CB biogenesis. An IgG's in vivo crystal morphology and crystallization propensity can thus be modulated by the properties genetically and biochemically encoded in the HC constant region. [Copyright &y& Elsevier]

The article deals with a study which described a case of signet ring cell lymphoma in a 3-year-old mixed-breed sow. Topics discussed include the macroscopical examination of the sow which revealed enlargement of superficial, thoracic and abdominal lymph nodes and multiple tumor masses in the liver, the characteristics of follicular lymphoma in humans, and the cytological variants of signet ring cell lymphoma.

A 7-year-old male castrated Jack Russell Terrier was presented to the oncology service at the University of California- Davis Veterinary Medical Teaching Hospital for evaluation of suspected lymphoma. The dog had several enlarged lymph nodes and moderate lymphocytosis. Aspirates of an enlarged inguinal lymph node contained a bimorphic population of large immature lymphocytes and smaller cells with plasmacytoid features. Both cell types often contained a single large cytoplasmic inclusion that varied from clear to pale pink to sky blue. Cytologic changes were interpreted as most consistent with lymphoid neoplasia. Based on the predominantly mature cell morphology and some morphologic heterogeneity, the peripheral lymphocytosis was interpreted as most likely reactive in nature. However, the immunophenotype of the cells ( CD20+, CD21+, CD79a+, MUM-1+, and MHCII+) and clonality assays showed that tissue and blood lymphocytes were neoplastic B cells with clonal identity despite their different morphologic appearances. The cytoplasmic inclusions were positive with periodic acid-Schiff and were immunoreactive for IgM and IgG. By transmission electron microscopy, inclusions consisted of aberrant rough endoplasmic reticulum; a few small Russell bodies were also noted. A final diagnosis of high-grade B-cell lymphoma with plasmacytoid differentiation, atypical cytoplasmic inclusions, and secondary leukemia was made. Chemotherapy was initiated, but the dog was euthanized due to severe and uncontrolled seizures 9 months after the initial diagnosis. This case extends the morphologic repertoire of canine plasmacytoid neoplasms and emphasizes their continuum with multicentric lymphoma. This case also demonstrates the need for advanced diagnostic techniques in establishing blood involvement in lymphoma in some instances. [ABSTRACT FROM AUTHOR]

Abstract: Russell bodies are intracellular aggregates of immunoglobulins. Although the mechanism of Russell body biogenesis has been extensively studied by using truncated mutant heavy chains, the importance of the variable domain sequences in this process and in immunoglobulin biosynthesis remains largely unknown. Using a panel of structurally and functionally normal human immunoglobulin Gs, we show that individual immunoglobulin G clones possess distinctive Russell body inducing propensities that can surface differently under normal and abnormal cellular conditions. Russell body inducing predisposition unique to each immunoglobulin G clone was corroborated by the intrinsic physicochemical properties encoded in the heavy chain variable domain/light chain variable domain sequence combinations that define each immunoglobulin G clone. While the sequence based intrinsic factors predispose certain immunoglobulin G clones to be more prone to induce Russell bodies, extrinsic factors such as stressful cell culture conditions also play roles in unmasking Russell body propensity from immunoglobulin G clones that are normally refractory to developing Russell bodies. By taking advantage of heterologous expression systems, we dissected the roles of individual subunit chains in Russell body formation and examined the effect of non-cognate subunit chain pair co-expression on Russell body forming propensity. The results suggest that the properties embedded in the variable domain of individual light chain clones and their compatibility with the partnering heavy chain variable domain sequences underscore the efficiency of immunoglobulin G biosynthesis, the threshold for Russell body induction, and the level of immunoglobulin G secretion. We propose that an interplay between the unique properties encoded in variable domain sequences and the state of protein homeostasis determines whether an immunoglobulin G expressing cell will develop the Russell body phenotype in a dynamic cellular setting. [Copyright &y& Elsevier]

An unusual and rare gastric mucosal lesion histologically consisting of Russell bodies and plasma cell infiltration and termed as Russell body gastritis is presented. In the literature there are only ten such case reports and of these, seven including this present case were associated with Helicobacter pylori infection. The high rate of Helicobacter pylori infections in cases of Russell body gastritis suggests that the correlation is not merely coincidental. All data in the literature related to Russell body gastritis were scanned, and histopathologic findings and the clinical characteristics associated with such lesions were discussed. [ABSTRACT FROM AUTHOR]

Antithrombin (AT) is a major plasma protease inhibitor with three intramolecular disulfide bonds and a deficiency of it is associated with venous thrombosis. Recently, we prepared CHO cells overexpressing a novel mutant, AT(C95R), with a disulfide bond removed, and revealed that this mutant remained for a long time in the endoplasmic reticulum (ER) without being degraded and also accumulated in newly formed membrane structures that resembled Russell bodies (RB) [Tanaka, Y. et al. (2002) J. Biol. Chem. 277, 51058–51067]. In this study, we replaced each of the individual cysteine residues of AT with an arginine and also two paired cysteine residues with arginines. We stably expressed these mutant ATs in CHO cells, and examined the roles of each cysteine residue or disulfide bond in the accumulation of mutant ATs and the formation of RB-like structures. In pulse-chase experiments, the secretion of mutant ATs with single mutations decreased ~1/5–1/50 times compared to that of the wild type AT. All of the mutant ATs were retained in the ER and were also found to accumulate in the RB-like structures. On the other hand, the fates of mutant ATs with double mutations fell into two categories. Secretion of mutant AT(C8R,C128R) decreased only ~1/2 times and no RB-like structures appeared. Mutants AT(C21R,C95R) and AT(C247R,C430R) exhibited similar secretion kinetics to the mutant ATs with the single mutations and were found in RB-like structures. On a sucrose gradient, all of the mutant ATs that induced RB-like structures migrated as oligomeric structures, whereas wild type AT and AT(C8R,C128R) migrated as monomers. Further, to clarify the morphological pathway through which RB-like structures are formed, we prepared CHO cells in which the expression of AT(C95R) was controlled by the Tet-On system. During expression of AT(C95R), RB-like structures formed through expansion of the ER. These results suggest that the correct folding with each disulfide bond is essential for the secretion of AT and oligomerization of mutant ATs in the ER is involved in the formation of RB-like structures. [ABSTRACT FROM PUBLISHER]

Our case was a 50-year-old female who presented at the outpatients department with dyspeptic symptoms. Microscopical examination of mucosal samples from the corpus and antrum showed widespread Helicobacter pylori within the superficial mucus network, marked neutrophilic cryptitis, widespread reactive/regenerative crypt hyperplasia, intestinal metaplasia, and increased lymphoplasmocytoid cells and plasma cells full of immunoglobulin in the lamina propria. Immunohistochemical staining showed the plasma cells to be CD3 (-), CD20 (-), CD79a (+), CD45 (+), Kappa (+), and Lambda (+). It is possible for a dense accumulation of Russell bodies to be observed on a background of H. pylori taking into account that Russell bodies contain immunoglobulin aggregates and side products of immunoglobulin synthesis. However, there are only a limited number of articles evaluating this aspect. e present a case to contribute to the few articles on Helicobacter gastritis characterized by an inflammatory reaction rich in ''Russell'' bodies. [ABSTRACT FROM AUTHOR]

Full-length immunoglobulins (Igs) are widely considered difficult to crystallize because of their large size, N-linked glycosylation, and flexible hinge region. However, numerous cases of intracellular Ig crystallization are reported in plasma cell dyscrasias. What makes some Ig clones more prone to crystallize during biosynthesis as well as the biochemical and cell biological requirements for this cryptic event are poorly understood. To investigate the underlying process of intracellular Ig crystallization we searched for model IgGs that can induce crystalline inclusions during recombinant overexpression. By testing various subunit combinations through mixing and matching of individual subunit chains derived from a panel of human IgG clones, we identified one secretion competent IgG2λ that induced needle-like crystalline inclusions in transfected HEK293 cells. Ig crystallization rarely occurred at steady-state cell growth conditions but was easily induced when ER-to-Golgi transport was pharmacologically blocked. Homology modeling revealed the presence of a prominent negatively-charged patch on the variable domain surface. The patch was composed of eight aspartic acids, of which five were in the heavy chain variable region and three were in the light chain. Crystallization occurred only when the two subunits were co-transfected and the intracellular crystals co-localized with ER resident proteins. Furthermore, subtype switching from IgG2 to IgG1 and stepwise neutralization of the acidic patch independently abrogated Ig crystallization events. The evidence supported that the formation of needle-like crystalline inclusions in the ER was underscored by multivalent intermolecular interactions between the acidic patch and undefined determinants present on the γ2 subunit constant region. [ABSTRACT FROM PUBLISHER]

Russell body gastritis refers to the accumulation of plasma cells containing Russell bodies within the lamina propria. This report describes the first case of monoclonal Russell body gastritis without the previously reported associations. [ABSTRACT FROM PUBLISHER]

Amino acid sequence differences in the variable region of immunoglobulin (Ig) cause wide variations in secretion outputs. To address how a primary sequence difference comes to modulate Ig secretion, we investigated the biosynthetic process of 2 human IgG2κ monoclonal antibodies (mAbs) that differ only by one amino acid in the light chain complementarity-determining region 1 while showing ∼20-fold variance in secretion titer. Although poorly secreted, the lower-secreting mAb of the 2 was by no means defective in terms of its folding stability, antigen binding, and in vitro biologic activity. However, upon overexpression in HEK293 cells, the low-secreting mAb revealed a high propensity to aggregate into enlarged globular structures called Russell bodies (RBs) in the endoplasmic reticulum. While Golgi morphology was affected by the formation of RBs, secretory pathway membrane traffic remained operational in those cells. Importantly, cellular protein synthesis was severely suppressed in RB-positive cells through the phosphorylation of eIF2α. PERK-dependent signaling was implicated in this event, given the upregulation and nuclear accumulation of downstream effectors such as ATF4 and CHOP. These findings illustrated that the underlining process of poor Ig secretion in RB-positive cells was due to downregulation of Ig synthesis instead of a disruption or blockade of secretory pathway trafficking. Therefore, RB formation signifies an end of active Ig production at the protein translation level. Consequently, depending on how soon and how severely an antibody-expressing cell develops the RB phenotype, the productive window of Ig secretion can vary widely among the cells expressing different mAbs.

A 64-year-old man was found to have a nodule in his right lung. He also complained of nausea and abdominal pain during the clinical course. Esophagogastroduodenoscopy revealed a duodenal ulcer associated with severe stenosis and a suspicion of malignancy. However, three subsequent biopsies revealed no evidence of malignancy. The fourth biopsy showed scattered large eosinophilic cells with an eccentric nucleus, leading to a diagnosis of Russell body duodenitis (RBD). RBD is an extremely rare disease, and little is known about its etiology and clinical course. The pathogenesis of RBD is discussed based on our experience with this case.

Normal and reactive plasma cells (PC) are easy to ascertain on human bone marrow films, due to their small mature-appearing nucleus and large cytoplasm, the latter usually deep blue after Giemsa staining. Cytoplasm is filled with long strands of rough endoplasmic reticulum and one large Golgi apparatus (paranuclear hof), demonstrating that PC are dedicated mainly to protein synthesis and excretion (immunoglobulin). Deregulation of the genome may induce clonal expansion of one PC that will lead to immunoglobulin overproduction and eventually to one among the so-called PC neoplasms. In multiple myeloma (MM), the number of PC is over 10% in most patients studied. Changes in the morphology of myeloma PC may be inconspicuous as compared to normal PC (30-50% patients). In other instances PC show one or several morphological changes. One is related to low amount of cytoplasm, defining lymphoplasmacytoid myeloma (10-15% patients). In other cases (40-50% patients), named immature myeloma cases, nuclear-cytoplasmic asynchrony is observed: presence of one nucleolus, finely dispersed chromatin and/or irregular nuclear contour contrast with a still large and blue (mature) cytoplasm. A peculiar morphological change, corresponding to the presence of very immature PC named plasmablasts, is observed in 10-15% cases. Several prognostic morphological classifications have been published, as mature myeloma is related to favorable outcome and immature myeloma, peculiarly plasmablastic myeloma, is related to dismal prognosis. However, such classifications are no longer included in current prognostic schemes. Changes related to the nucleus are very rare in monoclonal gammopathy of unknown significance (MGUS). In contrast, anomalies related to the cytoplasm of PC, including color (flaming cells), round inclusions (Mott cells, Russell bodies), Auer rod-like or crystalline inclusions, are reported in myeloma cases as well as in MGUS and at times in reactive disorders. They do not correspond to malignant changes of PC but are related to abnormal synthesis, trafficking, or excretion of the immunoglobulin that is stored in excess within the cytoplasm. Occurrence of crystalline inclusions within PC may be the first anomaly leading to the diagnosis of adult Fanconi syndrome. After a historical perspective, the authors report on the various morphological aspects of PC that may occur in multiple myeloma and related disorders, and discuss about their clinical and pathophysiological significance. Today, morphological identification and accurate determination of % PC within bone marrow remain ancillary criteria for the diagnosis of MM and help for the diagnosis of rare renal disorders., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The underlying reasons for why some mAb (monoclonal antibody) clones are much more inclined to induce a Russell body (RB) phenotype during immunoglobulin biosynthesis remain elusive. Although RBs are morphologically understood as enlarged globular aggregates of immunoglobulins deposited in the endoplasmic reticulum (ER), little is known about the properties of the RB-inducing mAb clones as secretory cargo and their physical behaviors in the extracellular space. To elucidate how RB-inducing propensities, secretion outputs, and the intrinsic physicochemical properties of individual mAb clones are interrelated, we used HEK293 cells to study the biosynthesis of 5 human IgG mAbs for which prominent solution behavior problems were known a priori. All 5 model mAbs with inherently high condensation propensities induced RB phenotypes both at steady state and under ER-to-Golgi transport block, and resulted in low secretion titer. By contrast, one reference mAb that readily crystallized at neutral pH in vitro produced rod-shaped crystalline bodies in the ER without inducing RBs. Another reference mAb without notable solution behavior issues did not induce RBs and was secreted abundantly. Intrinsic physicochemical properties of individual IgG clones thus directly affected the biosynthetic steps in the ER, and thereby produced distinctive cellular phenotypes and influenced IgG secretion output. The findings implicated that RB formation represents a phase separation event or a loss of colloidal stability in the secretory pathway organelles. The process of RB induction allows the cell to preemptively reduce the extracellular concentration of potentially pathogenic, highly aggregation-prone IgG clones by selectively storing them in the ER.

Russell bodies are globular and eosinophilic inclusion bodies in the cytoplasm of mature plasma cells. Plasma cells whose cytoplasm is filled with Russell bodies are designated as Mott cells. Russell body duodenitis (RBD) is a unique form of chronic duodenitis that is characterized by infiltration of numerous Mott cells. RBD is very rare; only two cases have been reported to date. In this paper, we report a case of RBD in a patient with retroperitoneal metastasis of ureteral cancer. A 77-year-old man was admitted to our hospital complaining of appetite loss, vomiting, and upper abdominal distension. He had undergone left nephroureterectomy for ureteral cancer 4 years earlier. Upper digestive tract endoscopy revealed edema, stenosis, and punctate redness of the mucosa of the duodenum, and a biopsy was performed. Histological analysis showed that numerous Mott cells had infiltrated the lamina propria mucosae, and the condition was diagnosed as RBD. A mass lesion in the retroperitoneum adjacent to the duodenum was detected by abdominal computed tomography, and was diagnosed as metastatic urothelial carcinoma by biopsy. It is possible that chemokines produced by tumor cells caused RBD in this case.

Russell body gastritis is an unusual form of chronic gastritis characterized by the permeation of lamina propria by numerous plasma cells with eosinophilic cytoplasmic inclusions. Very few cases have been reported in the literature; the majority of which have shown Helicobacter Pylori (H. pylori) infection, thus suggesting a correlation between plasma cell presence and antigenic stimulation by H. pylori. We present a case of Russell body gastritis in a 78-year-old woman who was undergoing esophagogastroduodenoscopy for epigastric pain. Gastric biopsy of the gastroesophageal junction showed the presence of cells with periodic acid-Schiff-positive hyaline pink bodies. Giemsa staining for H. pylori infection was negative, as well as immunohistochemical detection. The cells with eosinophilic inclusions stained positive for CD138, CD79a, and κ and lambda light chains, which confirmed plasma cell origin. In particular, κ and lambda light chains showed a polyclonal origin and the patient was negative for immunological dyscrasia. The histological observations were confirmed by ultrastructural examination. The cases reported in the literature associated with H. pylori infection have shown regression of plasma cells after eradication of H. pylori. Nothing is known about the progression of H. pylori-negative cases. The unusual morphological appearance of this type of chronic gastritis should not be misinterpreted during routine examination, and it should be distinguished from other common forms of chronic gastritis. It is mandatory to exclude neoplastic diseases such as gastric carcinoma, lymphoma and plasmocytoma by immunohistochemistry and electron microscopy, which can help with differential diagnosis. The long-term effects of plasma cells hyperactivation are still unknown, because cases of gastric tumor that originated in patients affected by Russell body gastritis have not been described in the literature. We are of the opinion that these patients should be scheduled for endoscopic surveillance.