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PubMed2002

The eye's view of antigen presentation.

A form of systemic tolerance is created when antigenic material is placed in the anterior chamber of the eye, an immune privileged site. Termed anterior chamber associated immune deviation (ACAID), this form of tolerance insures that the systemic immune response to eye-derived antigens is devoid of T cells that mediate delayed hypersensitivity and antibodies that fix complement. As a consequence, the eye is spared the disruptive blinding influence of immunogenic inflammation. ACAID arises when antigen is captured by intraocular antigen presenting cells, then carried to the marginal zone of the spleen where, in the presence of natural killer T cells and marginal zone B cells, a microenvironment is created that activates antigen-specific T cells to differentiate into regulatory cells that interfere with the induction of delayed hypersensitivity as well as its expression. Transforming growth factor beta-2 (TGFbeta-2), constitutively present in the aqueous humor of the eye, imposes distinctive properties on antigen presenting cells. Thrombospondin is an early activated gene following TGFbeta-2 treatment and as a consequence the eye-derived antigen presenting cells fail to secrete IL-12 or express CD40. The lack of these potent stimulators of Th1 cell differentiation is central to the induction of ACAID.

Animals↗
PubMed2005

Inhibitory oligodeoxynucleotides - therapeutic promise for systemic autoimmune diseases?

Recent studies have shed new light on a possible link between the innate activation of plasmocytoid dendritic cells and marginal zone B cells and the pathogenesis of systemic lupus erythematosus. Animal studies have identified that this response requires the Toll-like receptor 9 (TLR9). Engagement of the TLR9 by various ligands, including non-canonical CpG-motifs, can cause or aggravate pathogenic autoantibody production and cytokine secretion in lupus. Attempts to neutralize this activity either by blocking the acidification of the endosomal compartment with chloroquine and related compounds, or by preventing the interaction between the CpG-DNA sequences and TLR9 using inhibitory oligonucleotides could be a promising therapeutic option for lupus.

Animals↗
PubMed1991

Tissue distribution of restricted leukocyte common antigens. A comprehensive study with protein- and carbohydrate-specific CD45R antibodies.

A panel of monoclonal antibodies, specific for either protein or carbohydrate components of the leukocyte common antigen (LCA), were used to characterize the expression pattern of different variants of this antigen complex. Immunohistochemical and flow cytometric analysis was carried out on human lymphoid tissues from different anatomical compartments. We found that variations in terminal sialic acid or O-linked sugar moieties were associated with drastic differences in reactivity with some of the CD45R antibodies. For example, the carbohydrate determinants recognized by MT2 (CD45RA) and 2B11 (CD45) were not or were very weakly expressed on germinal center cells, whereas the carbohydrate determinant recognized by MT3 (CD45RB) was not expressed on the majority of mantle zone B cells. On the other hand, KiB3 (CD45RA) reacted with a protein determinant that is normally only exposed on mantle zone B cells but can be uncovered on marginal zone B cells and the CD45RA-positive T-cell subpopulation by enzymatic treatment. The findings suggest that differential biosynthesis and expression of the carbohydrate components of LCA are important mechanisms to generate additional LCA heterogeneity. Similar to the differential usage of the variable region, the exact carbohydrate composition is also linked to the stage of cell development. Heterogeneity in carbohydrate composition of the extracellular domain of LCA appears to enable interactions with different ligands, thereby holding the key to the regulation of LCA cytoplasmic tyrosine phosphatase activity.

Antibodies↗
PubMed1993

Comparative in vitro analysis of proliferation, Ig secretion, and Ig class switching by murine marginal zone and follicular B cells.

We have previously demonstrated that activation of murine B cells by dextran-conjugated anti-IgD antibodies may serve as a polyclonal, in vitro model system for studying immune responses to T cell-independent type 2 (TI-2) Ag, as exemplified by the bacterial polysaccharides. Because in vivo Ig responses to TI-2 Ag are mediated primarily by B cells resident in the splenic marginal zone, we wished to determine whether this reflected an intrinsic difference in the responsiveness of marginal zone B cells (MZB) compared with follicular B cells (FB) to this class of Ag. In this report we demonstrate that highly purified MZB, isolated by electronic cell sorting, exhibit a lower proliferative response in vitro in response to unconjugated anti-Ig antibody as well as to dextran- or Sepharose-conjugated anti-IgM or anti-IgD antibodies, whereas they proliferate equal to or better than FB when stimulated by other B cell mitogens including LPS, Salmonella typhimurium mitogen, or anti-CD3-activated CD4+ Th2 cell clone. Despite the different proliferative responses of MZB and FB induced by anti-Ig, Ag receptor cross-linkage stimulates comparable increases in intracellular free calcium concentrations in both of these B cell populations. Furthermore, MZB secrete Ig and undergo Ig isotype switching to a comparable degree, relative to FB, in response to both T cell-dependent and T cell-independent stimuli. This suggests that the compartmentalization of TI-2 responses to the splenic marginal zone rather than the follicular zone reflects something other than the intrinsic responsiveness of the B cells from these two sites.

Animals↗
PubMed2005

Cytogenetic analysis delineates a spectrum of chromosomal changes that can distinguish non-MALT marginal zone B-cell lymphomas among mature B-cell entities: a description of 103 cases.

The purpose of this study was to document the frequency and distribution of karyotypic changes present at diagnosis in 103 non-MALT marginal zone cell lymphoma (MZL) patients. This cytogenetic analysis of a large cohort extends previous observations and allows the identification of new cytogenetic features. Abnormalities identified in more than 15% of patients included +3/+3q (37%), 7q deletions (31%), +18/+18q (28%), 6q deletions (19%), +12/+12q (15%) and 8p deletions (15%). Trisomy 3/3q, 7q deletions, +18 and +12 were seen in different combinations in more than 30% of patients in comparison to 2% in lymphocytic lymphomas/chronic lymphocytic leukemias, 1% in mantle cell lymphomas and 7% in follicular lymphomas. The marked propensity of these abnormalities to be recurrently associated with the same tumoral clone of individual karyotypes allowed the delineation of a cytogenetic profile that may help to distinguish non-MALT MZL among other mature B-cell neoplasms. If +3/3q, +12/+12q, and 6q, 7q and 8p deletions were significantly associated with clinical prognostic factors previously reported to influence survival and time to progression, patients displaying these abnormalities did not experience a significantly shorter time to progression.

Adult↗
PubMed2006

Cutaneous marginal zone B-cell lymphoma in the setting of fluoxetine therapy: a hypothesis regarding pathogenesis based on in vitro suppression of T-cell-proliferative response.

INTRODUCTION: Drugs may be an important cause of atypical lymphocytic infiltration. Oftentimes, these infiltrates are in the context of pseudolymphomata. We report a patient who developed lymphocytoma cutis temporally associated with initiation of fluoxetine therapy that later went on to develop cutaneous marginal zone B-cell lymphoma. The response of peripheral blood lymphocytes to fluoxetine and other drugs was examined in an attempt to ascertain the potential role for drugs in the propagation of these infiltrates. MATERIALS AND METHODS: Routine light microscopic analysis and phenotypic studies were performed on tissue obtained from a skin biopsy. Lymphocyte mitogenic studies were carried out using increasing concentrations of fluoxetine, bupropion, and two anticonvulsants. RESULTS: An initial biopsy was consistent with lymphocytoma cutis. The patient stopped fluoxetine associated with lesional regression. The lesions recurred despite being off fluoxetine; a repeat biopsy was compatible with marginal zone lymphoma. Lymphocyte proliferation assays revealed a suppressive effect on T-lymphocyte proliferation at physiologic concentrations. Other tested drugs did not have a similar suppressive effect. CONCLUSIONS: Fluoxetine may be associated with pseudolymphomata and marginal zone lymphoma. The inhibitory effects on T-lymphocyte function and more specifically T-suppressor function may lead to excessive antigen-driven B-cell proliferation.

Anticonvulsants↗
PubMed2006

Schnitzler syndrome associated with systemic marginal zone B-cell lymphoma.

Schnitzler syndrome is a rare condition defined by chronic urticaria and monoclonal IgM gammopathy. Malignant evolution to Waldenström disease (WD) has been reported in several cases. We report a 49-year-old man who developed a marginal zone B-cell lymphoma (MZL) 3 years after the beginning of Schnitzler syndrome. This is the first report of MZL in association with Schnitzler syndrome. IgM gammopathy is a clue for the diagnosis of Schnitzler syndrome. This condition needs to be closely monitored; it can precede the onset of an authentic lymphoproliferative disorder including WD and rarely MZL.

Cell Transformation, Neoplastic↗
PubMedDate not supplied

Marginal zone B-cell lymphoma of the parotid gland associated with epithelioid granulomas. Report of a case with fine needle aspiration.

BACKGROUND: Although granulomas can occur in association with malignant neoplasms, including some subtypes of lymphoma, they have been described rarely in marginal zone B-cell lymphoma (MZCL). To our knowledge, the cytologic features of this association have not been documented. We present the cytologic findings with fine needle aspiration cytology (FNAC) of an unusual case of MZCL with concomitant granulomas. CASE: An 82-year-old male presented with a mass in the left parotid gland. The lesion was evaluated by FNAC. The smears showed syncytial aggregates of epithelioid histiocytes intermixed with small and medium-sized lymphoid cells containing round to irregular-shaped nuclei and small nucleoli. Some of these cells had a greater amount of cytoplasm and frequently had a plasmacytoid appearance. The lesion was removed, and histopathologic study showed MZCL associated with extensive nonnecrotizing granulomas. CONCLUSION: Granulomatous reactions can be seen in rare cases of MZCL. However, the cytologic features of the lymphoid infiltrate can suggest the possibility of MZCL in the clinical setting of FNAC performed from an extranodal location, such as the parotid gland.

Aged↗
PubMed2006

Primary cutaneous B-cell lymphoma (marginal zone) with prominent T-cell component and aberrant dual (T and B) genotype; diagnostic usefulness of laser-capture microdissection.

The presence of a dominant B- or T-cell clone is an important diagnostic criterion for distinguishing cutaneous lymphomas from lymphoid reactive infiltrates. Rarely, a combined B- and T-cell rearrangement can be detected from a single sample. In such instances, genotypic analysis does not permit differentiation of the coexistence of a T- and B-cell lymphoma from a single clone harbouring a monoclonal rearrangement for both immunoglobulin heavy chain and T-cell receptor genes. We herein report a case of a skin tumour consistent with a dense cutaneous lymphoid infiltrate showing a double prominent B- and T-cell component. A dual B- and T-cell clonality was detected by polymerase chain reaction from whole-tissue DNA sample. Genotypic analysis with DNA, obtained after laser-assisted microdissection from the B-cell population, again showed both T- and B-cell monoclonal rearrangements. Conversely, the microdissected T-cell population did not reveal a clonal pattern. The diagnosis of cutaneous B-cell lymphoma with a dual B- and T-cell genotype was established. This description illustrates the diagnostic usefulness of laser-capture microdissection in cutaneous lymphomas presenting dual genotype.

Aged↗
PubMed2005

Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes.

Pathogenic autoimmunity requires a combination of inherited and acquired factors. In as much as hormones influence the sexual dimorphism of the immune system, it is possible that they can initiate or accelerate an autoimmune process, and contribute to gender-biased autoimmune disorders. Not only natural hormones, but also endocrine disruptors, such as environmental estrogens, may act in conjunction with other factors to override immune tolerance to self-antigens. In lupus, murine and human studies demonstrate that female sex hormones are implicated in disease pathogenesis. In the B cell compartment, both prolactin and estrogen are immunomodulators that affect maturation, selection and antibody secretion. Their impact may be based on their capacity to allow autoreactive B cells to escape the normal mechanisms of tolerance and to accumulate in sufficient numbers to cause clinically apparent disease. Both hormones lead to the survival and activation of autoreactive B cells, but they skew B cell maturation towards different directions, with prolactin inducing T cell-dependent autoreactive follicular B cells and estrogen eliciting T cell-independent autoreactive marginal zone B cells. Differential modulation of the cytokine milieu by hormones may also affect the development and activation of specific mature B cell subsets. This novel insight suggests that targeted manipulation of these pathways may represent a promising avenue in the treatment of lupus and other gender-biased autoimmune diseases.

Animals↗
PubMed2002

Follicular hyperplasia presenting with a marginal zone pattern in a reactive lymph node lesion.

Histologically, the marginal zone pattern of the lymph node is characterized by lymphoid follicles with three distinct layers. The inner layer is composed of follicular center zones, the middle layer of darkly stained mantle zones, and the outer layer of marginal zones. However, the marginal zone pattern is rarely seen in reactive lymph nodes except for mesenteric lymph nodes. We describe the clinicopathologic, immunohistochemical and genotypic findings of six cases of reactive follicular hyperplasia exhibiting the marginal zone pattern. The patients comprised three males and three females (age range 24 to 63 years; medium 56 years). Follow-up data were obtained from five patients. None of them developed malignant lymphomas during the follow-up period of from 5 to 204 months (median 68 months). Histologically, the lesion was characterized by numerous lymphoid follicles and partial distortion of lymph node structure. Varying degrees of progressive transformation of the germinal center (PTGC) were noted in the four cases. The marginal zone pattern was observed in some or most of the lymphoid follicles including PTGC. The marginal zone B cells were small to medium-sized lymphocytes with round or slightly indented nuclei and a broad rim of pale cytoplasm. Some of them had a monocytoid appearance. They were CD20+, CD79a+, sIgM+/-, sIgD-, CD5-, CD10-, CD21-, CD23-, CD43-, CD45RO-, Bcl-6-, cyclin D1-, EMA- and p53-. A portion of them were Bcl-2 positive. Occasional large lymphoid cells with round or indented nuclei and moderate amounts of cytoplasm were observed in the marginal zone in four cases. These large lymphoid cells were usually CD20 positive, but Bcl-6 negative. A small number of them contained polytypic intracytoplasmic immunoglobulins. The polytypic nature of B lymphocytes was demonstrated by immunohistochemistry and polymerase chain reaction. Recognition of unusual marginal zone hyperplasia in reactive lymph node lesions is important to avoid confusion with nodal involvement in various low-grade B cell lymphomas presenting a marginal zone distribution pattern.

Adult↗
PubMed2001

Cells of the marginal zone--origins, function and neoplasia.

Splenic marginal zone B cells of humans and mice are anatomically positioned with specialized macrophages, dendritic and endothelial cells. Together, they function as the first line of defense against blood borne pathogens with a low triggering threshold for B cells providing a rapid proliferative and antibody response to infections. In humans, B cells with similar cytology and physical relations to follicles are found in lymph nodes and Peyer's patches. However, they also develop in mucosa-associated lymphoid tissue (MALT) and other sites, such as the thyroid and salivary gland, that normally lack organized lymphoid tissue. Chronic antigenic stimulation at these sites or in response to infection with Hepatitis C provides the milieu for mutations at FAS, API2/ML, TP53 and INK4a/p19ARF and the development of marginal zone lymphomas (MZL) in node, spleen and MALT. Only splenic MZL are seen in mice. A reduced threshold for triggering to proliferation may predispose the marginal zone B cell to neoplasia with mutations in genes regulating apoptosis playing a leading role.

Animals↗
PubMed2003

Nodal marginal zone B-cell lymphoma with a novel t(X;5)(q28;q22): conventional and molecular cytogenetic analysis.

Cytogenetic studies provide important information for the diagnosis and classification of malignant lymphomas that in some cases also has prognostic significance. Furthermore, the investigation of isolated novel cytogenetic findings in malignant lymphoma has led to the discovery of many important oncogenes and tumor suppressor genes. For this reason, a case of nodal marginal zone B-cell lymphoma in a 72-year-old woman is described in which analysis by conventional and molecular cytogenetic techniques demonstrated the presence of a t(X:5)(q28;q22) as the sole chromosomal abnormality. This translocation has not been previously reported in the literature.

Aged↗
PubMed2003

Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone.

The marginal zone of the spleen is a precisely ordered region that contains specialized subsets of B lymphocytes and macrophages. Disruption of the negative signaling inositol phosphatase, SH2-containing inositol-5-phosphatase 1 (SHIP), results in the loss of marginal zone B cells (MZBs) with reorganization of marginal zone macrophages (MZMOs) to the red pulp of the spleen. This primary macrophage defect, as revealed by selectively depleting SHIP in myeloid cells shows that MZMOs are specifically required for the retention of MZBs. The MZMO phenotype was reverted in SHIP/Bruton's tyrosine kinase (Btk) double knockout mice, thus identifying the Btk activating pathway as an essential component being regulated by SHIP. Furthermore, we identified a direct interaction between the MARCO scavenger receptor on MZMOs and MZBs. Activation or disruption of this interaction results in MZB migration to the follicle. The migration of the MZMOs was further studied after the response to Staphylococcus aureus, which induced MZMOs to move into the red pulp while MZBs migrated into the follicular zone. The marginal zone is therefore a dynamic structure in which retention and trafficking of B cells requires specific macrophage-B cell interactions.

Animals↗
PubMed1998

[A case of marginal zone B-cell lymphoma].

A 60-year-old woman had an abnormal shadow in the right lower lung field on chest roentgenogram. Transbronchial lung biopsy revealed findings consistent with malignant lymphoma, and a right middle lobectomy was performed. Pathological findings showed that tumor cells had infiltrated the epithelium, forming so-called lymphoepithelial lesions. Flow cytometric analysis of the resected specimen revealed that B-cell associated antigens (CD 19, 20) were expressed, and that the tumor cells were CD 5-, CD 10-. A marked increase in the number of lymphocytes with an IgM kappa component suggested monoclonal origin for the tumor cells in the resected specimen. Southern blot analysis showed clonal rearrangement of the heavy chain of the immunoglobulin gene. A diagnosis of malignant lymphoma of bronchus-associated lymphoid tissue was made. This tumor was defined according to the revised European. American classification of lymphoid neoplasms as a marginal zone B-cell lymphoma.

Antigens, CD19↗
PubMed2003

Cutaneous marginal zone B-cell lymphoma: a case accompanied by massive plasmacytoid cells.

A 36-year-old man presented with a red nodule on his left shoulder. Histologically, there were variously sized, irregularly shaped nests throughout the dermis partly extending into the subcutaneous tissue. Masses of centrocyte-like cells were situated in the center of the tumor nests and accompanied by adjacent secondary follicle structures. Partial follicular colonization was seen. Massive plasmacytoid cells were located in the papillary dermis and the periphery of the tumor nests. Immunohistochemically, these centrocyte-like cells were positive for CD19 and alkaline phosphatase, and negative for CD5 and CD10. Cytoplasm of the plasmacytoid cells was positive for IgG and lambda-light chain, and negative for IgM, IgA, and kappa-light chain. Monotypic immunoglobulin staining including light chain restriction was shown. Clonal immunoglobulin heavy chain gene rearrangement by Southern blot analysis was shown in the tumor tissue. Morphologic, immunohistochemical, and molecular studies revealed that this patient had a cutaneous marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type. Electron beam (total 40 Gy) irradiation was applied. The tumor disappeared completely. Neither local recurrence or metastasis have appeared during 3 years of follow-up.

Adult↗
PubMed1990

A study of the properties of a low-grade mucosal B-cell lymphoma using a monoclonal antibody specific for the tumour immunoglobulin.

Primary low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) are tumours with distinctive clinico-pathological characteristics, two of which are studied in this paper, namely the tendency of the tumours to remain localized and the morphologic and phenotypic resemblance of the malignant cells to splenic marginal zone B cells. We have made a detailed study of a small intestinal lymphoma and a gastric lymphoma, which together with the spleen were resected from the same patient. Using a monoclonal antibody (7G3) raised against a unique determinant on the small intestinal tumour, we were able to detect disseminated small intestinal tumour cells in the stomach and spleen. The tumour in the stomach was genetically related, but non-identical to that in the small intestine, and was not recognized by 7G3. Lymphocytes expressing the marker of the small intestinal tumour (7G3) were present in lymphoid nodules in the stomach, and 7G3+ plasma cells were present beneath the gastric epithelium. In the spleen, cells expressing 7G3 were present in the marginal zone and plasma cells expressing the same marker were present in the red pulp. These findings suggest that low-grade MALT lymphomas may migrate beyond the primary tumour site, but that tumour cells distant to the primary site may differentiate into mature, non-dividing plasma cells. The localization of small intestinal tumour cells in the splenic marginal zones reinforces the suggestion of lineage homology between these populations of cells.

Antibodies, Monoclonal↗