scholarly journals RHEUMATOID FACTOR AND THE PATHOGENESIS OF RHEUMATOID ARTHRITIS

1961 ◽  
Vol 113 (2) ◽  
pp. 475-484 ◽  
Author(s):  
Robert C. Mellors ◽  
Adam Nowoslawski ◽  
Leonhard Korngold ◽  
Beth L. Sengson
Keyword(s):  
Rheumatoid Arthritis ◽  
Lymph Nodes ◽  
Rheumatoid Factor ◽  
Immune Complex ◽  
Germinal Center ◽  
Plasma Cells ◽  
Fluorescent Antibody ◽  
Serological Tests ◽  
Cellular Origin ◽  
And Function

In analogy with the two categories of reactants which are used in the serological tests for the unusual category of macroglobulins called rheumatoid factor, two fluorescent reactants have been prepared for the detection of rheumatoid factor in situ in tissue sections: fluorescent antigen-rabbit antibody (immune) complex, in the present study, and fluorescent aggregated human γ-globulin, in previous work. Plasma cells in the synovial membrane and germinal center cells and internodular plasma cells in lymph nodes are the sites of origin of rheumatoid factor in active rheumatoid arthritis, whether occurring in adults or children. Plasma cells and germinal center cells which form rheumatoid factor detectable with fluorescent immune complex are less numerous than those which contain factor demonstrable with fluorescent aggregate. In the same tissues, plasma cells and germinal center cells which contain macroglobulin (19S human γ-globulin) detectable with fluorescent antibody—but not showing the reactivity of rheumatoid factor—are more abundant than those containing rheumatoid factor. While macroglobulin and rheumatoid factor are almost exclusively formed in the cytoplasm, these proteins are also detectable in the nucleus of an occasional plasma cell. Normal and pathological synovial and capsular tissues, lymph nodes, and connective tissues obtained from individuals without rheumatoid arthritis are not stained with fluorescent immune complex or, except for an unusual example of Waldenstrom's macroglobulinemia, with fluorescent aggregate. The cellular origin, as well as certain chemical and immunological attributes, of rheumatoid factor suggests an antibody-like nature and function. The observations cited are consistent with the behavior anticipated for cellular rheumatoid factor, were it primarily an antibody direct to an altered human γ-globulin and cross-reacting with rabbit γ-globulin. However, it is also possible that there are two or more cellular rheumatoid factors. Lesion-associated protein precipitates having the composition anticipated for rheumatoid factor-antigen complex are localized in the amyloid depositions in kidney and spleen of an individual who died with amyloidosis secondary to rheumatoid arthritis.

scholarly journals CELLULAR ORIGIN OF RHEUMATOID FACTOR

1959 ◽  
Vol 110 (6) ◽  
pp. 875-886 ◽  
Author(s):  
Robert C. Mellors ◽  
Ralph Heimer ◽  
Josué Corcos ◽  
Leonhard Korngold
Keyword(s):  
Rheumatoid Arthritis ◽  
Lymph Nodes ◽  
Rheumatoid Factor ◽  
Active Rheumatoid Arthritis ◽  
Plasma Cells ◽  
Germinal Centers ◽  
Secretory Process ◽  
Subcutaneous Nodules ◽  
Synovial Membranes ◽  
Arthritis Rheumatoid

Fluorescein-labelled aggregated human γ-globulin was found to react in precipitin-type tests with serums of individuals with rheumatoid arthritis. This reagent was also highly reactive and specific for the localization of rheumatoid factor in frozen sections of synovial membranes, lymph nodes, and subcutaneous nodules. In synovial membranes from patients with active rheumatoid arthritis, rheumatoid factor was present in the cytoplasm of plasma cells at various stages of development and maturity. The appearance of the cytoplasm and the occasional presence nearby of extracellular particles suggested the possibility of a secretory process. All other cells were devoid of rheumatoid factor. Some plasma cells contained 7S and/or 19S γ-globulin and many lacked detectable γ-globulin. In lymph nodes from a patient with active rheumatoid arthritis, rheumatoid factor was present in approximately one in ten germinal centers as well as in internodular plasma cells. The rheumatoid factor was localized in the cytoplasm and the characteristic protoplasmic processes of the germinal-center cells. All other cells were devoid of rheumatoid factor. 7S and/or 19S γ-globulin was demonstrated in approximately eight in ten germinal centers in these lymph nodes. Plasma cells with rheumatoid factor were also seen on occasion in rheumatoid subcutaneous nodules. Tissue sections of comparable structure prepared from normal and pathological control material did not contain rheumatoid factor. Staining for rheumatoid factor was blocked by pretreatment of sections either with unlabelled aggregated human γ-globulin or with rabbit antiserum against 19S human γ-globulin.

scholarly journals CELLULAR SITES OF FORMATION OF GAMMA GLOBULIN

1957 ◽  
Vol 106 (5) ◽  
pp. 627-640 ◽  
Author(s):  
L. G. Ortega ◽  
R. C. Mellors
Keyword(s):  
Germinal Center ◽  
Gamma Globulin ◽  
Plasma Cells ◽  
Serum Proteins ◽  
Fluorescent Antibody ◽  
Germinal Centers ◽  
Fluorescent Antibody Technique ◽  
Antibody Technique ◽  
Reticular Cells ◽  
Parenchymal Cells

The cellular sites of formation of γglobulin in lymphatic tissues of man and in a representative human lymphoid infiltrate have been studied by fluorescent antibody technique. The findings indicate that γ-globulin is formed in the germinal centers of lymphatic nodules and in the cytoplasm of mature and immature plasma cells of two types—those with and those without Russell bodies. The germinal center cells that synthesize γ-globulin have been designated "intrinsic" cells to distinguish them from the medium and large lymphocytes, and the primitive reticular cells that occur elsewhere and do not produce γ-globulin. Unlike the plasma cells, which function as individual units, the intrinsic cells apparently form γ-globulin only when they are arranged in discrete aggregations. The function, the blood supply, and the systematic cellular arrangement of germinal centers justifies the postulate that they are miniature organs of internal secretion of γ-globulin. The release of γ-globulin from its sites of formation appears to be accomplished by holocrine and apocrine secretion. Presumably, these secretory mechanisms are adaptations required for the production of antibody since they have not been described in parenchymal cells that form the other serum proteins. The cells found to form γ-globulin appear to be identical with those previously shown to form specific antibody in response to a variety of antigens in the experimental animal. This evidence indicates that normal γ-globulin, if it exists, originates in the same cells that produce antibody. It is suggested, also, that each of the 3 morphologically distinct categories of cells that synthesize γ-globulin represents a response to a particular form of antigenic stimulation. Nuclear participation in the process of γ-globulin synthesis was not detected by the technique employed.

scholarly journals Production of Macroglobulins in Vitro and a Study of Their Cellular Origin

Blood ◽  
1962 ◽  
Vol 20 (1) ◽  
pp. 56-64 ◽  
Author(s):  
DOROTHEA ZUCKER-FRANKLIN ◽  
EDWARD C. FRANKLIN ◽  
NORMAN S. COOPER
Keyword(s):  
Bone Marrow ◽  
Tissue Culture ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Plasma Cells ◽  
Buffy Coat ◽  
Cellular Origin

Abstract Lymph nodes of three patients with macroglobulinemia of Waldenström were studied in tissue culture and shown to synthesize 19S γ-globulin in vitro. Lymph node imprints, bone marrow, and buffy coat smears of the same patients consisted almost entirely of lymphocytes. When these were stained with fluorescein-conjugated antiserum to macroglobulin, large and medium-sized lymphocytes and lymphoblasts rather than mature lymphocytes or plasma cells were shown to contain the protein. It is suggested that 19S γ-globulin may also be synthesized by cells belonging to the lymphoid series under normal circumstances.

Die Bedeutung der Plasmazellen als Antikörperbildner

1964 ◽  
Vol 1 (5) ◽  
pp. 423-453 ◽  
Author(s):  
G. Trautwein
Keyword(s):  
Blood Serum ◽  
Antibody Formation ◽  
Plasma Cells ◽  
Fluorescent Antibody ◽  
Experimental Investigations ◽  
Antibody Concentration ◽  
Fluorescent Antibody Technique ◽  
Antibody Technique ◽  
And Function

During the last two decades, it has been shown by a great number of morphological, clinical, and experimental investigations that the humoral antibodies are formed by plasma cells. Plasma cells are immobile connective tissue cells which are formed in the medullary cords of lymph nodes, the red pulp of the spleen, the bone marrow, and in the adventitia of small blood vessels. The theory of the plasmacellular antibody formation is based on these clinical and experimental observations: (1) Correlation of hypergammaglobulinemia in the blood serum and proliferation of plasma cells in the tissue in various diseases of men and animals. (2) Correlation of antibody concentration in the blood serum and plasma cell proliferation in hyperimmunized experimental animals. (3) Demonstration of antibody formation in plasma cells by in vitro experiments and extraction of γ-globulin from plasma cells. (4) Detection of antibodies in plasma cells with the fluorescent antibody technique. Macrophages and lymphocytos also play a role in antibody formation. While it is the function of the macrophages to transform corpuscular antigen into soluble immunogenic antigen, the lymphocytes play the role of a co-factor. In newborns the thymus lymphocytes transmit substances which are necessary for the development and function of the antibody producing system. The complicated problems of globulin synthesis in the antibody producing cell are explained in the light of the genetic theory of antibody formation advanced by Ehrich.

THYMIC ALYMPHOPLASIA WITH HYPER-IgE-GLOBULINEMIA

PEDIATRICS ◽  
1973 ◽  
Vol 51 (4) ◽  
pp. 690-696
Author(s):  
Yumio Kikkawa ◽  
Kikuro Kamimura ◽  
Tokiro Hamajima ◽  
Tokihiko Sekiguchi ◽  
Tadashi Kawai ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Neutralizing Antibodies ◽  
Congenital Heart ◽  
Plasma Cells ◽  
Fluorescent Antibody ◽  
Fluorescent Antibody Technique ◽  
Antibody Technique ◽  
Serum Ige ◽  
Heart Lesion ◽  
Ige Synthesis

The clinical and autopsy findings of a 5-month-old patient with thymic alymphoplasia and increased serum IgE levels are reported. A congenital heart lesion was diagnosed at 15 days of age, eczema at 1 month of age, and infections of the skin, ears, and respiratory tract recurred until death. Peripheral lymphocytopenia and eosinophilia, and increased concentrations of serum IgE (16.2µg/ml) and IgM were present. The serum contained normal levels of IgG and IgA. Isohemagglutinins and viral neutralizing antibodies were not present in the serum. Bacterial and drug antibodies were present, as demonstrated by PK reaction. At autopsy the thymus was hypoplastic and without Hassall's corpuscles. There were few small lymphocytes but follicular lymphocytes and plasma cells were relatively normal in lymph nodes. IgE forming cells were found in the lymph nodes and lamina propria of intestine by fluorescent antibody technique. Peripheral lymphocytes showed blastlike transformation but not mitosis. The findings suggest that the thymus plays a role in the regulation of IgE synthesis.

Pathological findings in sheep experimentally infected with parapoxvirus

2015 ◽  
Vol 15 (2) ◽  
pp. 66-70
Author(s):  
G Soyolmaa ◽  
A Altanchimeg ◽  
D Ganbold ◽  
B Mungun-Ochir ◽  
P Baatarjargal ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Germinal Center ◽  
Plasma Cells ◽  
Virulent Strain ◽  
Common Method ◽  
Lymphocyte Infiltration ◽  
Pathological Findings ◽  
Immune Organs ◽  
Agricultural Sciences

We have investigated patho-morphologic findings in some parenchymal and immune organs of sheep infected with high virulent strain ‘’Stavropoliskii’’ of parapoxvirus by a common method (MNS 5451:2005). By means of the microscope were found desquamation of some epithelium of epidermis, eosinophil and lymphocyte infiltration and vacuolization in the derma, and also edema and hyperemia in lung alveoli. Germinal center of lymph nodes was reduced and the number of plasma cells was decreased.Mongolian Journal of Agricultural Sciences Vol.15(2) 2015; 66-70

scholarly journals Pi3k/Akt/Mtor Pathway Activity Is Increased in Lymph Node Tissue from Idiopathic Multicentric Castleman Disease Patients with Tafro Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1121-1121
Author(s):  
Dustin Shilling ◽  
Dale M Kobrin ◽  
David C Fajgenbaum
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Signaling Pathways ◽  
Germinal Center ◽  
Plasma Cells ◽  
Human Herpesvirus ◽  
Castleman Disease ◽  
Mtor Signaling ◽  
Breast Cancer Patients ◽  
Color Deconvolution

Abstract Castleman disease (CD) describes a group of heterogeneous diseases defined by shared lymph node histopathology, including atrophic or hyperplastic germinal centers, prominent follicular dendritic cells, hypervascularization, polyclonal lymphoproliferation, and/or polytypic plasmacytosis. Unicentric CD (UCD) involves a solitary enlarged lymph node that displays CD histopathology, and patients rarely experience systemic symptoms. In contrast, multicentric CD (MCD) involves multiple regions of enlarged lymph nodes, systemic inflammation, cytopenias, and vital organ dysfunction due to a cytokine storm often including interleukin-6. MCD is caused by uncontrolled infection with Kaposi sarcoma-associated/human herpesvirus-8 (HHV-8) in ~50% of cases. The etiology of the remaining HHV-8-negative MCD cases is idiopathic (iMCD). In iMCD patients, blockade of IL-6 signaling with siltuximab, the only FDA-approved iMCD treatment, induced responses in 34% of cases in the phase II registrational trial. The large proportion of non-responders suggest that alternative pathways are responsible for driving disease pathogenesis in some patients. For these individuals, identification of molecular and cellular abnormalities for therapeutic targeting is urgently needed, particularly for those with the most severe clinical presentations. In fact, a clinical subgroup of iMCD was recently described with a very severe presentation: thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (iMCD-TAFRO). We previously reported increased phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling--a central pathway downstream of multiple cell surface receptors, implicated in both autoimmune and oncologic disorders--in a treatment refractory iMCD-TAFRO case that experienced an extended remission on treatment with an mTOR inhibitor. To extend these findings, herein we report immunohistochemistry for phosphorylated ribosomal protein S6 (phospho-S6), a marker of mTOR activation, in lymph node tissue from additional iMCD-TAFRO cases (n=10) and sentinel lymph nodes from breast cancer patients without evidence of metastasis (n=5). Anti-phospho-S6 (Ser235/236, Clone D57.2.2E) was used following standard protocols, and Aperio ImageScope and Image Analysis Toolkit software (color deconvolution v9 algorithm) were used to quantify pixel staining intensity in the germinal center, mantle zone, follicular and interfollicular regions. This analysis identified an increased number of pixels staining weak, medium, and strong for phospho-S6 in the interfollicular region of iMCD-TAFRO cases (p<0.005 for all comparisons) and an increased number of pixels staining weak for phospho-S6 in the germinal center (p<0.05) compared to control cases. Given that T cells are largely represented in the interfollicular region and mTOR signaling is critical to T cell proliferation, we hypothesized that the observed increase in phospho-S6 signal would occur in CD3+ cells. However, co-immunofluorescence assays for phospho-S6 and CD3 (Dako, A0452) across iMCD-TAFRO cases identified 0.08 ± 0.16% (mean ± standard deviation; n = 4 cases) of phospho-S6-positive cells as expressing CD3. In contrast, co-immunofluorescence for phospho-S6 and CD138 (Dako, Clone MI15) revealed 17.89 ± 11.26% of phospho-S6-positive cells as plasma cells. iMCD is considered an IL-6 driven disorder; however, anti-IL-6 therapy is effective in only a portion of cases. Alternative signaling pathways driving CD pathogenesis are poorly understood. This study provides the largest quantification to-date of aberrant PI3K/Akt/mTOR activity in iMCD-TAFRO, the first systematic study demonstrating increased mTOR activation in iMCD-TAFRO, and the first to identify a cell type, plasma cells. These findings are key to advancing our understanding of the pathological cell types and disrupted signaling pathways in iMCD. Disclosures Fajgenbaum: Janssen Pharmaceuticals, Inc.: Research Funding.

scholarly journals THE CELLULAR ORIGIN OF HUMAN IMMUNOGLOBULINS (γ2, γ1M, γ1A)

1963 ◽  
Vol 118 (3) ◽  
pp. 387-396 ◽  
Author(s):  
Robert C. Mellors ◽  
Leonhard Korngold
Keyword(s):  
Germinal Center ◽  
Plasma Cells ◽  
Individual Cell ◽  
Germinal Centers ◽  
Small Extent ◽  
Fetal Thymus ◽  
Cellular Origin ◽  
Human Immunoglobulins ◽  
Intermediate Size ◽  
Reticular Cells

A study was made of the cellular origin of human immunoglobulins (γ2, γ1M, γ1A). The results indicated that two closely related families of cells form immunoglobulins in human lymphoid tissue: germinal (reticular) centers and plasma cells. Thus their cellular origin in addition to their known antigenic relations further justifies placing the immunoglobulins in one family of proteins. Immunoglobulins were also formed to a small extent in primitive reticular cells which resembled those of germinal centers but were separated from them. Possibly such cells were undergoing transition to the much more numerous plasma cells with which they were commonly associated. The mantles of small lymphocytes which surrounded germinal centers did not contain detectable quantities of immunoglobulins. While in general only one type of immunoglobulin was present in an individual cell or germinal center, γ2- and γ1M-globulin were identified on occasion in the same plasma cell and germinal center. A peculiarity of the fetal thymus gland was the presence of immunoglobulin, mainly γ1M, in a small number of cells of small and intermediate size and primitive reticular appearance and in Hassall's corpuscles.

scholarly journals THE ULTRASTRUCTURE AND FUNCTION OF THE CELLS IN LYMPH FOLLOWING ANTIGENIC STIMULATION

1967 ◽  
Vol 125 (1) ◽  
pp. 91-110 ◽  
Author(s):  
J. G. Hall ◽  
Bede Morris ◽  
Giuliana D. Moreno ◽  
Marcel C. Bessis
Keyword(s):  
Immune Response ◽  
Endoplasmic Reticulum ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Plasma Cells ◽  
The Body ◽  
Lymphoid Cells ◽  
Effector Cells ◽  
Classical Plasma ◽  
And Function

When a lymph node receives an antigenic stimulus the cell population in the efferent lymph changes and large basophilic cells appear. During a secondary immune response cells of this type may account for over 50% of the cells present in lymph. When examined by electron microscopy, many of these cells were found to be primitive undifferentiated blast cells with many free ribosomes in their cytoplasm and only an occasional piece of endoplasmic reticulum. Their nuclear chromatin was sparse and the nuclei contained several nucleoli. Many other cells which were judged to be more differentiated had large numbers of ribosomes arranged in clusters which took the form of rosettes or spirals. These cells also had more ergastoplasm but this occurred usually in the form of short pieces of disorganized endoplasmic reticulum. No cells with the ultrastructure of classical plasma cells were found in efferent lymph although these cells were abundant in the stimulated lymph nodes. It was shown that when the lymph which contained these cells was collected quantitatively no systemic immunity developed even though a vigorous immune response took place in the lymph node with the formation of many plasma cells. Failure of the systemic immune response to develop could not be explained merely in terms of the loss of antibody. It was concluded that these basophilic cells rather than antigen are responsible for propagating the immune response throughout the body and that they depend on an intact lymphatic pathway for their immediate transport. This view was supported by experiments which showed that these cells are capable of initiating immune responses in other lymph nodes of the same animal and of transferring active immunity between chimeric twins. The most likely explanation of these results is that the basophilic lymphoid cells carry out their messenger function by developing into plasma cells at sites remote from the site at which antigen is localized. However this has yet to be proven and the possibility remains that these mobile, highly motile, RNA-rich cells may express their messenger function by transferring information to other effector cells.

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