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R C MELLORS

Publications and source records attributed to R C MELLORS.

At least 19 recordsLinked to original sources
PubMed1965

AUTOIMMUNE DISEASE IN NZB/BL MICE. I. PATHOLOGY AND PATHOGENESIS OF A MODEL SYSTEM OF SPONTANEOUS GLOMERULONEPHRITIS.

This study, based upon 528 laboratory examinations and 16 complete autopsies of NZB/Bl mice, deals with autoimmune manifestations (as shown by hypergammaglobulinemia, Coombs positive hemolytic anemia, and the occasional presence of lupus- and rheumatoid-like factors) and mainly with the pathology and the pathogenesis of glomerulonephritis in these mice, a model system of membranous glomerulonephritis with spontaneous and insidious onset, progression through chronic stages, and almost certainly induced by immunological, and autoimmune, mechanisms. The earliest and lasting histological change was hyaline thickening of the capillary walls and adjacent intercapillary regions of the glomerular tufts, corresponding in location to polysaccharide-rich capillary basement membrane and mesangial materials. Distributed focally and diffusely in the glomerular tuft and eventually sparing no glomerulus, hyaline, granular, and fibrillar ("spongy fiber") materials produced narrowing of capillary lumens by concentric or eccentric encroachment upon them. In the later stages hyaline lobulation and sclerosis of the glomerular tufts occurred. Thus the lesions corresponded to those seen in human focal and diffuse membranous, chronic lobular, and lastly (intracapillary) sclerosing glomerulonephritis. In all instances of glomerulonephritis the glomerular tufts contained selective localizations of mouse immunoglobulins corresponding in distribution to that of the hyaline and (PAS-positive) polysaccharide-rich materials in the focal and diffuse membranous and lobular lesions and in amounts increasing with the severity of glomerular disease. The mouse immunoglobulins were extracted from frozen sections of glomerulonephritic kidneys and were then capable of recombination with glomerular tufts in sections of autologous or isologous glomerulonephritic kidneys from which in vivo localized immunoglobulins had been extracted. The pattern of recombination with glomerular tufts was similar to that of in invo localized immunoglobulins. The extracted immunoglobulins did not show affinity for mouse red cells (in the indirect Coombs test) nor for autologous or isologous cell nuclei (in the immunofluorescence test). The serum of mice with severe glomerulonephritis contained immunoglobulins with in vitro affinity for extracted autologous or isologous glomerular tufts. Thus circulating as well as localized antibodies were demonstrated. The immunogenic materials (autoantigens) may have been formed in the glomerular tufts or accumulated in them from some other source, such as the circulating plasma; however they corresponded in location to polysaccharide-rich capillary basement membrane and mesangial materials. The spleen was identified at the cellular level as the main site of formation of autoantibodies to red cells, as well as the main site of red cell destruction. Some evidence was brought forth suggesting that these autoantibodies were "heavy" or gammaM-globulins. More studies are in progress.

Animals↗
PubMed1963

THE CELLULAR ORIGIN OF HUMAN IMMUNOGLOBULINS (GAMMA-2, GAMMA-1M, GAMMA-1A).

A study was made of the cellular origin of human immunoglobulins (gamma(2), gamma(1M), gamma(1A)). 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, gamma(2)- and gamma(1M)-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 gamma(1M), in a small number of cells of small and intermediate size and primitive reticular appearance and in Hassall's corpuscles.

Cell Biology↗
PubMed1962

Studies in molecular pathology. I. Localization and pathogenic role of heterologous immune complexes.

After intravenous injection in mice, rabbit immune complexes, solubilized in antigen excess and containing fluorescent antigens (BSA* or OA*) or fluorescent antibody, or both, were promptly localized in reticuloendothelial cells, and polymorphonuclear leukocytes, of the sinusoids of liver and the red pulp of spleen; in glomeruli and elsewhere in kidney; in capillary endothelium of heart and lung; and in hepatic cells. Thereafter manifold processes occurred. Within 48 hours the immune complexes were scarcely detectable in liver and splenic red pulp but now were localized in the germinal centers of white pulp where heretofore they had been seen only in trace amounts. This new localization presumably was associated with the antibody-forming activity of the germinal centers, for the immune phase of antigen clearance from the blood had already begun. Although the immune complexes were localized in various regions of the nephrons and their appertaining blood vessels, the initial sites of predilection were the glomerular capillary walls and intercapillary spaces. After 48 hours the immune complexes were still detectable, although in diminished amounts, in the glomeruli but had by now essentially disappeared from other renal sites. The localization of immune complexes in the kidney was associated with proteinuria and with structural changes which closely simulated in some instances those of human membranous glomerulonephritis, of focal and diffuse types, and consisted mainly of eosinophilic swellings of the glomerular capillary walls, intercapillary spaces, and basement membranes. There was a close correspondence between the distributions of the eosinophilic swellings and the fluorescent immune complexes. The renal localization and persistence of fluorescent antigens (BSA* or OA*), after separate injections in mice, differed from that of fluorescent immune complexes in several respects. For example BSA* showed predilection for the glomerular basement membranes and was localized sparsely in the capillary walls and intercapillary spaces; OA* was localized only in minute amounts; and neither was detectable in more than trace amounts at 48 hours after injection. These fluorescent proteins (of low molecular weights, 40,000, 70,000) did not cause glomerulonephritis within the time interval studied, whereas fluorescent immune complexes, containing on the average two molecules of antigen to one of antibody (with minimum molecular weights of 240,000 to 300,000) produced glomerulonephritis in some instances, in confirmation of the observations of others. Since the localization of the immune complexes occurred immediately and without known immunologic relation to the kidney itself, the selective physical retention of proteins by structures comprising the glomerular ultrafilters appeared to be of pathogenic significance in this form of membranous glomerulonephritis in mice, as perhaps also in nephrotic glomerulonephritis in man. If after injection of fluorescent immune complex, homologous antiserum was also administered intravenously so as to produce acute anaphylactic death, coarse and occlusive depositions of immune precipitates occurred in pulmonary, myocardial, and renal capillaries, and in hepatic sinusoids.

Animals↗
PubMed1961

Rheumatoid factor and the pathogenesis of rheumatoid arthritis.

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 gamma-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 gamma-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 gamma-globulin and cross-reacting with rabbit gamma-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.

Adult↗
PubMed1960

Cellular localization of Rous sarcoma virus as studied with fluorescent antibody.

A study has been made of the immunospecific, apple-green staining patterns imparted by fluorescent antibody to Rous virus in frozen sections of wing tumors produced in young chickens by various initiating doses of virus. Variations in the cellular site (cytoplasm, cell membrane, and nucleus), the distribution (particulate or homogeneous), and the quantity (little or much) of Rous viral antigens were seen. The per cent of sarcoma cells containing viral antigens was related to the tumor initiating dose of virus and to the infectivity titer of virus extracted from the wing tumor. With certain assumptions it was estimated that a quantity of virus approaching one tumor-producing dose (1 TD(50)) per tissue section was detectable with fluorescent antibody. Sarcoma cells containing viral antigens were identified as early as 4 days after inoculation of Rous virus. At this time viral antigens were also localized in the skeletal muscle of the inoculated wing in a characteristic focal pattern of deposition near or on the sarcolemma. This association between viral antigens and skeletal muscle fibers was observed also at 3 days after virus inoculation, when sarcoma cells were not yet demonstrable in the tissue sections. Viral antigens were detected in sarcoma cells in lung tumors of young chickens and in tumors of the chorioallantoic membrane of chick embryos.

Animals↗
PubMed1957

Cellular sites of formation of gamma globulin.

The cellular sites of formation of gammaglobulin in lymphatic tissues of man and in a representative human lymphoid infiltrate have been studied by fluorescent antibody technique. The findings indicate that gamma-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 gamma-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 gamma-globulin. Unlike the plasma cells, which function as individual units, the intrinsic cells apparently form gamma-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 gamma-globulin. The release of gamma-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 gamma-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 gamma-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 gamma-globulin represents a response to a particular form of antigenic stimulation. Nuclear participation in the process of gamma-globulin synthesis was not detected by the technique employed.

Antibodies↗
PubMed1957

Fluorescent antibody detection of the antigens of the Shope papilloma virus in papillomas of the wild and domestic rabbit.

The results obtained by a fluorescent antibody study of the Shope papilloma virus in papillomas of the wild and domestic rabbit are presented. In the wild rabbit papillomas the viral antigens occurred exclusively in the nucleus and were present in the differentiating cells of the keratohyaline layers and in the keratinized layers. The antigens were not present in the deeper proliferating epithelial cells of the papillomas. The Shope viral antigens were present in very minute amounts in papillomas of the domestic rabbit, as compared with papillomas of the wild rabbit, and were only detected in the superficial keratinized layers. It is postulated that virus is present in the nuclei of the proliferating cells of the papillomas of the wild and domestic rabbit but exists there in an early stage of development, consisting mainly of nucleic acid and deficient in protein, therefore non-antigenic and not demonstrable by fluorescent antibody. The nucleic acid moiety of the virus may be infective, and the protein component may provide immunologic specificity and serve to preserve transmissibility. The protein-deficient virus can be referred to as masked virus.

Animals↗
PubMed1957

Role of gamma globulins in pathogenesis of renal lesions in systemic lupus erythematosus and chronic membranous glomerulonephritis, with an observation on the lupus erythematosus cell reaction.

Utilizing the fluorescent antibody method for the histologic demonstration of localized gamma-globulins, we have made the following observations (in contradistinction to the lack of such findings in a variety of normal and pathologic, control kidneys). In systemic lupus erythematosus (a) gamma-globulins were localized in the thickened capillary walls, the "wire-loop" lesions, and the so called "hyaline thrombi" in glomeruli; (b) these sites of localization of gamma-globulins were correlated to a considerable degree with the pattern of accentuated eosinophilia of the glomeruli, as seen in hematoxylin-eosin sections, or with the pattern of PAS-positive areas in the glomeruli in sections stained with the periodic acid-Schiff reaction; (c) and gamma-globulins were localized rarely in large cytoplasmic granules in tubular epithelium and occasionally in glomerular capsular crescents, tubular protein casts, and inflammatory cells, particularly in the cytoplasm of cells identified as immature and mature plasma cells. In nephrotic glomerulonephritis (a) gamma-globulins were localized in the glomerular basement membrane and appertaining structures in chronic membranous glomerulonephritis; (b) gamma-globulins were apparently localized in the altered mesangium in chronic lobular glomerulonephritis; and (c) in the tubular protein casts, presumably representing abnormal glomerular filtrates, gamma-globulins were present in a lesser concentration and other serum proteins in a greater concentration than found in the glomeruli. In positive lupus erythematosus preparations the nuclei of leukocytes, while undergoing transformation and subsequent phagocytosis to form lupus erythematosus cells, were the sites of localization of gamma-globulin (presumably the lupus erythematosus factor) whereas in control preparations no nuclear localization of gamma-globulin occurred. These observations are discussed in relation to the pathogenesis of renal lesions in systemic lupus erythematosus, chronic membranous glomerulonephritis, and amyloidosis.

Amyloidosis↗