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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.

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.

The frequency and nature of IgG anti-cardiolipin and anti-ds-DNA antibodies among MRL/lpr, MRL/+ and NZB/W Fl mice (murine lupus strains) and non-autoimmune inbred strains of mice (NIH/Swiss and Balb/c) were analysed by ELISA. High titres of anti-ds-DNA were detected in autoimmune strains (MRL/lpr, 69%; MRL/+, 50%; and NZB/W, 80% positive), whereas anti-cardiolipin antibodies were detected only in MRL/lpr (69%) and MRL/+ (17%) mice. IgG subclass analysis of these antibodies in 20 MRL/lpr sera revealed that all four subclasses were represented. When tested for fine antigenic specificity, anti-cardiolipin antibodies in MRL/lpr and MRL/+ mice bound to acidic phospholipids rather than to neutral phospholipids and were not inhibited by DNA. In MRL/lpr mice, anti-cardiolipin antibodies were first detected at 2 months, peaked around 5 months and then declined preterminally. To determine whether complications associated with anti-cardiolipin antibodies were present in MRL/lpr mice, blood counts were performed and litter sizes were determined. Although no significant decreases in the red and white blood cell counts were observed in MRL/lpr mice, platelet counts were significantly lower compared with NIH/Swiss (P<0.001) and Balb/c (P<0.005) mice. MRL/lpr mice had significantly fewer pups per delivery compared with a normal strain (MRL/lpr, 5.3 + 2.6; NIH/Swiss, 7.2 ± 2.1; P<0.002). These observations indicate that the serological characteristics of IgG anti-cardiolipin antibodies in MRL/ lpr mice are similar to those of anti-cardiolipin antibodies in humans with lupus. Whether these autoantibodies are pathogenetically related to thrombocytopenia and a small litter size in MRL/lpr mice remains to be determined. [ABSTRACT FROM AUTHOR]

NZB mice were found to produce natural thymocytotoxic autoantibody in high prevalence and antibody titre. This autoantibody in NZB mice was detectable by the cytotoxicity test at both 4°C and 37°C; the prevalence and antibody titre were generally higher at 4°C. Mice of other strains also produced natural thymocytotoxic autoantibody although in lower prevalence and antibody titre and in some instances the activity was greater at 37°C than at 4°C. Natural thymocytotoxic autoantibody in NZB mice reacted equally with the thymocytes of virtually all strains of mice tested but to a lesser degree with the thymocytes of SJL/J mice. A serum pool obtained from old NZB mice had an extremely high titre of natural thymocytotoxic autoantibody (l:1024 at 4°C). Nevertheless, the cells in lymph nodes, spleen and blood leucocytes were only partially sensitive to this serum pool, and bone marrow cells were for the most part negative. By absorption, the antigen reacting with natural thymocytotoxic autoantibody was found in thymus, lymph node, spleen and brain of adult mice, thymus of newborn mice and some leukaemias. Natural thymocytotoxic autoantibody in NZB mice was an IgMglobulin as determined by sensitivity to 2-mercaptoethanol treatment and by Sephadex G-200 column chromatography in contrast to other natural antibodies (antinuclear, antierythrocyte and G antibodies) of IgG-globulin class. NZB mice also produced natural antibodies against thymocytes of the rat and the hamster; these antibodies were species-specific and did not react with the thymocytes of any but the homologous species. [ABSTRACT FROM AUTHOR]

NZB mice naturally produce an autoantibody which in the presence of complement is specifically cytotoxic for thymocytes and thymus-dependent lymphocytes (T-cells) in the peripheral lymphoid tissues (lymph nodes and spleen) and the circulation of mice. Using a direct cytotoxicity test with a NZB mouse serum pool which contained the high titred autoantibody, a progressive decrease was observed with a g e in the proportion of the autoantibody-sensitive cells in mesenteric lymph node, spleen, and blood of NZB mice in comparison with mice of other strains (C57BL/ 6J and NZW). The numerical decrease in the population of autoantibody-sensitive cells was evident at younger age and greater degree in the peripheral blood than in t h e lymph node and spleen. The age-decrease in the number of autoantibody sensitive cells in lymph node and spleen contrasted with the numerical increase in nucleated cells in these organs. The age-decrease in the proportion and number of t h e autoantibody-sensitive cells in the blood exceeded the decrease in the blood lymphocyte count. This finding indicated that T-cells in the blood are selectively depleted with the ageing of NZB mice. A similar observation was made on the blood lymphocytes of (NZB × NZW)F1 hybrid mice. The depletion of T-cells in the blood in association with the production of natural thymocytotoxic autoantibody is termed autoimmune thymus-dependent lymphocytopenia. [ABSTRACT FROM AUTHOR]