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Biomedical subjects

R L Riley

Publications and source records attributed to R L Riley.

At least 37 records · Page 2Linked to original sources
PubMed1990

Bone marrow stromal cells modulate both kappa light chain and Ly1 antigen expression on Ly1+ pre-B cell lines in vitro.

Murine Ly1+ pre-B cell lines, including 70Z/3 and three pre-B cell lines derived from long-term bone marrow cultures, exhibited selective adherence to bone marrow stromal cells. In contrast, splenic B cells, the A20 B-cell lymphoma, and four Ly1- B cell lines derived from long-term bone marrow cultures failed to adhere substiantially to bone marrow cultures failed to adhere substiantially to bone marrow stroma. Ly1+ pre-B cell lines were induced to express kappa light chains by exposure to either lipopolysaccharide (LPS), recombinant interleukin-1 (IL-1), or stromal cells. However, induction of kappa light chains failed to prevent pre-B cell adherence to stromal cells. Supernatants derived from primary bone marrow stromal cells decreased Ly1 expression on the Ly1+ pre-B cell lines. These experiments suggest that (1) expression of immunoglobulin light chains by developing Ly1+ pre-B cells is mediated by bone marrow stromal cells; (2) loss of specific adherence to stroma is progressive and occurs post-light chain induction; and (3) soluble products of stromal cells may downregulate expression of surface Ly1 on otherwise Ly1+ pre-B cells. The importance of these observations to the development of both the Ly1- and Ly1+ B cell lineages in the mouse is discussed.

Animals↗
PubMed1990

The age-dependent loss of bone marrow B cell precursors in autoimmune NZ mice results from decreased mitotic activity, but not from inherent stromal cell defects.

The formation of B lymphocytes is abnormal in autoimmune NZB and (NZB x NZW)F1 mice. With age, the proportion of sIg- Ly-5(220)+ pre-B cells and less mature B cell progenitors in the bone marrow progressively declines, reaching only approximately one-third of normal levels in 20-wk-old NZ mice. To determine the mechanisms responsible for the deficiency of NZ B lineage precursors, the mitotic activity of sIg- Ly-5(220)+ bone marrow cells in vivo was determined in NZ and conventional inbred mice as a function of age. The proportion of sIg- Ly-5(220)+ B cell precursors in (S + G2/M) stages of the cell cycle steadily decreased with age in NZ autoimmune mice. Furthermore, upon metaphase arrest, the rate of entry of sIg- Ly-5(220)+ bone marrow cells into G2/M also decreased with age in NZ mice. Therefore, the mitotic activity of sIg- Ly-5(220)+ B cell precursors is substantially decreased in NZ mice greater than or equal to 20 wk of age. The capacity of the bone marrow stromal microenvironment of NZ mice to support B lineage precursor growth was tested in two ways: 1) the capacity of preformed NZ bone marrow stroma to support B lineage cell growth in long term bone marrow cell culture under lymphopoietic conditions was assessed and 2) the capacity of NZ bone marrow B lineage precursors to expand in vivo after sublethal (200 rad) whole body irradiation was determined. Stroma derived from adult NZ mice supported the growth and development of B lineage lymphocytes in long term bone marrow cell culture to a greater extent than did age-matched conventional murine stroma. Furthermore, sublethal irradiation of older adult NZ mice resulted in some expansion of bone marrow sIg- Ly-5(220)+ B cell precursors in vivo. Therefore, the deficiency of B cell progenitors in the bone marrow of older NZ autoimmune mice is associated with diminished mitotic activity. However, this does not result from defects in the capacity of NZ bone marrow stroma to permit B lineage cell expansion as determined by both in vitro and in vivo experiments. In the absence of a detectable stromal cell defect, it is possible that an active inhibitory process within the bone marrow influences the mitotic activity of B cell precursors in NZ mice.

Aging↗
PubMed1989

Effects of interleukin 4 on neonatal B lymphocyte tolerance.

Perturbation of antigen receptors on mouse neonatal B cells by rabbit antimouse IgM antibody was shown to inhibit cell proliferation in response to the B cell mitogen lipopolysaccharide. When these antibody-inactivated cells were challenged with lipopolysaccharide in the presence of the helper T cell product interleukin 4, a strong proliferative response was observed. Interleukin 4 alone did not cause proliferation of the antibody-treated B cells. Pretreatment with interleukin 4 did not prevent neonatal B cell inactivation by the antibody. Our results show that neonatal B cells inactivated directly through their antigen receptors can be reactivated by the combined signals of interleukin 4 and lipopolysaccharide.

Animals↗
PubMed1989

Abnormal development of B cells and B cell progenitors in autoimmune (NZB x NZW)F1 mice.

The (NZB x NZW)F1 (BWF1) autoimmune strain displays reduced numbers of both c mu+ pre-B cells and Ly5(220)+ B cell progenitors in the bone marrow. The loss of these B cell precursor populations in the bone marrow increases with age. In contrast, the bone marrow of BWF1 mice possesses sIg+ B cells comparable in both number and surface phenotype to that observed in conventional strains. Analysis of the surface densities of both sIg and Ly5(220) antigens indicates that BWF1 bone marrow B cells comprise a heterogeneous population of both immature and mature B cells. In addition, BWF1 bone marrow still possessed progenitor cells capable of yielding newly generated B cell precursors and B cells in vitro. The diminished levels of intermediate B cell progenitors observed in BWF1 bone marrow may reflect abnormal regulation of B lineage differentiation during the life span of this autoimmune strain.

Animals↗
PubMed1986

The affinity threshold for antigenic triggering differs for tolerance susceptible immature precursors vs mature primary B cells.

The specificity of antibody responses is dependent on the extent to which a given antigen selectively stimulates cells from within a diverse B cell repertoire. Previous studies have shown that the triggering of B cells by T cell-dependent antigens is a highly discriminatory process, and that tolerance induction of immature B cells by antigen is equally discriminatory. This symmetry in the requirements for stimulation and tolerance induction could provide a basis for the capacity of antibody responses to discriminate among foreign antigens and yet minimize self recognition. The extent to which this potential for discriminate recognition is applicable to the mature immune system remains controversial, because B cells reactive to self antigens have been identified and, in addition, several investigators have identified heteroclitic immune responses, such as the response to NP of Ighb mice, wherein antibodies are found with higher affinities for analogues of the immunogen than for the immunogen itself. To further investigate the capacity of B cells to discriminate among closely related antigenic determinants, we analyzed the fine specificity and idiotypic distribution of monoclonal antibodies derived from both splenic B cells and immature sIg- bone marrow B cell precursors stimulated in fragment culture with NP-Hy and its structural analogues NIP-Hy and NNP-Hy. The results indicate that the majority of responsive B cells discriminate among these haptenic determinants; however, lambda-bearing B cells responsive to the NP and NIP determinants represent a highly overlapping set of clonotypes. Comparison of the responses to NP-Hy and NIP-Hy of splenic vs sIg- precursors of this clonotype family suggests that the T cell-dependent stimulation of both mature and immature B cells by antigen is highly affinity dependent. Significantly, the affinity thresholds for both stimulation and tolerance induction of immature B cells appears to be higher than that required for the stimulation of mature splenic B cells. Such a disparity in the requisites for triggering mature vs immature B cells could readily account for the presence of low-affinity self-reactive B cells in the mature B cell pools of normal individuals.

Animals↗
PubMed1985

Tolerance and B cell repertoire establishment.

We have probed the mechanism by which immature B cells are uniquely susceptible to antigen-induced inactivation. Our studies have demonstrated that this tolerance trigger is an active process that requires both energy metabolism and the biosynthesis of various macromolecules, including protein, RNA, and DNA. However, the tolerance trigger is resistant to inhibitors of patching and capping, as well as an inhibitor of mitosis. The tolerance trigger requires a high-affinity interaction between a multivalent antigen and the cells' Ig receptor, but apparently does not require interactions with other cell surface molecules, or interactions with T cells or macrophages. Our efforts to demonstrate the physiological applicability of this tolerance trigger have concentrated on an attempt to demonstrate potentially self-reactive cells within the immature bone marrow population that do not appear in the mature splenic B cell population. To date we have identified prereceptor B cells of several specificities whose frequency is much lower in the spleen and whose elimination appears to involve tolerance rather than antiidiotypic regulation. However, the demonstration that such cells are eliminated by contact with self-antigens has not as yet been accomplished.

2,4-Dinitrophenol↗
PubMed1985

Differences in antibody repertoires for (4-hydroxy-3-nitrophenyl)acetyl (NP) in splenic vs immature bone marrow precursor cells.

To evaluate the contribution of environmental regulatory mechanisms in fashioning the primary B cell repertoire, we have compared the repertoire of (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific primary splenic B cells with that of precursor cells present as surface immunoglobulin-negative (sIg-) cells in adult bone marrow of C.B20 (Ighb) mice. Previous analyses using a variety of antigens have led to the conclusion that the antibody repertoire expressed in the spleen is similar to that expressed in newly generated B cell precursors with respect to both repertoire diversity and the representation of various predominant clonotypes. However, in the response to NP of C.B20 precursor cells, two marked disparities have been identified between the repertoire of sIg- bone marrow cells vs splenic precursor cells. The first concerns precursor cells that give rise to lambda-bearing NP-specific antibodies with heteroclitic fine specificity. Such antibodies normally dominate the primary response of Ighb mice; however, the representation of precursor cells giving rise to lambda-bearing antibodies is disproportionately low in the sIg- bone marrow cell population of C.B20 mice. Thus, during the maturation of these cells, post-sIg receptor expression, there is an apparent increase in the proportionate representation of lambda-bearing NP-specific cells. The second disparity concerns precursor cells whose antibody products bear kappa-light chains and exhibit high affinity and homoclitic binding for the NP haptenic determinant. Such precursor cells are poorly represented in the spleen, but represent a sizeable proportion of the sIg- NP-specific precursor cell population. Thus, there seems to be a selective elimination of high affinity, kappa-homoclitic anti-NP antibody-bearing cells as they acquire their sIg receptors. The elimination of this cell population could partially account for the dominance of lambda-heteroclitic antibodies in the serum responses to NP of C.B20 mice.

Animals↗
PubMed1983

B cell repertoire diversification precedes immunoglobulin receptor expression.

68 monoclonal antibodies specific for the hemagglutinin (HA) of the influenza virus, PR8, were obtained from sIg- bone marrow B cell precursors stimulated in splenic fragment cultures. Reactivity pattern (RP) analysis demonstrated that these anti-HA antibody responses included at least 29 distinguishable clonotypes. Comparison of the specificities of anti-HA antibodies obtained from sIg- bone marrow cells with those obtained from adult spleen cells indicates that the anti-HA repertoires of the two populations are comparable in diversity. Since the sIg- bone marrow B cell precursor pool presumably has not encountered V region-specific regulatory mechanisms in vivo, our data suggest that substantial diversification of the B cell repertoire precedes surface immunoglobulin (sIg) expression and subsequent interaction with environmental regulatory processes.

Animals↗
PubMed1983

The contagiosity of tuberculosis.

Although a few advanced thinkers understood the contagious nature of tuberculosis in the middle of the last century, more precise concepts of transmission awaited Pasteurs's demonstration in 1862 that organisms exist in the air and Koch's identification of the tubercle bacillus in 1882. At the end of the last century Cornet presented evidence that tuberculosis was dust-borne, and Flügge presented equally convincing evidence that tuberculosis was droplet-borne. Chapin, in 1910, summarized evidence against the prevaling belief in airborne transmission of many common infections but made an exception of tuberculosis. Chapin emphasized transmission by direct contact (touching). In the 1930's William F. Wells introduced the droplet nucleus hypothesis. In the 1950's droplet nuclei were shown to be the carriers of infection from tuberculosis patients to guinea pigs breathing air vented from the patients' ward. Subsequent evidence has indicated that direct contact is unimportant, although close proximity facilitates airborne transmission. Attempts to control the spread of tuberculosis by air disinfection or by immunization have been disappointing. Specific antituberculosis drugs, widely used since the 1950's, cause patients to become noninfectious for others very rapidly, even before organisms in the sputum disappear. Chemotherapy is now recognized as the corner stone of contagion control.

Air Microbiology↗
PubMed1982

A postscript to Circulation of the blood: men and ideas.

Since 1964, when Fishman and Richards published Circulation of the Blood: Men and Ideas, Guyton's model of the circulation, in which mean circulatory pressure serves as the upstream pressure for venous return, has been extended, and the concept of vascular smooth muscle tone acting like the pressure surrounding a Starling resistor has been postulated. According to this scheme, the positive zero flow intercepts of rapidly determined arterial pressure-flow curves are the effective downstream pressures for arterial flow to different tissues. The arterioles, like Starling resistors, determine the downstream pressures and are followed by abrupt pressure drops, or "waterfalls." Capillary pressures are closely linked to those of the venules into which they flow. Capillary-venular pressures are the upstream pressures for venous return. In exercising muscles, reduced arteriolar tone lowers arteriolar pressure and increases arterial flow. This, in turn, raises capillary-venular pressure and increases venous flow. The arteriolar-capillary waterfall is decreased or eliminated. Total blood flow is increased by diversion of blood from tissues with slow venous drainage to muscles with fast venous drainage (low resistance X compliance). The heart pumps away the increased venous return by shifting to a new ventricular function curve.

Animals↗
PubMed1982

Immune responses to complex protein antigens I. MHC control of immune responses to bovine albumin.

Murine T cell proliferative and antibody responses to the multi-determinant protein bovine serum albumin (BSA) are controlled by Ir genes mapping within the H-2 gene complex. Strains possessing the H-2k, H-2a, and H-2d haplotypes are classified as high responders to BSA. In contrast, H-2b strains are low responders to BSA. Genetic mapping experiments employing strains with recombinant H-2 haplotypes indicate that both T cell proliferative and antibody responses are at least in part regulated by genes within the I-A subregion. Studies on the inhibition of T cell proliferation by monoclonal anti-Ia antibodies are consistent with the assignment of an Ir gene for BSA to the I-A subregion and strongly suggest a role for genes within the I-E/C subregions as well. The MHC-mediated control of antibody responses did not affect the affinity or the isotype of the antibody produced. The relative quantities of antibody specific for each of the three domains of BSA appears to be regulated by H-2-linked BSA Ir genes, and domain III antigenic determinants were found to be dominant in the responses of low-responder mice and in the early response of high-responder mice. This domain III epitope dominance essentially disappears by the tertiary response of high-responder mice.

Animals↗