IgA myeloma proteins of kappa- and lambda-types were isolated from two patients. These were used to produce and purify anti-idiotype antibodies of both broad (myeloma-related) and narrow (individual myeloma) specificities. The anti-idiotype antibodies were conjugated with fluorochromes and used as immunofluorescent probes to trace in the patients clonal expansion at different levels of B-cell differentiation. Our results (a) confirm that B lymphocyte precursors in IgA plasma-cell myelomas are involved in the malignant process, (b) show that B lymphocytes of the malignant clone include those expressing each of the major heavy-chain isotypes, mu, delta, gamma, and alpha, and (c) provide strong circumstantial evidence that pre-B-cell members of the malignant clone are also increased in frequency. T cells expressing idiotypic determinants were not detected. These findings argue that the initial oncogenic event may occur in a B-stem cell and is not influenced through stimulation by antigen. An interesting association was the increased frequency of related clones of B lymphocytes as detected by their reactivity with anti-idiotype antibodies of broad specificity. Neither plasma cell nor pre-B-cell members of these related clones were increased in frequency. Anti-idiotype antibodies or helper T cells reactive with myeloma-related idiotypes could be responsible for this phenomenon. We discuss other implications of these findings and speculate that all of the various phenotypes of B-lineage malignancies may result from oncogenic processes affecting stem cell targets.

https://rupress.org/jem/article-pdf/150/4/792/1393557/792.pdf

Studies on the clonal origin of multiple myeloma. Use of individually specific (idiotype) antibodies to trace the oncogenic event to its earliest point of expression in B-cell differentiation.

Mouse pre-B cells synthesize and secrete mu heavy chains but not light chains.

https://www.cell.com/immunity/pdf/1074-7613(94)90036-1.pdf

Rabbit IgH sequences in appendix germinal centers: VH diversification by gene conversion-like and hypermutation mechanisms.

It has lotig been evident that humans are not fully immunocompetent at birth. An inability of newborns to defend successfully against infectious agents can be a grim reminder of this fact. Since learning that immunocompetent cells begin their development well before the end of the first trimester of gestation and are abundant by the time of birth, the idea of immunological inexperience has become an attractive explanation for the heightened susceptibility of newborns to overwhelming infections. Functional immaturity of nonspecific systems of immunity, such as phagocytic cells and the cotnplement system, has also been invoked. While these factors may contribute to the relative immunodeficiency, it is also well documented that specific immune responses may be quantitatively and qualitatively deficient in newborns and young infants. In studies of the ontogeny of antibody responsiveness, the intriguing observation was made that the capacity to respond to different antigens may be acquired at different times during development (Silverstein 1972). The acquisition ofthe ability to respond first has been referred to as antigenic hierarchy. The idea that clonal diversification of immunocompetent cells is a gradual process, perhaps due to somatic mutational mechanisms, was once held to be a likely explanation. Although not fully discredited, our present understanding of the genetic basis for clonal diversity of immunocompetent cells renders this idea far less appealing. Over the last few years, it has become apparent that specific immune responses, both positive and negative, depend upon a network of interactions between multiple subpopulations of immunocompetent cells. Viewed in its simplest form, this can be thought of in terms of interactions between helper T cells, suppressor T cells and B cells of diverse clones that are initiated via antigen presentation by macrophages. or other la* cells, which may also facilitate T and

A Distinctive Pattern of B Cell Immaturity in Perinatal Humans

It is now well known that B cells characteristically express immunoglobulin receptors on their surface. On average, each B lymphocyte bears approximately 10̂ immunoglobulin molecules on its outer cell membrane. A relatively small portion of the carboxy terminal end of the immunoglobulin molecule is embedded in the fluid membrane, and the rest of the surface antibody receptor is exposed. Since these receptors for antigen are intimately involved both in antigen triggering of the immune response and in the induction of specific immune tolerance, it is perhaps not surprising that cross-linkage of surface immunoglobulins with divalent ;mti-Ig antibodies may have either positive or negative effects. Our studies of the effects of anti-Ig antibodies have been concerned chiefly with their inhibitory effects on B cells. We have used antibodies specific for immunoglobulin isotype and allotypic determinants to examine different stages in the life history of B cells. These studies, conducted in chickens, mice, rabbits and humans, led directly to demonstration of the existence of an immature IgM* B lymphocyte whose development is easily blocked by cross-linkage of surface IgM molecules and which has the capacity to give rise to B cells which produce other immunoglobulin isotypes. Indirectly these studies led to the identification of a very immature cell type of B lineage in mammals, the so-called pre-B cell, which has the unusual feature of expressing;/ chains only in the cytoplasm, i.e., surface immunogiobulin receptors are lacking. It is during this stage in differentiation that allelic exclusion is expressed and the process of clonal diversity is initiated.

Effects of Anti‐Ig Antibodies on the Development and Differentiation of B Cells

Pre-B cells in developing rabbits were identified by immunofluorescence as cells containing small amounts of cytoplasmic IgM (cIgM) but lacking surface immunoglobulin (sIg). During ontogeny the first pre-B cells appeared in fetal liver at 23 days gestation, 2 days before the appearance of sIgM+ B lymphocytes. Pre-B cells were relatively frequent in fetal and adult bone marrow, but were not found in other tissues except rarely in fetal spleen. Allelic exclusion is apparently established at this early stage of development, because individual pre-B cells and B lymphocytes from heterozygous rabbits expressed only one of the alternative alleles in amounts sufficient for detection. Development of isotype diversity among rabbit B lymphocytes followed the general pattern seen in mouse and man. sIgM+ cells were detected before birth. Expression of sIgG was detected in neonatal rabbits on cells which were also sIgM+ but in older animals most sIgG+ cells lacked sIgM. Cells bearing sIgA were not found until 5-6 days of age, and had no other isotype on their surface.

https://rupress.org/jem/article-pdf/148/5/1367/1089604/1367.pdf

Pre-B and B cells in rabbits. Ontogeny and allelic exclusion of kappa light chain genes.

Progestins, synthetic compounds designed to mimic the activity of natural progesterone (P4), are used globally in menopausal hormone therapy. Although the older progestins medroxyprogesterone acetate (MPA) and norethisterone (NET) have been implicated in increased breast cancer risk, little is known regarding newer progestins, and no significant risk has been associated with P4. Considering that breast cancer is the leading cause of mortality in women, establishing which progestins increase breast cancer incidence and elucidating the underlying mechanisms is a global priority. We showed for the first time that the newer-generation progestin drospirenone (DRSP) is the least potent progestin in terms of proliferation of the estrogen-responsive MCF-7 BUS breast cancer cell line, while NET and P4 have similar potencies to estradiol (E2), the known driver of breast cancer cell proliferation. Notably, MPA, the progestin most frequently associated with increased breast cancer risk, was significantly more potent than E2. While all the progestogens enhanced the anchorage-independent growth of the MCF-7 BUS cell line, MPA promoted a greater number of colonies than P4, NET or DRSP. None of the progestogens inhibited E2-induced proliferation and anchorage-independent growth. We also showed that under non-estrogenic conditions, MPA and NET, unlike P4 and DRSP, increased the expression of the estrogen receptor (ER) target gene, cathepsin D, via a mechanism requiring the co-recruitment of ERα and the progesterone receptor (PR) to the promoter region. In contrast, all progestogens promoted the association of the PR and ERα on the promoter of the PR target gene, MYC, thereby increasing its expression under non-estrogenic and estrogenic conditions. These results suggest that progestins differentially regulate the way the PR and ER converge to modulate the expression of PR and ER-regulated genes. Our novel findings indicating similarities and differences between P4 and the progestins, emphasize the importance of comparatively investigating effects of individual progestins rather than grouping them as a class. Further studies are required to underpin the clinical relevance of PR/ERα crosstalk in response to different progestins in both normal and malignant breast tissue, to either confirm or refute their suitability in combination therapy for ER-positive breast cancer.

/pdf/upregulation-of-an-estrogen-receptor-regulated-gene-by-first-1ien6wng.pdf

Upregulation of an estrogen receptor-regulated gene by first generation progestins requires both the progesterone receptor and estrogen receptor alpha

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Pre-B and B cells in rabbits. Ontogeny and allelic exclusion of kappa light chain genes.

Upregulation of an estrogen receptor-regulated gene by first generation progestins requires both the progesterone receptor and estrogen receptor alpha