William E. Gathings

A Distinctive Pattern of B Cell Immaturity in Perinatal Humans

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

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

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.

Immunoglobulin Isotype Expression of Normal Pre-B Cells as Determined by Immunofluorescence

We have undertaken an immunofluorescent analysis of the immunoglobulin heavy and light chains expressed by pre-B cells from normal human fetal and adult bone marrow using purified mouse monoclonal and goat antibodies to human immunoglobulin isotypes. Our results indicate that (i) the great majority of normal pre-B cells in both fetuses and adults expresses intracytoplasmic μ chains only, (ii) immunoglobulin light-chain synthesis may be initiated during a late stage in pre-B-cell development, and (iii) heavy-chain isotype switching at the pre-B-cell stage may not occur during normal B-cell development.

X-linked B lymphocyte deficiency. I. Panhypo-γ-globulinemia and dys-γ-globulinemia in siblings

In two families with x-linked B lymphocyte deficiency, siblings were found to have either panhypo-γ-globulinemia or dys-γ-globulinemia. Despite differences in serum immunoglobulin patterns and severity of symptoms, a marked deficiency in surface immunoglobulin-bearing lymphocytes occurred in all affected males. These studies suggest that the primary defect in these patients is in the development of circulating B lymphocytes and that normal levels of serum IgA and IgD can be attained despite this deficiency.

Expression of Three Immunoglobulin Isotypes by Individual B Cells During Development: Implications for Heavy Chain Switching*

ABSTRACT: Previous studies in mice and humans have shown that the first IgA+ and IgG+ B cells appearing during ontogeny also bear IgM on the surface. The acquisition of IgD seems to occur at a later stage in differentiation. In this study we have combined autoradiography with two‐color immunofluorescence to directly detect human B cells expressing three surface isotypes. We report that the vast majority of IgA+ cells in the neonate also bear IgM and IgD; the same holds true for IgG+ cells. This phenotype is peculiar of newborns, while in the adult the majority of IgA+ and IgG+ cells are single. We discuss the genetic implications of such a finding for heavy chain switching.