B lymphocytes: how they develop and function

Publisher Summary This chapter discusses the impact of new information concerning IgA physiology on the immune system. IgA should not be considered only as an isotype providing specific humoral protection of mucosal surfaces but as an integral component of the entire immune system. An unusual structural feature of human IgA is the heterogeneity of the molecular forms with characteristic distribution in various body fluids. Though most IgA in serum displays a typical four-polypeptide chain structure of the basic molecule with two Q and two light (L) chains, external secretions contain dimeric and tetrameric, disulfide-linked molecules associated with additional polypeptides-J (joining) chain and secretory component (SC). IgA-producing plasma cells are distributed in various lymphoid and nonlymphoid tissues and are particularly preponderant in the lamina propria of the gut; in salivary, lacrimal, and lactating mammary glands; and in the human bone marrow. IgA occurs in different body fluids in predominantly polymeric or monomeric (plasma, cerebrospinal fluid) forms with a characteristic distribution of IgAl and IgAz molecules. Under normal conditions, an absolute majority of IgA-containing cells in secretory glands and tissues also contain J chain whereas such cells in, for example, normal bone marrow does not. Staining with fluorochrome-labeled anti-J chain is enhanced by the pretreatment of alcohol-fixed tissue sections with acid urea, which leads to the exposure of masked antigenic determinants of intracellular J chain. Specialized lymphoid tissues associated with mucosal surfaces play an essential role in the induction and regulation of generalized immune responses in external secretions.

Immunoglobulin A (IgA): molecular and cellular interactions involved in IgA biosynthesis and immune response.

Malignant Lymphomas Other than Hodgkin’s Disease

In this Review, Nicole Baumgarth describes the development and functions of B-1 cells. These innate-like B cells serve as the major source of natural antibody in mice, and can have important roles in defence against mucosal pathogens and in maintaining tissue homeostasis. During their development, B and T cells with self-reactive antigen receptors are generally deleted from the repertoire to avoid autoimmune diseases. Paradoxically, innate-like B-1 cells in mice are positively selected for self-reactivity and form a pool of long-lived, self-renewing B cells that produce most of the circulating natural IgM antibodies. This Review provides an overview of the developmental processes that shape the B-1 cell pool in mice, outlines the functions of B-1 cells in both the steady state and during host defence, and discusses possible functional B-1 cell homologues that exist in humans.

The double life of a B-1 cell: self-reactivity selects for protective effector functions

Most Gram-positive bacteria incorporate membrane- or peptidoglycan-attached carbohydrate-based polymers into their cell envelopes. Such cell-wall glycopolymers (CWGs) often have highly variable structures and have crucial roles in protecting, connecting and controlling the major envelope constituents. Further important roles of CWGs in host-cell adhesion, inflammation and immune activation have also been described in recent years. Identifying and harnessing highly conserved or species-specific structural features of CWGs offers excellent opportunities for developing new antibiotics, vaccines and diagnostics for use in the fight against severe infectious diseases, such as sepsis, pneumonia, anthrax and tuberculosis.

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Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions

Publisher Summary Paralysis is seriously considered only in the “two specific signal” hypothesis by postulating that the first signal, generated by the combination of antigen with the specific receptor, results in tolerance rather than induction, except if the cell is simultaneously exposed to the second specific signal, generated by the recognition of the antigen by associative antibody. This model of associative recognition is designed in order to explain self-nonself discrimination and denies the existence of truly thymus-independent (TI) antigens as well as the possibility of triggering B cells by any mechanism not involving the first specific signal. The main general conclusion concerning induction of paralysis by TI antigens is that specific B cells are turned off at higher concentrations of the TI antigen than those causing activation. TI antigens do induce specific B cells directly and one cannot exclude that at least some of them also activate other cell types, including T cells, nor that some or possibly all of them interact with macrophages. It is suggested that the effects on other cell types represent trivial or optimizing events on top of the basic, fundamentally effective mechanism of direct B-cell activation. All TI antigens are competent to activate B cells polyclonally and this nonspecific property seems to be responsible for induction of specific cells. The inactivation of competent specific cells is also a result of the interaction between nonspecific surface receptors and the competent ligand.

Thymus-independent B-cell induction and paralysis.

CERTAIN antigens are known to be immunogenic in the absence of thymus-derived (T) lymphocytes1–5. One extreme explanation of this is that all antigens are fundamentally thymus-independent, whereas the contrary view is to deny the experimental evidence for the existence of this type of antigen6. Another explanation for thymus-independency is based on the structure of these molecules, which are characterized by repeating antigenic determinants. This special structure would make it possible for the molecules to establish multiple interactions with the immunoglobulin receptors of the B cells and thus cause their activation7.

B cell mitogenic properties of thymus-independent antigens.

The present experiments were performed in order to analyze the mechanism by which thymus-independent antigens (nonspecific B-cell mitogens) can induce specific immune responses to antigenic determinants present on the same molecule. The hapten NNP was coupled to the B-cell mitogen, lipopolysaccharide (LPS). The conjugate retained full mitogenic activity and bound specifically to NNP-reactive cells. NNP-LPS activated polyclonal as well as specific anti-NNP antibody synthesis, but the optimal concentrations for induction of specific anti-NNP cells were several orders of magnitude lower than the concentrations required for polyclonal activation. These low concentrations failed to activate nonspecific cells, but they induced specific thymus-independent responses of high-avidity NNP-specific cells with the typical kinetics of antigenic responses in vitro. Furthermore, hapten-specific cells were paralyzed by NNP-LPS concentrations that were optimal for induction of polyclonal activation. Specific activation and paralysis could be abolished by free hapten indicating that selective binding of NNP-LPS to hapten-specific cells was responsible for the specificity of the response. However, the triggering signal lacked specificity, since high-avidity specific anti-NNP cells could still be activated by stimulating concentrations of NNP-LPS in the presence of free hapten, even though the Ig receptor combining sites were presumably occupied by NNP. The findings show that B cells with specific Ig receptors for the antigenic determinants on mitogen molecules preferentially bind these molecules and become activated at concentrations still unsufficient to trigger other B cells that lack specific receptors. It is suggested that activation for primary IgM responses in B cells is the result of "one nonspecific signal." This nonspecific signal is provided by the mitogenic properties of some antigens (highly thymus independent or, alternatively, by nonspecific T-cell factors (for highly T cell-dependent antigens), or both, and the surface structures responsible for triggering are not the Ig receptors. The specific Ig receptors only act as passive focusing devices for nonspecific stimuli, entitling the cell to be selectively activated, even though both the signal and the receptors for the triggering are nonspecific.

https://rupress.org/jem/article-pdf/139/1/74/1392889/74.pdf

Mechanism of thymus-independent immunocyte triggering : mitogenic activation of b cells results in specific immune responses

We studied the pattern of responsiveness of normal spleen cells to three different B cell mitogens: dextran sulfate (DS), lipopolysaccharide (LPS) and purified protein derivative of tuberculin (PPD). Activation by DS results in extensive proliferation of cells, most of which are not high-rate antibody-secreting cells and can be reactivated. PPD activates high-rate antibody synthesis in cells which are more restricted in mitotic capacity. LPS seems to activate both of these subsets of B cells.



LPS exhibits strong mitogenicity in vivo and a large fraction of LPS-activated cells are high-rate antibody-secreting end cells.



It is suggested that these distinct subsets of B cells include cells at different stages of differentiation.

Selective triggering of B cell subpopulations by mitogens.

Mouse spleen cells were successfully activated by mitogens in serum-free medium. The T cell mitogen, concanavalin A (ConA), was found to activate DNA synthesis in the presence or absence of serum to the same extent, although the dose response curve was shifted. Thus, concentrations ten times lower were optimally stimulating in serum-free medium. The strain differences existing with regard to Con A activation were the same whether serum was present or not. B cell mitogens, such as lipopolysaccharide (LPS) and purified protein derivative (PPD) of tuberculin, were equally active in the presence or absence of serum with regard to dose response curves and kinetics for the induction of DNA synthesis.



When added to normal spleen cells in culture in the absence of serum, Con A also activated antibody synthesis against a variety of antigens and haptens. It had no such effect on spleen cells from nude animals, indicating that it exerted its B cell-activating effect via T cells. It was also effective when DNA synthesis in the lymphocytes had been suppressed with mitomycin.



LPS and PPD activated antibody synthesis to haptens in normal and nude spleen cells, the response in nude animals being markedly stronger.



Since there is virtually no background antibody synthesis in unstimulated cultures in the absence of serum, but a substantial background in serum, it follows that the factor of activation caused by T and B cell mitogens is more pronounced in the absence of serum.

A. Coutinho

Papers

Thymus-independent B-cell induction and paralysis.

B cell mitogenic properties of thymus-independent antigens.

Mechanism of thymus-independent immunocyte triggering : mitogenic activation of b cells results in specific immune responses

Selective triggering of B cell subpopulations by mitogens.

In vitro activation of mouse lymphocytes in serum-free medium: effect of T and B cell mitogens on proliferation and antibody synthesis.