Antibody-specific immunoregulation and the immunodeficiency of aging.

Abstract

One manifestation of the aging process is a gradual decrease in the ability of aged individuals to mount a humoral immune response (1-4) . Studies at the cellular level demonstrated that much of this diminished reactivity can be attributed to the environment of the aged animal itself, which limits the responsiveness of the available B cells (3)(4)(5)(6)(7)(8) .This laboratory (9) and others (10) have observed that, after immunization with a given antigen, immunoregulatory mechanisms develop that are best evidenced by the suppression of the capacity of primary B cells to respond to the same antigenic determinant . In our experiments, this suppression appears to be specific for idiotypic determinants expressed on the primary B cell receptors, because such suppression obtains only for B cells specific for the immunizing antigen and is not capable of suppressing B cells of murine strains differing in the idiotype-allotype genetic locus (9) . Thus, for example, BALB/c mice immunized with 2,4-dinitrophenyl (DNP)-hemocyanin and subsequently used as the adoptive irradiated hosts in B cell transfer experiments suppress the response of primary BALB/c DNP-specific B cells but facilitate the response of primary B cells from B10 .D2 or CB20 donors that differ from BALB/c mice in the immunoglobulin heavy chain locus .Because the effects of this antibody-specific immunoregulation appear to be longlasting, we reasoned that the antigenic experiences of a lifetime could eventuate in the accumulation of suppressive recognition for a large proportion of an individual's normal primary B cell repertoire . The experiments described in this report test this hypothesis . We have assessed the capacity of the environment or cells of aged individuals, who have never been immunized to the hapten DNP, to suppress the responses of primary DNP-specific B cells derived from young syngeneic or allotype allogeneic donors. The results indicate that aged individuals have indeed accumulated the capacity to suppress the responses of syngeneic primary B cells but not the responses of primary B cells differing in the heavy chain allotype locus . Materials and MethodsAntigens. The proteins hemocyanin (Hy) and bovine serum albumin, and the antigens DNPt o-Hy and DNPIS-bovine serum albumin were prepared and characterized as previously described (9) .Animals and Immunization . 24-26-mo-old BALB/c male mice and their 2-mo-old cohorts were obtained from the Charles River Breeding Laboratories, Inc ., Wilmington, Mass. 2-mo-old * Supported by grants AGO 1514 and AGO 1743 from the United States Public Health Service . J . Exp. MED.

Aging and the Immune Response

“…Zharhary (1986), for example, reports that T-cell-defìcient ("athymic nude") mutant mice do not exhibit an age-dependent de cline in hapten-specific frequencies in splenic fragment culture, and shows fur ther that allowing B or pre-B cells to devel op (in irradiated young host mice) in the presence of T cells from old animals leads to a decline in the frequencies of respon sive B cells, in comparison to hosts that had received T cells from young controls. Klinman ( 1981 ) has also demonstrated a Tcell-dependent alteration in B-cell ac tivity: hapten-specifìc B cells fail to func tion well in old hosts if the host and B-cell donor are identical at the Ig heavy-chain gene locus. T cells in the aged hosts were apparently able to limit the responses of introduced, Ig-matched B cells by recogni tion of specific idiotypic determinants.…”

Old mice recover the ability to produce IgG and high-avidity antibody following irradiation with partial bone marrow shielding.

“…Aged mice also have an increased incidence of autoantibodies and produce more anti-idiotype (Id) autoantibody following primary immunization (2,3). The increased anti-Id autoantibody response of old animals reflects changes in the peripheral B-cell population.…”

Age-Associated Changes in Antibody-Forming Cells (B Cells)

“…This anti-idiotypic antibody (Ab2) could down-regulate the production of idiotypic antibody. We and others have shown that with aging there occurs a marked increase in the production of auto-anti-idiotypic antibody (Ab2) in mice (26,27,32) and in adult humans (48). At the serologic level, we were able to demonstrate that, following immunization with the same antigen, animals of different ages show a change in the expression of the antibody repertoire.…”

“…That is to say that the predominant response to a defined antigen in animals of different ages produces antibodies that utilize different genes. Concomitant with these changes in the expressed antibody repertoire in aged animals, regulatory mechanisms involving the idiotypic network are markedly increased in the immune response of the aged (26,27,32). Simply stated, it has been suggested that antibodies that recognize the variable portion of another antibody can affect the immunoglobulin level present in the serum.…”

“…Although the kinetics of the immune response are similar, the magnitude of the response to thymic-independent and thymic-de-pendent (TD) antigens are both generally depressed (24)(25)(26)(27). The increased affinity of antibody seen in sera after antigenic stimulation (known as the maturation of the immune response) with a thymic-dependent antigen in the young adult is profoundlj altered in the immune response of the aged.…”