Loss of immune competence with age may be due to auto-anti-idiotypic antibody regulation

Szewczuk, Myron R.; Campbell, Rita J.

doi:10.1038/286164a0

Cited by 70 publications

(24 citation statements)

References 17 publications

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“…Because polyclonal activation appears to circumvent regulatory T cells that normally suppress autoreactive clones, it was proposed that inefficient T cell suppression in aging animals allows these clones to produce demonstrable autoantibodies (28). Agerelated deficiencies in suppression of autoreactive clones might also account for dysregulation of auto-anti-idiotype antibody responses, which were found to increase in aging mice immunized with T-independent (29) or T-dependent (30) antigens.…”

mentioning

confidence: 99%

Immunoregulation in senescence: increased inducibility of antigen-specific suppressor T cells and loss of cell sensitivity to immunosuppression in aging mice.

Doria¹,

Mancini²,

Adorini³

1982

Proc. Natl. Acad. Sci. U.S.A.

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Azobenzenearsonate (ABA)-specific T cell-mediated suppression has been studied in aging mice. ABA-specific suppressor T cells were induced in young and old mice by injection ofABA conjugated to syngeneic spleen cells (ABA-SC). These suppressor cells were tested for their ability to suppress the in vitro anti-trinitrophenyl (TNP) antibody response of lymph node cells obtained from ABA-keyhole limpet hemocyanin (KLH)-primed young or old mice and cultured with TNP-ABA-KLH. Suppressor T cells were found to be more easily induced in old than in young mice but to suppress less efficiently the antibody response of cells from old than from young mice. The increased inducibility of antigen-specific suppressor T cells in old mice is compatible with the age-dependent decline of immune responsiveness to exogenous antigens. The loss of cell sensitivity to antigen-specific immunosuppression as well as the lack of evidence for increased nonspecific suppression in old mice is consistent with the age-related increase in autoimmune disorders. These findings provide a unifying explanation for the most relevant immunological phenomena of senescence.Immunologic mechanisms are involved to a large extent in the biologic processes of aging, as reviewed by Walford (1). The maximal lifespan, which appears to be regulated by a finite set of genes (2), is significantly influenced by the major histocompatibility complex (3), which plays a fundamental role in the genetic control of immunologic functions (4). Morphologic, functional, and pathologic alterations occurring in aging animals are associated with both progressive decline of immune responsiveness to exogenous antigens and increasing incidence of autoimmune phenomena (5).The decline of immune responsiveness results mostly from alterations of lymphoid cell populations rather than from changes in the animal milieu during senescence (6). Number and activity of macrophages seem to be unaffected by aging (7-9). Most reports indicate no or only a slight decrease in lymphocyte number but profound functional defects in B cell and helper T cell populations during senescence (10-17). The decrease in helper activity has been attributed to thymus involution (18) and subsequent reduced concentration ofthymic factors (19-21) involved in the differentiation ofprecursor cells into functionally mature T cells (22).The incidence of autoantibodies in mice and men shows a dramatic increase with age (23). The B cell resistance to tolerance induction to foreign antigens in old mice (24), the increased level ofT cells binding autologous erythrocytes in old mice (25) and men (26), and the increased response of old mice to chemically altered syngeneic erythrocytes (27) underlie an enhanced propensity to lose self-tolerance during senescence. Age-dependent changes in the capacity to maintain self-tolerance have also been suggested by the higher efficiency of polyclonal activators, such as lipopolysaccharide, to stimulate an autoantibody response against syngeneic erythrocytes in old mice. Because poly...

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mentioning

confidence: 99%

Immunoregulation in senescence: increased inducibility of antigen-specific suppressor T cells and loss of cell sensitivity to immunosuppression in aging mice.

Doria¹,

Mancini²,

Adorini³

1982

Proc. Natl. Acad. Sci. U.S.A.

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“…These antibodies could bind anti-TNP antibodies of the same strain origin, but not TNP itself [29]. Furthermore, these anti bodies were of the IgG2a and lgG3 classes [27], and revealed anti-[anti-TNP F(ab'h IgG] titer as assayed by passive hemaggluti nation [27,29], In recent studies, it has been shown that auto-anti-idiotypic antibodies may be in part responsible for an age-associated decline in immune responsiveness to T-dependent [26,28] and T-independent [12,26] antigens. We have also reported that the age-associated regulation by auto-anti-idiotypic antibody in C57BL/6J mice appears to be a general phe nomenon for immune responses to haptenconjugated antigens as well as to soluble pro tein antigens [26],…”

Section: Discussionmentioning

confidence: 99%

“…This suppressive effect of auto-anti-idiotypic antibody was at tributed possibly to its simultaneous binding of surface Ig and Fc receptors on the surface of the B cell, thus inhibiting antibody secre tion [11], In previous studies, we have shown that the decline in the number of plaque forming cells (PFC), loss of high affinity PFC, and the increase in hapten-augmentable PFC with age in the spleen of C57BL/6J male mice may be due to auto-anti-idiotypic anti body regulation [28], In contrast, mucosal immunity in old C57BL/6J mice, as mea sured in PFC responses of the mediastinal (BLN) and mesenteric (MLN) lymph nodes, was not reduced [31]; further, there was no loss of high affinity antibody-secreting cells [30], and there was no appreciable appear ance of anti-idiotype-blocked, hapten-aug mentable PFC [29] in these areas. These find ings support the hypothesis that the systemic and mucosal B cell repertoires do not un dergo parallel changes with age [33].…”

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confidence: 99%

Age-Related Strain Differences in the Development of Auto-Anti-Idiotypic Antibody Regulation in the Splenic and Mucosal-Associated Lymphoid Systems

Szewczuk¹,

Wade²

1985

Gerontology

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In the present study, we examined the changes that occur with age in anti-idiotype-blocked, hapten-augmentable PFC in the mucosal-associated lymph nodes (MLN and BLN) and spleen of various strains of mice. 2-month-old 129/J, AKR/J, and C57L/J mice had a high percentage of hapten-augmentable PFC in their spleen, MLN, and BLN; however, by 6–11 months these values had declined considerably in the spleen, while mucosal values remained high. In contrast, 2-month-old C57BL/6J, DBA/2J, and C3H/HeJ mice had a low percentage of hapten-augmentable PFC in their spleen, MLN, and BLN; but by 6–11 months these values had increased considerably in the spleen, while mucosal values remained low. CBA/J and SJL/J mice maintained high and low levels, respectively, of hapten-augmentable PFC in their spleens, MLN, and BLN over the age span. NZB/BinJ mice were found to be low producers in the spleen, but high in the MLN and BLN at 2 and 6 months of age. These data indicate that there are strain differences in the development of auto-anti-idiotypic antibody regulation with age.

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“…T cells from Id-suppressed mice when added did rescue the anti-Id response of Pn-primed B cells while T cells from normal Pn-primed mice did not do so. Addition of 1610 5 T cells from Id-suppressed mice determined an increase, even though not statistically significant, of the number of anti-Id AFC as compared to the same amount of T cells from normal BALB/c (16 ± 4 and 8 ± 4 respectively). Addition of higher number of T cells from Id-suppressed mice led to a further increase of anti-Id response.…”

Section: In Vitro Anti-id Responsementioning

confidence: 99%

“…Anti-Id antibody has been implicated in the down-regulation of antigen-specific response and B-cell tolerance, 2,3 the decline of antigen-specific response in aging, 4,5 suppression of allograft rejection in pregnancy 6 and in the pathogenesis of various diseases related to immune disorders. 7 The antibody response to phosphorylcholine (PC), an immunodominant epitope of certain pneumococci, has been extensively studied both at cellular and molecular level 8,9 and it was found that the PC-specific response was dominated by antibody molecules encoded by V H -1(S-107), D H FL16.1, J H 1, V k 22 and J K 5 and that expressed the public idiotype T15.…”

Section: Introductionmentioning

confidence: 99%

Autologous anti‐idiotypic antibody response is regulated by the level of circulating complementary idiotype

Borghesi

Nicoletti

1996

Immunology

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SUMMARYBALB/c mice injected with lyophilized vaccine from Streptococcus pneumoniae R36a (Pn) predominantly responded with antibody molecules the vast majority of which expressed the public idiotype T15 and were directed to the immunodominant epitope phosphorylcholine (PC). However, after a single immunization with Pn vaccine young (3-month-old) BALB/c mice did not produce any specific anti-T15 antibody response. In contrast, young D1.LP mice were able to mount a specific anti-T15 response upon primary immunization with pneumococcal vaccine. The anti-PC response in the two mouse strains differed in that the proportion of antibody molecules that expressed the T15 idiotype for Pn-primed D1.LP mice showed a smaller proportion of PC-specific antibody expressing the T15 idiotype. Neonatal injection of anti-T15 monoclonal antibodies led to a long-term suppression of the PC-specific T15 B-cell clones but at young/adult age these mice maintained the ability to produce a normal amount of PC-specific antibody. Interestingly, the idiotypically-suppressed BALB/c mice mounted a significant anti-T15 response during the primary response to Pn. We interpreted these data as showing that the level of circulating idiotype may regulate the production of the complementary antiidiotypic antibody. In addition, in vitro experiments demonstrated that the lack of the anti-T15 response during primary antibody response in BALB/c mice is probably because of a state of tolerance that is regulated by T cells.

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Loss of immune competence with age may be due to auto-anti-idiotypic antibody regulation

Cited by 70 publications

References 17 publications

Immunoregulation in senescence: increased inducibility of antigen-specific suppressor T cells and loss of cell sensitivity to immunosuppression in aging mice.

Immunoregulation in senescence: increased inducibility of antigen-specific suppressor T cells and loss of cell sensitivity to immunosuppression in aging mice.

Age-Related Strain Differences in the Development of Auto-Anti-Idiotypic Antibody Regulation in the Splenic and Mucosal-Associated Lymphoid Systems

Autologous anti‐idiotypic antibody response is regulated by the level of circulating complementary idiotype

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