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The new immunosenescence paradigm (2015) was an attempt to explain a mechanism by which macrophages could be immunosuppressed and dysfunctional, yet paradoxically release proinflammatory factors in an unregulated manner. This mechanism was linked to the loss of dehydroepiandrosterone (DHEA) with aging and thus explained how immunosenescence could be causally related to the risk of stress and/or age-associated chronic diseases. At the center of this paradigm was lipid body negative (LB-) foamy macrophage (CD14+CD16+) which produced human endogenous retrovirus K102 (HERV-K102) particles. HERV-K102 may be a protector foamy virus of humans, and its induction may generate trained innate immunity, a special type of autoimmunity, in response to intracellular pathogens, their constituents, toxins, and/or tumors. Overwhelming evidence now suggests that the proinflammatory foamy macrophages driving ASCVD are LB-. Moreover, the monocyte/macrophage phenotype implicated in atherosclerosis-cardiovascular disease (ASCVD) appears to be the CD14+CD16+ intermediate phenotype. These and other observations directly challenge the cholesterol hypothesis. For the prevention and treatment of ASCVD, it is important to address the putative cause of ASCVD -- immunosenescence, rather than the signs or symptoms such as inflammation or elevated cholesterol. Therefore, strategies to reverse or prevent immunosenescence, which improve or maintain an optimal cortisol/DHEA ratio such as isoflavonoids, would be expected to alleviate not only ASCVD but the risk of many other age-associated chronic diseases. Here, the new immunosenescence paradigm will be appraised for its suitability to explain ASCVD risks.

The radiation hypersensitivity disorder ataxia-telangiectasia (A-T) is uniquely characterized by a failure to immediately inhibit DNA synthesis in response to low dose ionizing radiation which is referred to as radioresistant DNA synthesis (RDS). As it remains controversial as to whether p53 abnormalities are central to RDS and the A-T radiation hypersensitivity disorder, post-irradiation p53 responses and cell cycle alterations were investigated in EBV immortalized B cells (LCL's) from normal individuals (N LCL's) and A-T patients (A-T LCL's). Here it is shown that mutations in p53 are insufficient to give cells such as HL-60 cells RDS potential. Furthermore, RDS which is demonstrable at 2 Gy, does not correlate with radiation induced alterations in p53 or with alterations in the Gt/S block. However, at 10 Gy, abnormalities in p53 and cell cycle changes were noted for A-T LCL's. Although the results suggest that p53 abnormalities are not central to RDS or the A-T ionizing radiation hypersensitivity disorder, the demonstration of a threshold effect for secondary abnormalities in p53 and cell cycle changes post-irradiation, may help resolve conflicting reports on the involvement of p53 downstream of the central defect in A-T.

The mechanism of paradoxical growth enhancement by alpha-fetoprotein (AFP), a nonmitogenic factor, was explored in HL-60 cells using novel AFP agonists, the 167H.1 and 167H.4 monoclonal antibodies (MAbs) to AFP receptor (AFPr) isoforms. The conditions underwhich AFP led to increases in thymidine incorporation were found to promote activation induced cell death (AICD) associated with adherence in 96 well plates. The ensuing death was judged to be apoptosis based on morphology, shrinkage of dying cells, inducibility, reversibility, a sensitivity to levels of FCS, kinetics, DNA fragmentation pattern and internal program (passage number) of the cells investigated. Both AFP and the 167H.1 MAb but not the 167H.4 MAb blocked the induction of cell death under these conditions indicating apparent growth enhancement by AFP relates to the abrogation of cell death and not that AFP contains bona fide growth factor-like activity. We additionally report that HL-60 cells spontaneously senescence during normal propagation in vitro which correlated with an increased susceptibility to and earlier kinetics of AICD. In substantiation of this was the correlation of the loss of expression of the AFPr with increasing passage number and the induction of AICD. Overall, our findings lend further support to the recent proposals that AFP by binding to AFP receptors may block cellular senescence and that there may be differential expression of AFPr isoforms related to commitment (167H.1 reactive) or resistance (167H.4 reactive) of cells to apoptosis/programmed cell death (PCD).

In an attempt to characterize a Peanut Agglutinin (PNA) autoantigen widely expressed in common human adenocarcinomas, monoclonal antibodies (MAbs) were made against PNA-affinity purified glycoproteins from pooled breast cancer membrane biopsy materials. Two IgM MAbs, 167H.1 and 167H.4, were found to react strongly with frozen tissue sections of various adenocarcinomas and the antigen was characterized further. By immunoprecipitation, western blotting, and gel filtration, both MAbs were found to react with a 67 kilodalton (kD) antigen. The 67 kD antigen was purified and determined to be specifically PNA reactive and naturally occurring antibodies were demonstrated to the purified antigen. In conclusion, the 167H.1 and 167H.4 MAbs identify a non-mucinous, PNA-reactive autoantigen widely expressed in human adenocarcinomas.

Accumulating evidence based on alpha-fetoprotein (AFP) cell binding and uptake has shown the presence of a receptor for AFP on the surface of fetal and neoplastic cells. In order to further study this receptor, monoclonal antibodies (MAbs) made against pooled human mammary tumor membrane extracts were screened for their ability to inhibit the binding of radiolabeled AFP to the Ichikawa and TA3/Ha malignant cell lines. IgM-producing clones 167H.1 and 167H.4 were found to inhibit the binding of AFP to its receptor. Conversely, the MAb reaction was inhibited by an excess of AFP but not by serum albumin at an equal molar concentration. The possibility that these MAbs recognize AFP has been ruled out. In addition, we describe a method for the purification of the AFP receptor which yielded fractions reactive to both 167H.4 and AFP. The results obtained strongly suggest that 167H.1 and 167H.4 are directed against the binding site for AFP on the AFP receptor. Using 167H.4 we found positive immunohistochemical staining in 6/6 human mammary tumor specimens whereas 3/3 benign mammary adenomas were negative. Immunostaining of fetal muscle with either 167H.4 or an anti-AFP antiserum yielded a similar staining pattern. The staining of live Ichikawa cells with 167H.4 showed a surface receptor distribution (capping) similar to the one described in previous reports using labeled AFP. The widespread expression of the AFP receptor observed previously is consistent with the results obtained using the MAbs described herein. The potential use of these MAbs for basic and clinical studies is discussed.