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Biomedical subjects

T C Rodman

Publications and source records attributed to T C Rodman.

At least 19 recordsLinked to original sources
PubMed2004

Multiple sclerosis: etiological mechanisms and future directions.

Multiple sclerosis (MS) is a complex human autoimmune-type disease with a predominantly unknown etiology. Immunologic destruction of myelin basic protein (MBP) throughout the nervous system is the major pathology of multiple sclerosis. This review will attempt to update new information about basic mechanisms and therapeutic management of the disease. The significance of the structure of MBP is discussed with respect to the contribution of such structures to the disease process. A number of MBP peptides that serve as the immunodominant antigens in MS patients have been identified. These peptides have been studied in animal models for their antigenic characteristics and ability to induce disease. Evidence for genetic contributions is reviewed with multigenerational twin studies providing the best evidence for susceptible haplotypes. The role of microorganisms/viruses and environmental agents are discussed as potential etiological factors but are now thought to be of minor importance to the primary causal development of the disease. Of major consideration are immunological mechanisms that contribute to the development of autoimmunity. In particular, antigen expression, cytokine and leukocyte interactions, and regulatory T-cells are discussed. Particular attention is given to regulatory T-cells (Treg), which help balance/modulate other T-cells such as Th1 and Th2 cells, and how such Treg regulate autoimmunity is addressed. The importance of the role of Tregs is exemplified by the demonstration that administration of oral antigens can induce specific Tregs that counteract experimental autoimmune encephalomyelitis in animal models. The significance of animal studies to human multiple sclerosis is discussed. A potential role for natural antibodies and innate immune mechanisms to help provide resistance to disease development is also reviewed. Finally, a variety of therapeutic agents that have been and continue to be utilized for multiple sclerosis is reviewed. Trials with oral antigens, such as glatirmer acetate (copolymer 1) especially in combination with interferon-beta, have shown promise. Antibody therapy and bone marrow transplantation are also briefly discussed.

Animals↗
PubMed2001

Circulating natural IgM antibodies and their corresponding human cord blood cell-derived Mabs specifically combat the Tat protein of HIV.

OBJECTIVE: IgM antibodies reactive with each of two specifically defined sequences of HIV Tat protein have been identified in sera from both HIV(+) and normal (HIV(-)) humans. This study was designed to confirm that those antibodies are innate immune factors capable of restriction of specific mechanisms of HIV pathogenicity attributed to the Tat protein. MATERIALS AND METHODS: Antibody-secreting hybridomas were generated from human cord blood cells and processed for monoclonality. Those Mabs reactive with each of the sequences of Tat with which the circulating antibodies are reactive were isolated and their heavy and light chains identified and DNA sequenced. Pools of IgM isolated from blood of normal humans, chimpanzees, rhesus macaques, and mice and the isolated Tat reactive Mabs were tested for capacity to inhibit Tat-induced human T-cell apoptosis. RESULTS: Human and chimpanzee IgM pools, as well as the human cord blood cell-derived Mabs, showed a definite capacity to inhibit the Tat-induced apoptosis, while the IgM pools of rhesus macaques or of mice did not. CONCLUSIONS: These studies establish that the circulating IgM of normal humans include innate antibodies capable of restriction of HIV Tat-induced pathogenesis. That capacity is shared by chimpanzee IgM but not by IgM of other primates or of mice. The identification of those human circulating antibodies as innate is confirmed by the display of similar epitopic identity and apoptosis inhibition capacity by Mabs from human cord blood cell hybridomas. Thus, the arsenal of human cord blood cell hybridomas provides a resource by which, specifically, the potential therapeutic role of the identified HIV Tat-reactive Mabs and, broadly, the fundamental role of innate antibodies in infection control may be explored.

Adult↗
PubMed1999

Two human neonatal IgM antibodies encoded by different variable-region genes bind the same linear peptide: evidence for a stereotyped repertoire of epitope recognition.

Two monoclonal IgM Abs have been produced from lymphocytes isolated from two human umbilical cord bloods. These mAbs recognize a conformational epitope present in a CNBr digestion fraction of lactoferrin. Linear epitopes recognized by each mAb were selected from several phage display peptide libraries. In each case, phages displaying a peptide with a motif defined by [WF],G,[EQS],N were recovered. Phages displaying that motif bound equally well to either mAb but did not bind to control IgM. A peptide bearing this motif competed with the phage-displayed peptides for binding to either mAb. The same peptide also competes with a component of the CNBr digestion fraction of lactoferrin for Ab binding in ELISA. The Abs use different families of VH, JH, and VK gene cassettes but use the same JK cassette. All segments are virtually identical to their germline gene counterparts. This work provides further evidence that certain innate specificities are stereotyped among individuals.

Antibodies, Monoclonal↗
PubMed1999

The human uniqueness of HIV: innate immunity and the viral Tat protein.

We have previously reported, and confirm here, that the human innate system of natural antibodies includes two, each of which is reactive, presumably by happenstance, with a specific sequence of HIV Tat protein. Comparison of cohorts of HIV+ and normal (HIV-) sera indicate that, following a period of post-infection latency, the titers of those natural antibodies decline and other Tat reactive antibodies, as evidence of induced immune response, do not arise. That human-typical pattern of innate/adaptive reactivity with HIV Tat protein is shared by chimpanzees, but not by other mammals tested in this study, in which those natural antibodies are not present, and apparently induced Tat-reactive antibodies do arise. Evidence of a temporal relationship between the decline of the Tat reactive natural antibodies and progression of HIV pathogenesis, including demise of CD4+T cells, suggests a role for those antibodies in retardation of that pathoprogression. However, that providential arrest of Tat-related pathogenicity may be limited by the immune system recognition of the natural antibody-reactive sequences of Tat as "self" with consequent induction of tolerance and restriction of production of those antibodies. The limited occurrence of progression to AIDS in chimpanzees may reflect an additional innate characteristic, one of resistance to tolerance-based diminishment of the protective natural antibodies. Although not yet defined, that characteristic may be shared by the occasionally observed HIV+ humans known as LTNP (longterm-non-progressors).

Animals↗
PubMed1997

Innate natural antibodies. Primary roles indicated by specific epitopes.

Two members of a unique class of natural antibodies have been identified in all of a large cohort of sera from clinically normal humans of broad age distribution. By means of a series of 10-12 mer peptides the epitope for each of those antibodies was characterized with regard to amino acid identity and conformation. Similar epitope specificity was revealed for the IgM isotopes of cord blood and early post natal sera and for IgM and IgG of adult sera, suggesting that the class of natural antibodies represented by the two identified in this study includes those genomically coded for at their effector level of maturation in the B cells of the neonate. Assay of series of specimens from each of four clinically normal adults revealed that those two natural antibodies are present at relatively constant titer, unique to each individual, over four to five and a half year periods. Those observations imply that the primary function of that class of natural antibodies may be related to maintenance of homeostasis and the molecular identity of each of the two epitopes suggests a role, for each, as monitor or control in intracellular traffic. The previous identification of those epitopes in a conserved protein of HIV also provides support for the proposition that a secondary function of natural antibodies, arising from fortuitous coincidence of the identity of the epitopes, may be that of early defense against infectious invaders.

Adult↗
PubMed1997

An innate natural antibody is reactive with a cryptic sequence of lactoferrin exposed on sperm head surface.

Lactoferrin (LF), an 80-kDa glycoprotein of ubiquitous occurrence in body fluids, is multifunctional and capable of assuming different configurations to serve those functions. The capacity of LF to undergo endocytosis and the recent demonstration of LF binding to sequence specific DNA indicate that a function or capability of LF, in addition to iron chelation, bacteriostasis, and receptor-specific lymphocyte binding, may be that of gene activation or silencing. The data of this report present a human physiological system, that of sperm entry into the oocyte in performance of fertilization in which, since LF is a component of the sperm protein coat, that capability could be expressed. However, the configuration of LF in that locus is one in which a revealed cryptic sequence provides the specific binding site for a natural antibody present in the fertilization milieu. The presence of that antibody suggests that a system of control of the potential interaction of LF with the intra-ooplasmic DNA, that of gametes or pronuclei, is operative. The configuration of LF on the sperm surface and designation of the reactive site for the natural antibody were enabled by a monoclonal antibody secreted by a hybridoma derived from a human cord blood B cell. Thus, in addition to information concerning the molecular flexibility of LF, these observations support the proposition that the repertoire of natural antibodies provides an innate homeostatic system, with each antibody serving a specific role.

Antigen-Antibody Reactions↗
PubMed1993

Epitopes for natural antibodies of human immunodeficiency virus (HIV)-negative (normal) and HIV-positive sera are coincident with two key functional sequences of HIV Tat protein.

We have previously shown that IgM antibodies that react with human immunodeficiency virus (HIV) Tat, a regulatory protein essential for viral replication, are present in sera of all normal, HIV-negative individuals and deficient in sera of HIV-positive individuals at progressively greater frequency as diagnosis of AIDS nears. That IgM was designated as a set of natural antibodies, a repertoire of the normal humoral immune system believed to provide early defense against infectious invaders. In the prior study, by means of a series of synthetic peptides representing the amino acid sequence of HIV-1 Tat, one epitope for the IgM natural antibodies was defined within the cysteine-rich domain, shown in cell transfection studies to participate in Tat function. In this study we have defined another epitope, within the basic domain, with which the natural antibodies react. The specific sequence and amino acid residues required for that epitope are coincident with those required for the role of Tat in viral replication. The IgM antibodies reactive with the two epitopes of Tat make up two distinct sets, which, together, account for the total Tat reactivity of both HIV-negative and HIV-positive sera. The striking coincidence of the two epitopes with the two functional sequences of Tat suggests a potential role of those natural antibodies in control of HIV pathogenesis. By inference from the extensive evidence for the presence of extracellular Tat in cultures of HIV-infected cells, Tat may be expected to be present in the circulating plasma of infected people. We propose, therefore, that the Tat-reactive natural antibodies, documented in these studies to be present in the circulating plasma in the pre-AIDS stages of HIV infection, may inhibit cell entry of plasma-borne Tat and thereby curtail HIV propagation. Thus, those natural antibodies may be a host factor for delay in HIV pathogenetic progression.

Amino Acid Sequence↗
PubMed1992

Human immunodeficiency virus (HIV) Tat-reactive antibodies present in normal HIV-negative sera and depleted in HIV-positive sera. Identification of the epitope.

We have detected, in sera of normal human immunodeficiency virus (HIV)-free subjects, IgM antibodies reactive with the Tat protein of HIV in significant titers and at very high frequency, and, in HIV-positive sera, progressively lower titers as HIV pathogenesis ensues. Epitope analysis indicates that the Tat-reactive antibodies of both HIV-negative and HIV-positive sera are homologous, suggesting, therefore, that their decline in HIV-positive sera may represent attrition of a host defense factor. The identified epitope displays minimal homology with that previously defined for another set of IgM antibodies shown to be present in normal sera, deficient in HIV-positive sera, and postulated to be natural antibodies. We propose that the Tat-reactive antibodies, as well, are a set of natural antibodies and that the normal humoral immune system includes a repertoire of antibodies, nonimmunogenic in origin, that contribute to immune homeostasis and, consequently, to host resistance to HIV pathogenesis.

Amino Acid Sequence↗
PubMed1991

Caveats and suggestions for the ELISA.

This study identifies three categories of errors that may arise from faulty procedures utilized in the ELISA and offers suggestions for their recognition and avoidance. The first deals with the potential sources of 'background' values indicating that the practice of subtracting those values from the total OD measurements of the reactivity of a specific antigen-antibody system is not valid in all instances. A simple method of curve analysis has been devised for determining whether that correction is valid. The second consideration is that of stoichiometry of binding of second antibody to the test antibody-antigen complex which is shown to be restricted to a narrow range of concentrations and a short period of incubation of that reagent. The need and method to determine the conditions for stoichiometry for each ELISA protocol is demonstrated. Thirdly, the need for and properties of a suitable blocking agent to prevent binding of ambiguous reactants to the surfaces of the test wells are reiterated and the greater efficiency of BSA, compared with other frequently recommended blocking agents, is demonstrated.

Antigen-Antibody Reactions↗
PubMed1990

Identification of a low-affinity subset of protamine-reactive IgM antibodies present in normal, deficient in AIDS, sera: implications for HIV latency.

We demonstrate here that the protamine-reactive IgM antibodies previously shown to be present in normal adult sera include two subsets differing in binding affinity. The principal, high-affinity subset was detected in AIDS and ARC as well as normal sera. The secondary, low-affinity subset, however, was absent or markedly deficient in AIDS or ARC sera. Protamine-reactive IgM antibodies were also detected in normal pediatric sera, suggesting that one subset of that class of antibodies may be "natural," i.e., not antigenically induced. The proportionate titer of the low-affinity protamine-reactive IgM antibodies was determined for HIV-positive males who were asymptomatic or mildly immune deficient at specimen collection. Of those who subsequently remained AIDS free for 18 months to 7 years, more than 90% had titers in the range established for the normal sera, while of those diagnosed with AIDS or ARC within 12 months, more than 80% had titers below the normal range. We propose that the low-affinity subset of adult sera corresponds to the natural antibodies of pediatric sera and that a relationship of those natural antibodies to resistance to progression of HIV pathogenesis is suggested.

AIDS-Related Complex↗
PubMed1988

Protamine-reactive natural IgM antibodies in human sera. Characterization of the epitope demonstrates specificity of antigenic recognition; occurrence indicates obscurity of origin and function.

We have identified a set of natural IgM antibodies in human serum that are reactive with protamines, a class of low molecular weight basic nucleoproteins that are synthesized de novo in the postpubertal testis and are unique to sperm. Those antibodies were detected by ELISA in significant titer in all of 100 sera of normal adult males and females and in 26 of 28 sera of normal pediatrics aged 7 d to 2 yr. Commonality between the protamine-reactive IgM antibodies of pediatric and adult sera was established by the demonstration of similarity in antigen recognition and reaction kinetics. Therefore, the role of protamines as either immunogenic stimulus or antigenic target of that set of natural antibodies is not likely. The antigenic site recognized by the protein-reactive serum IgM antibodies was characterized by comparison with the pattern of antigen recognition by a monoclonal antibody to human sperm protamines (HPmAb). By the use of synthetic peptides simulating the amino acid sequences of various segments of human protamine 2 and of polyarginine, polylysine, and histones as test antigens, the principle characteristic of the antigenic site recognized by both HPmAb and the serum IgM antibodies was inferred to be that of clustered arginyl residues with an apparent minimum requirement of four arginyl residues, including a triplet, within a six residue piece; for both, the reaction was shown to be not dependent upon charge attraction. A series of immunoabsorption procedures indicated that the protamine-reactive serum IgM antibodies are a discrete set with a high order of specificity. A search of protein data bases revealed that the putative minimum epitope is present in four or five human autogenous proteins, all moieties of the immune system, and in a number of viral proteins. The possible implications of those findings are discussed in the light of early hypotheses concerning the origin and function of natural antibodies and the many recent reports of identification of natural antibodies in normal human sera. The set of natural antibodies identified in this study may be unique or may represent a class of antibodies present in the repertoire that, by virtue of the obscurity of their origin or function, have not been previously or extensively recognized.

Adolescent↗
PubMed1987

Phosphorylation state of protamines 1 and 2 in human spermatids and spermatozoa.

The basic nuclear proteins of a fraction of elongating spermatids from human testes and of a fraction of motile spermatozoa from the ejaculate, separated by ion-exchange chromatography, were compared. Analysis by acetic acid-urea polyacrylamide gel electrophoresis (PAGE) showed that, in both fractions, four proteins of lower mobility were coeluted with protamine 1 by 23% guanidinium chloride (GuCl) while protamine 2 alone was eluted by 50% GuCl. Treatment with alkaline phosphatase identified those four proteins as phosphorylated protamines, and cyanogen bromide (CNBr) treatment of the dephosphorylated protamines distinguished them as variants of protamine 2 and not of protamine 1. Thus far, phosphorylated forms of protamine 1 have not been detected in either spermatids or spermatozoa. Those observations indicate that protamine 2 functions in the cycle of phosphorylation-dephosphorylation, which is essential to the process of sperm chromatin condensation, while the role of protamine 1 in human spermiogenesis is not yet defined. The presence of phosphorylated protamine in motile, presumably mature spermatozoa appears to be characteristic of human sperm but not of the sperm of other mammals and is probably the basis for the heterogeneity of chromatin condensation frequently observed in human spermatozoa.

Alkaline Phosphatase↗
PubMed1986

An ELISA for IgM titer of human serum.

An ELISA for the measurement of serum immunoglobulins (Ig) of specific isotype is described which is reproducible, more sensitive than currently used methods and simple to perform. Data are presented to support the need to include a reference serum of known Ig content on the same plate as the specimen sera in order to compensate for plate-to-plate variability due to ambient conditions. This method should prove useful for monitoring changes in levels of specific Ig classes in the progression of diseases with immune system involvement or during a therapeutic regimen.

Enzyme-Linked Immunosorbent Assay↗
PubMed1986

Reactivity of natural IgM antibodies with sperm head surface proteins. Use of an ELISA to characterize the reaction.

The data and system of analysis presented in this report have defined a subset of natural IgM antibodies in human sera that are reactive with specific members of a fraction of proteins extracted from human sperm heads. An ELISA has been developed in which, by use of a standardized reference serum, the relative values for total IgM and for sperm protein-reactive IgM may be derived for each serum. Those values, determined for 32 adult and 9 neonatal sera, indicate that the sperm protein-reactive IgM antibodies represent a reasonably constant proportion of the total serum IgM titer. Other assay data indicate that the reactivity between the antigenic sperm proteins and IgM antibodies is of high affinity. Although immunotransfers of this study have confirmed an earlier report (Rodman et al., 1985) that the immunoreactive elements of the sperm protein fraction include 7-9 separate bands or doublets, the data suggest that the reactivity is not a composite of multiple heterogeneous reactions but may be that of a few or a specific reaction, possibly involving homologous or cross-reactive antigenic determinants.

Antibodies↗
PubMed1985

Naturally occurring antibodies reactive with sperm proteins: apparent deficiency in AIDS sera.

A set of naturally occurring immunoglobulin M (IgM) antibodies that are reactive with a defined subset of proteins in the acrosomal cap region of human sperm has been identified. These antibodies are present in a broad spectrum of human sera from males and females, 1 day to 40 years of age, and are absent or markedly deficient in a large proportion of sera from individuals with the acquired immune deficiency syndrome (AIDS) or at risk for AIDS. The subset of proteins with which the IgM antibodies are reactive includes a factor (or factors) capable of inhibiting lectin-induced T-lymphocyte proliferation. The prevalence of the sperm-reactive IgM antibodies indicates that they are not elicited by sperm. Further, immunoreactivity of the sperm proteins resulting in depletion of specific circulating IgM antibodies, or other interactions between the sperm proteins and elements of the immune system, may be a factor in the suppressed state of the immune system in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Proteins of demembraned mouse sperm heads. Characterization of a major sperm-unique component.

A 15-kilodalton protein has been identified as a major component of the residual protein fraction of mouse epididymal/vas spermatozoal heads, demembraned by treatment with Triton X-100 and sequentially extracted with 1 M NaCl/2-mercaptoethanol/DNase I. Two-dimensional electrophoresis of that protein before and after treatment with alkaline phosphatase indicated that it is present in epididymal/vas spermatozoa as a series of five differentially phosphorylated molecules with pI 6.0-7.0. Cyto-immunofluorescence with an affinity-purified antibody to the 15-kDa protein localized that protein to a circumscribed region of the demembraned mouse sperm head mediad from the dorsal margin. By radioimmunoassay, the 15-kDa protein was shown to be sperm-unique and species-specific. The antibody was nonreactive with homogenates of meiotic spermatogenic cells and round spermatids (stages 1-11) but was reactive with a non-phosphorylated 15.5-kDa protein of elongating spermatids (stages 12-16) and testicular spermatozoa. Following alkaline phosphatase treatment, the spermatozoal 15-kDa protein migrated to the position of the spermatidal 15.5-kDa protein on a sodium dodecyl sulfate gel. Thus, we conclude that the 15-kDa protein of mouse spermatozoa is synthesized during the elongation phase of spermiogenesis (stages 12-16) and is phosphorylated in the terminal period of that phase and/or after excursion of spermatozoa from the seminiferous tubules.

Alkaline Phosphatase↗
PubMed1984

Protamine-DNA association in mammalian spermatozoa.

We have previously identified two subsets of basic nuclear proteins of mouse sperm: the protamines and a group of less basic proteins and, with the aid of a polyvalent antiserum, we have demonstrated their differential extractibility by NaCl in reducing solution (Rodman et al., J cell sci 53 (1982) 227) [9]. By affinity purification with isolated mouse sperm protamines we have obtained a protamine-specific fraction of that antiserum and a fraction that contains antibodies to the subset of less basic proteins. With those immunochemical probes we have shown the following The antigenic sites recognized by the protamine-specific antibodies are accessible, intranuclearly, only after the DNA has been removed by DNase I. The antibodies and DNA compete for binding sites on the protamines. DNA removal and consequent availability of the antigenic sites of the protamine molecules to the antibodies are possible only after displacement of the less basic proteins and chromatin decondensation have been induced. Immunoreactivity by the less basic proteins takes place without intervention of DNase. Those data indicate that the protamines are DNA-bound but that the less basic proteins are not or, alternatively, their putative DNA-binding sites do not coincide with their immuno-reactive sites. Those data also suggest that a function of the subset of less basic proteins may be to provide a shield for the protamine-DNA complex. The mouse protamine-affinity-bound antibodies are highly cross-reactive with protamines of other mammalian sperm suggesting that, despite considerable molecular diversity among mammalian protamines, the DNA-binding sites are conserved.

Animals↗