Structural and thermodynamic approach to peptide immunogenicity

In the conventional paradigm of humoral immunity, B cells recognize their cognate antigen target in its native form. However, it is well known that relatively unstable peptides bearing only partial structural resemblance to the native protein can trigger antibodies recognizing higher-order structures found in the native protein. On the basis of sound thermodynamic principles, this work reveals that stability of immunogenic protein-like motifs is a critical parameter rationalizing the diverse humoral immune responses induced by different linear peptide epitopes. In this paradigm, peptides with a minimal amount of stability (ΔGX0 kcal/mol) trigger antibodies recognizing full protein but not peptide, and unstable peptides (ΔGX>8 kcal/mol) fail to generate antibodies against either peptide or protein. Immunization experiments involving peptides derived from the autoantigen histidyl-tRNA synthetase verify that selected peptides with varying relative stabilities predicted by molecular dynamics simulations induce antibody responses consistent with this theory. Collectively, these studies provide insight pertinent to the structural basis of immunogenicity and, at the same time, validate this form of thermodynamic and molecular modeling as an approach to probe the development/evolution of humoral immune responses. © 2008 Camacho et al

The Humoral Theory of Transplantation: Epitope Analysis and the Pathogenicity of HLA Antibodies.

Central to the humoral theory of transplantation is production of antibodies by the recipient against mismatched HLA antigens in the donor organ. Not all mismatches result in antibody production, however, and not all antibodies are pathogenic. Serologic HLA matching has been the standard for solid organ allocation algorithms in current use. Antibodies do not recognize whole HLA molecules but rather polymorphic residues on the surface, called epitopes, which may be shared by multiple serologic HLA antigens. Data are accumulating that epitope analysis may be a better way to determine organ compatibility as well as the potential immunogenicity of given HLA mismatches. Determination of the pathogenicity of alloantibodies is evolving. Potential features include antibody strength (as assessed by antibody titer or, more commonly and inappropriately, mean fluorescence intensity) and ability to fix complement (in vitro by C1q or C3d assay or by IgG subclass analysis). Technical issues with the use of solid phase assays are also of prime importance, such as denaturation of HLA antigens and manufacturing and laboratory variability. Questions and controversies remain, and here we review new relevant data

“Youth is Drunke with Pleasure, and therefore Dead to all Goodnesse”: Regulating the Excess of the Erotic Early Modern Body

This article investigates the erotic and youthful body in John Fletcher’s play The Faithful Shepherdess, written for The Children of the Queen’s Revels c.1607. For many early modern scholastic, medical, and conduct manual writers, the life stage of Youth was a particularly dangerous moment in an individuals’ life, a time where the body was in a constant state of flux and ruled by unhealthy bodily excess. Fletcher’s play presents an assortment of characters who are all ruled by or obsessed with their own youthful passions. This article engages with Galenic humoral theory, an area that has been neglected in scholarship on Fletcher’s play, to provide a close analysis of Youth and erotic excess on the early modern stage

Selective Realism vs. Individual Realism for Scientific Creativity

Individual realism asserts that our best scientific theories are (approximately) true. In contrast, selective realism asserts that only the stable posits of our best scientific theories are true. Hence, individual realism recommends that we accept more of what our best scientific theories say about the world than selective realism does. The more scientists believe what their theories say about the world, the more they are motivated to exercise their imaginations and think up new theories and experiments. Therefore, individual realism better fosters scientific creativity than selective realism

Not All Antibodies Are Created Equal: Factors That Influence Antibody Mediated Rejection.

Consistent with Dr. Paul Terasaki's "humoral theory of rejection" numerous studies have shown that HLA antibodies can cause acute and chronic antibody mediated rejection (AMR) and decreased graft survival. New evidence also supports a role for antibodies to non-HLA antigens in AMR and allograft injury. Despite the remarkable efforts by leaders in the field who pioneered single antigen bead technology for detection of donor specific antibodies, a considerable amount of work is still needed to better define the antibody attributes that are associated with AMR pathology. This review highlights what is currently known about the clinical context of pre and posttransplant antibodies, antibody characteristics that influence AMR, and the paths after donor specific antibody production (no rejection, subclinical rejection, and clinical dysfunction with AMR)

The Absolute and Relative Pessimistic Inductions

The absolute pessimistic induction states that earlier theories, although successful, were abandoned, so current theories, although successful, will also be abandoned. By contrast, the relative pessimistic induction states that earlier theories, although superior to their predecessors, were discarded, so current theories, although superior to earlier theories, will also be discarded. Some pessimists would have us believe that the relative pessimistic induction avoids empirical progressivism. I argue, however, that it has the same problem as the absolute pessimistic induction, viz., either its premise is implausible or its conclusion does not probably follow from its premise

Transition between immune and disease states in a cellular automaton model of clonal immune response

In this paper we extend the Celada-Seiden (CS) model of the humoral immune response to include infectious virus and cytotoxic T lymphocytes (cellular response). The response of the system to virus involves a competition between the ability of the virus to kill the host cells and the host's ability to eliminate the virus. We find two basins of attraction in the dynamics of this system, one is identified with disease and the other with the immune state. There is also an oscillating state that exists on the border of these two stable states. Fluctuations in the population of virus or antibody can end the oscillation and drive the system into one of the stable states. The introduction of mechanisms of cross-regulation between the two responses can bias the system towards one of them. We also study a mean field model, based on coupled maps, to investigate virus-like infections. This simple model reproduces the attractors for average populations observed in the cellular automaton. All the dynamical behavior connected to spatial extension is lost, as is the oscillating feature. Thus the mean field approximation introduced with coupled maps destroys oscillations.Comment: 27 pages LaTeX + 7 Figures Postscrip

Trade-offs between personal immunity and reproduction in the burying beetle, N. vespilloides

We know that parental investment and immune investment are costly processes, but it is unclear which trait will be prioritised when both may be required. Here we address this question using the burying beetle Nicrophorus vespilloides, carrion breeders that exhibit biparental care of young. Our results show that immunosuppression occurs during provision of parental care. We measured Phenoloxidase (PO) on Day 1-8 of the breeding bout and results show a clear decrease in PO immediately from presentation of the breeding resource onwards. Having established baseline immune investment during breeding we then manipulated immune investment at different times by applying a wounding challenge. Beetles were wounded prior to and during the parental care period and reproductive investment quantified. Different effects on reproductive output occur depending on the timing of wounding. Challenging the immune system with wounding prior to breeding does not affect reproductive output and subsequent Lifetime Reproductive Success (LRS). LRS is also unaffected by applying an immune elicitor prior to breeding, though different arms of the immune system are up/downregulated, perhaps indicating a trade-off between cellular and humoral immunity. In contrast, wounding during breeding reduces reproductive output and to the greatest extent if the challenge is applied early in the breeding bout. Despite being immunosuppressed, breeding beetles can still respond to wounding by increasing PO, albeit not to pre-breeding levels. This upregulation of PO during breeding may affect parental investment, resulting in a reduction in reproductive output. The potential role of juvenile hormone in controlling this trade-off is discussed

Rationalism, Empiricism, and Evidence-Based Medicine: A Call for a New Galenic Synthesis

Thirty years after the rise of the evidence-based medicine (EBM) movement, formal training in philosophy remains poorly represented among medical students and their educators. In this paper, I argue that EBM’s reception in this context has resulted in a privileging of empiricism over rationalism in clinical reasoning with unintended consequences for medical practice. After a limited review of the history of medical epistemology, I argue that a solution to this problem can be found in the method of the 2nd-century Roman physician Galen, who brought empiricism and rationalism together in a synthesis anticipating the scientific method. Next, I review several of the problems that have been identified as resulting from a staunch commitment to empiricism in medical practice. Finally, I conclude that greater epistemological awareness in the medical community would precipitate a Galenic shift toward a more epistemically balanced, scientific approach to clinical research