The question of which protein antigens, such as HLA class I or class II molecules, will bind, and how well, to a given antibody is often assumed to depend exclusively on the details of protein ...surface structure. These structures are usually based on static models resulting from X-ray crystallography. While these notions are useful, the ultimate causal factors determining how well a given antigen binds a given antibody are based in thermodynamics and can include atomic mobility and the time-varying conformations of proteins. In this article, fundamental biophysical principles of antibody-antigen interaction are discussed, concepts critical for a deeper understanding of the pertinent molecular phenomena are highlighted, and common misunderstandings are identified and debunked.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The adaptive humoral immune response is responsible for the generation of antimicrobial proteins known as immunoglobulin molecules or antibodies. Immunoglobulins provide a defense system against ...pathogenic microbes and toxins by targeting them for removal and/or destruction. Historically, antibodies have been thought to be composed of distinct structural domains known as the variable and constant regions that are responsible for antigen binding and mediating effector functions such as opsonization and complement activation, respectively. These domains were thought to be structurally and functionally independent. Recent work has revealed however, that in some families of antibodies, the two regions can influence each other. We will discuss the body of work that led to these observations, as well as the mechanisms that have been proposed to explain how these two different antibody regions may interact in the function of antigen binding.
The role of genetics in determining measured differences in mean IQ between putative racial groups has been a focus of intense discussion and disagreement for more than 50 years. While the last ...several decades of research have definitively demonstrated that genetic variation can influence measures of cognitive function, the inferences drawn by some participants in the controversy regarding the implications of these findings for racial differences in cognitive ability are highly dubious. Of equal importance, there is no compelling scientific rationale for focusing on and devoting substantial effort to determining mean differences in intelligence or other cognitive functions between groups with incompletely defined and dynamic (and therefore not definitively definable) boundaries.
In this interview, Vishva Dixit, MD, talks with Neil S. Greenspan, MD, PhD, senior editor of Pathogens and Immunity aboutwhat his career in science has revealed about biology in humans, but also what ...it has revealed about how to be successful in science. Dr. Dixit is a world-famous immunologist and biochemist who has made major contributions to the study of innate immunity in general and particularly to understanding inflammasome activation. He is vice president and senior fellow in physiological chemistry at Genentech.
The editors of Pathogens and Immunity are commemorating this month, the 80th anniversary of the publication of the landmark article by Oswald Avery, Colin MacLeod, and Maclyn McCarty in the Journal ...of Experimental Medicine on February 1, 1944 1. The study by Avery et al determined with extraordinary rigor the chemical nature of the so-called transforming principle inferred to exist by Frederick Griffith based on experiments he published in 1928.
The seminal discovery in the early 1970s, credited to Peter Doherty and Rolf Zinkernagel, of major histocompatibility complex (MHC) restriction exhibited by cytotoxic T cells represented a major ...conceptual advance in understanding antigen recognition by conventional T cells. This advance also led to other major new insights into the ontogeny and immunobiology of T cells and catalyzed a renaissance in viral immunology. In this commentary in honor of Peter Doherty, I offer five brief reflections on different aspects of the phenomenon of MHC restriction and the process by which it was discovered and explained. In the first of these sections, I offer a reinterpretation of MHC restriction that reframes the constraints on self-MHC recognition in terms of the probabilities of recognizing a given nominal antigen peptide in the context of an MHC molecule that is nonself on the basis of differing in amino acid sequence from the self-restriction element at one or more positions. Subsequent sections address: (i) the ways in which general ideas, developed subsequent to the discovery of MHC restriction, about the intricacies of antigen recognition by antibodies apply to T cell receptors binding to MHC/peptide complexes; (ii) how to reconcile the existence of MHC restriction with the impressive magnitude of T cell responses to nonself MHC antigens; (iii) the possible relevance to MHC restriction and immune system function of ideas from mathematical logic that relate to the consequences of self-reference; and (iv) the implications for the philosophy of science of MHC restriction and the processes of its discovery and acceptance within the immunology research community.
Drew Weissman, MD, PhD, received the 2023 Nobel Prize in Physiology or Medicine together with Katalin Karikó, PhD. Dr. Weissman received his bachelor's and master's degrees from Brandeis University, ...Waltham, MA, in 1981. He received his MD and PhD in 1987 from Boston University, Boston, MA, and this was followed by a residency at Beth Israel Deaconess Medical Center, Boston, MA. He then completed a fellowship at the National Institute of Allergy and Infectious Diseases under the supervision of Anthony Fauci, MD. He joined the Faculty at the University of Pennsylvania, Philadelphia, in 1997, where, in collaboration with Dr. Katalin Karikó, he explored the use of messenger RNA (mRNA) to drive heterologous gene expression in human cells. They overcame the notorious susceptibility of RNAs to degradation by packaging the mRNA in lipid nanoparticles and learned to both optimize protein expression and attenuate the inflammatory response to the exogenous RNAs by covalently modifying bases in the RNA sequence. This work has revolutionized immunization technology and allowed for the production of the most effective vaccines to prevent COVID-19.
Environmental factors and host microbiota strongly influence type 1 diabetes (T1D) progression. We report that neonatal immunization with group A Streptococcus suppresses T1D development in NOD mice ...by promoting clonal expansion of N-acetyl-d-glucosamine (GlcNAc)-specific B-1 B cells that recognize pancreatic β cell-derived Ags bearing GlcNAc-containing posttranslational modifications. Early exposure to Lancefield group A cell-wall carbohydrate Ags increased production of GlcNAc-reactive serum Abs and enhanced localization of innate-like GlcNAc-specific B cells to pancreatic tissue during T1D pathogenesis. We show that B-1 B cell-derived GlcNAc-specific IgM engages apoptosis-associated β cell Ags, thereby suppressing diabetogenic T cell activation. Likewise, adoptively transferring GlcNAc-reactive B-1 B cells significantly delayed T1D development in naive recipients. Collectively, these data underscore potentially protective involvement of innate-like B cells and natural Abs in T1D progression. These findings suggest that previously reported associations of reduced T1D risk after GAS infection are B cell dependent and demonstrate the potential for targeting the natural Ab repertoire in considering therapeutic strategies for T1D.
We consider the multiple senses of several key terms that are used to discuss the ongoing COVID-19 pandemic and clarify meanings of the corresponding concepts. Topics addressed include: 1) the ...meaning of immunity to an infectious agent in varying medical and scientific contexts, 2) the scientific factors that influenced the rapid generation and clinical implementation of safe and effective vaccines for COVID-19, 3) the difference between mutational abrogation of reactivity with B- or T-cell antigen receptors (immune escape) versus active interference with host immune mechanisms mediated by gene products encoded within the genome of the infectious agent (immune evasion), 4) the different ways by which the COVID-19 pandemic has “caused” deaths, and 5) briefly, the challenge of precisely defining the term pathogen.
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